A. [Reserved]
B. Capitalization and Indebtedness
Not applicable.
C. Reasons for the Offer and Use of Proceeds
Not applicable.
D. Risk Factors
You should carefully consider
the risks we describe below, in addition to the other information set forth elsewhere in this Annual Report on Form 20-F, including our
consolidated financial statements and the related notes beginning on page F-1, which could materially adversely affect our business,
financial condition and future results. If any of the following risks actually occur, our business, financial condition and results of
operations could be materially and adversely affected. In that event, the trading price of Purple Biotech’s ordinary shares and
American Depositary Shares could decline.
Risks Related to Our Financial Condition and
Capital Requirements
We are a clinical stage
biotechnology company with a history of operating losses. We expect to incur significant additional losses in the future and may never
be profitable.
We are a clinical stage biotechnology
company, and we are focused on the development and commercialization of innovative pharmaceutical drugs. We currently have a preclinical
tri-specific antibodies platform, CAPTN-3, with its leading therapeutic candidates, IM1240 and IM1305, and two other oncology therapeutic
candidates that are in the clinical trial phase, CM24 and NT219, neither of which has been approved for marketing and are not being sold,
marketed or commercialized. Each of our therapeutic candidates will require additional preclinical and/or clinical trials or other testing
before we can obtain regulatory approval, if we are able to obtain regulatory approval at all. We must obtain regulatory approval for
these therapeutic candidates, or any other therapeutic candidate that we may develop or acquire in the future before we can sell such
therapeutic candidates. We have incurred losses from commencement of our pharmaceutical research and development activities through December
31, 2025, of approximately $171 million as a result of revenue and cost of goods, research and development activities, clinical trial
related activities, investment/acquisition activities, listing for trading and fund-raising related activities, selling, general and
administrative, finance expenses and other expenses. We may incur significant additional losses as we continue to focus our resources
on advancing our current therapeutic candidates, or other therapeutic candidates that we may develop, in-license, or acquire in the future.
Our ability to generate revenue and achieve profitability depends mainly upon our ability, alone or with others, to successfully develop,
in-license, or acquire, and obtain the required regulatory approvals for our oncology therapeutic candidates in the United States and
various other territories and then to successfully commercialize our oncology therapeutic candidates. We may be unable to achieve any
or all these goals with regard to our current therapeutic candidates, or any other therapeutic candidates that we may develop, in-license,
or acquire in the future. As a result, we may never be profitable or achieve significant or sustained revenues.
1
Our limited operating
history as a biotechnology research and development company makes it difficult to evaluate our business and prospects, and we depend
on the success of a limited portfolio of therapeutic candidates for our future revenue, which could impair our ability to achieve profitability.
We have a limited operating
history as a biotechnology research and development company, and our operations to date have been limited primarily to developing our
therapeutic candidates, CAPTN-3, our tri-specific platform with its leading therapeutic candidates, IM1240 and IM1305, CM24 and NT219;
research and development; raising capital; and recruiting scientific, CMC, regulatory and management personnel and third-party partners.
To date, the only revenue we have received has been the initial milestone payments in connection with commercialization agreements for
Consensi, which were terminated in 2021. We may not be able to commercialize or obtain regulatory approval for our current therapeutic
candidates, or any additional therapeutic candidate we may develop, in-license and/or acquire in the future. Our future growth and success
depend upon our ability to continue funding the development of our therapeutic candidates and on the successful commercialization of
such therapeutic candidates. If we are unable to obtain regulatory clearances or approvals for our therapeutic candidates and future
products, our ability to gain any revenues and to achieve profitability would be adversely affected. Consequently, any predictions about
our future performance may not be accurate, and you may not be able to fully assess our ability to complete development of or commercialize
our therapeutic candidates, acquire or in-license other therapeutic candidates, obtain regulatory approvals, or achieve market acceptance
or favorable pricing for our therapeutic candidates.
We will need to raise
additional capital to achieve our strategic objectives of developing and commercializing our therapeutic candidates, and to develop,
acquire and/or in-license additional therapeutic candidates, and our failure to raise sufficient capital would significantly impair our
ability to fund our future operations, develop our current or future therapeutic candidates, seek regulatory approval that is a prerequisite
to selling any product, attract development or commercial partners and retain key personnel.
We will need to continue
to expend substantial funds in research and development, including CMC, preclinical and clinical trials of our therapeutic candidates,
as well as to acquire or in-license additional therapeutic candidates. We plan to fund our future operations through the out-licensing
and/or commercialization of our therapeutic candidates and by raising additional capital through grants or debt or equity financing.
However, we cannot be certain that we will be able to raise capital on commercially reasonable terms or at all, or that our actual cash
requirements will not be greater than anticipated. We may have difficulty raising the needed capital or securing a development or commercialization
partner in the future as a result of, among other factors, our lack of revenues from commercialization of our therapeutic candidates,
as well as the inherent business risks associated with our company and present and future market conditions. In addition, global and
local economic and geopolitical conditions may make it more difficult for us to raise needed capital or secure a development or commercialization
partner in the future and may impact our liquidity. If we are unable to obtain future financing, we may be forced to delay, reduce the
scope of, or eliminate one or more of our research, development or commercialization programs related to our therapeutic candidates or
any other therapeutic candidates that we may acquire, in-license or develop in the future, or to delay the acquisition or in-license
of any additional therapeutic candidates, any of which may have a material adverse effect on our business, financial condition and results
of operations.
To
the extent that we raise additional capital through the sale of equity, including under our At The Market Offering Agreement (the “2025
Sales Agreement”) that we entered into with H.C. Wainwright & Co., LLC (“Wainwright”) on September 19, 2025, for
the offer and sale, from time to time, of ADSs through an “at-the-market” equity offering program (“ATM program”),
with Wainwright acting as our agent, or under our Form F-3 shelf registration statement filed with the SEC in December 2022, as amended,
your ownership interest will be diluted, and the terms of any securities so sold may include liquidation or other preferences that adversely
affect your rights as a shareholder. Debt financing, if available, would result in increased fixed payment obligations and may involve
agreements that include covenants limiting or restricting our ability to take specific actions such as incurring debt, making capital
expenditures or declaring dividends. If we raise additional funds through grants, collaboration, strategic alliance and licensing arrangements
with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams or product candidates, or grant
licenses on terms that are not favorable to us.
2
Our long-term capital
requirements are uncertain and subject to numerous risks.
We estimate that so long
as no significant revenues are generated from our oncology therapeutic candidates, we will need to raise substantial additional funds
to develop and/or commercialize our therapeutic candidates and to develop, acquire or in-license any additional therapeutic candidates,
as our current cash and short-term investments are not sufficient to complete the research and development of our therapeutic candidates
in their current phase of development and any additional therapeutic candidates that we may acquire, in-license or develop in the future,
and to fund our related expenses. Our long-term capital requirements are expected to depend on many potential factors, including, among
others:
● our ability to successfully out-license and/or commercialize our oncology therapeutic candidates, or any other therapeutic candidates that we may acquire, in-license, or develop in the future, including securing commercialization agreements with third parties and favorable pricing and market share;
● the progress, success, and cost of our preclinical and/or clinical trials and research and development programs;
● our ability to successfully complete the required CMC development for our oncology therapeutic candidates or any other therapeutic candidates that we may acquire, in-license, or develop in the future;
● the costs, timing and outcome of regulatory review and obtaining and maintaining regulatory approval of our oncology therapeutic candidates or any other therapeutic candidates that we may acquire, in-license, or develop in the future, and addressing regulatory and other issues that may arise post-approval for such oncology therapeutic candidates;
● the costs of obtaining new patents and enforcing our issued patents and defending intellectual property-related claims;
● the costs of developing and maintaining our third parties’ cGMP manufacturing standards;
● our consumption of available resources more rapidly than currently anticipated, resulting in the need for additional funding sooner than anticipated;
● our ability to obtain recommendations and publish studies regarding the efficacy and/or safety of our oncology therapeutic candidates or any other therapeutic candidates that we may acquire or develop in the future that may be published by government agencies, professional organizations, academic or medical journals or other key opinion leaders;
● sufficient coverage and reimbursement by third-party payers for our therapeutic candidates; and
● the costs of seeking out and acquiring or engaging in-licensing or similar transactions for other oncological candidates and the costs associated with its long-term obligations.
If we are unable to obtain
approval, commercialize or out-license our oncology therapeutic candidates, or any other therapeutic candidates that we may acquire,
in-license or develop in the future, maintain approval, or obtain future financing, we may be forced to delay, reduce the scope of, or
eliminate one or more of our research and development programs related to the therapeutic candidates, which may have a material adverse
effect on our business, financial condition and results of operations.
3
Risks Related to Our
Business, Operations and Regulatory Matters
Our clinical trials
may fail to demonstrate adequately the safety and efficacy of our therapeutic candidates, which would prevent or delay regulatory approval
and commercialization.
The clinical trials of our
therapeutic candidates are, and the manufacturing and marketing of our products will be, subject to extensive and rigorous review and
regulation by numerous government authorities including the United States and in other countries where we may seek to test and market
our therapeutic candidates. Before obtaining regulatory approvals for the commercial sale of any of our therapeutic candidates, we must
demonstrate through lengthy, complex and expensive preclinical testing and clinical trials that our therapeutic candidates are both safe
and effective for use in their target indications. In particular, because some of our therapeutic candidates are subject to regulation
as biological drug products, we will need to demonstrate that they are safe, pure and potent for use in their target indications. Each
product candidate must demonstrate a favorable risk/ benefit profile in its intended patient population and for its intended use. The
risk/benefit profile required for drug product approval will vary depending on these factors and may include not only the ability to
show tumor shrinkage, but also adequate duration of response, a delay in the progression of the disease, and/or an improvement in survival.
For example, increased response rates from the use of our therapeutic candidates may not be sufficient to obtain regulatory approval
unless we can also show an adequate progression free survival or overall survival benefit. Clinical testing is expensive and can take
many years to complete, and its outcome is inherently uncertain. Failure can occur at any time during the clinical trial process. The
results of preclinical studies and early clinical trials of our therapeutic candidates may not be predictive of the results of later-stage
clinical trials. The results of studies in one set of patients or line of treatment may not be predictive of those obtained in another.
Therapeutic candidates proceeding through clinical trials historically have experienced high rates of attrition. Therapeutic candidates
in later stages of clinical trials may fail to show the desired safety and efficacy profile despite having progressed through preclinical
studies and initial clinical trials, which ultimately could result in interruption, delay, or suspension of our clinical trial, and/or
a failure to obtain regulatory approval necessary to commercialize our product candidates. Companies in the pharmaceutical industry have
suffered significant setbacks in advanced clinical trials due to lack of efficacy or safety issues, notwithstanding promising results
in earlier trials. A large proportion of therapeutic candidates that begin clinical trials are never approved by regulatory authorities
for commercialization.
In addition, even if such
trials are successfully completed, we cannot assure that the FDA or foreign regulatory authorities will interpret the results as we do,
and more trials could be required before we submit our therapeutic candidates for approval. To the extent that the results of the trials
are not satisfactory to the FDA or foreign regulatory authorities for support of a marketing application, we may be required to expend
significant resources, which may not be available to us, to conduct additional trials in support of potential approval of our therapeutic
candidates.
Regulations are constantly
changing, and in the future our business may be subject to additional regulations that could increase our compliance costs or delay our
ability to market our product candidates, if at all.
We believe we have a general
understanding of the current laws and regulations to which our products are subject and may become subject. However, federal, state and
foreign laws and regulations relating to the approval and marketing of product candidates are subject to future changes, as are administrative
interpretations of such laws and regulations. If we fail to comply with such future changes in federal, state, and foreign laws and regulations,
we may be unable to obtain approval to market our product candidates, or may become subject to enforcement actions. In addition, if such
federal, state, and foreign laws and regulations change, we may incur additional costs in seeking or maintaining regulatory approval.
If we are slow or unable to adapt to changes in such laws and regulations, or to new laws or regulations, we may be unable to obtain
regulatory approval.
The ability of the FDA and
foreign regulatory authorities to review and approve new products can be affected by a variety of factors, including government budget
and funding levels, statutory, regulatory, and policy changes, the ability of the FDA’s or foreign regulatory authorities to hire
and retain key personnel, the payment of user fees, and other events that may otherwise affect the FDA’s or foreign regulatory
authorities’ ability to perform routine functions. Average review times at the FDA and foreign regulatory authorities have fluctuated
in recent years as a result.
4
Disruptions at the FDA
and other agencies may also slow the time necessary for new drugs, biologics, or modifications to approved drugs and biologics, to be
reviewed and/or approved by necessary government agencies, which could adversely affect our business. For example, over the last several
years, the U.S. government has shut down several times and certain regulatory agencies, such as the FDA, have been required to furlough
employees and suspend certain regulatory activities. Further, in 2025, the U.S. administration issued a memorandum instructing certain
U.S. executive agencies to prepare for workforce reductions, which also included the FDA. Actions taken by the U.S. Department of Health
and Human Services, or HHS, that result in a reduction in the FDA’s workforce, may lead to significant delay in the review and
approval of our product candidates.
Our therapeutic candidates
may cause undesirable side effects or have other properties that could halt clinical development, prevent regulatory approval, limit
commercial potential, or result in significant negative consequences.
Undesirable side effects
or adverse events caused by our therapeutic candidates, or related to the combination therapies, could cause us or regulatory authorities
to interrupt, delay, or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval
by the FDA or other foreign regulatory authorities. Results of our trials could reveal a high rate or severity of side effects. Serious
adverse events may include organ toxicity and may lead to temporary or permanent disability or even death, including, but not limited
to, organ toxicity or even death
If unacceptable side effects
arise in the development of our therapeutic candidates, the FDA or other foreign regulatory authorities could place our clinical trials
on hold or deny approval of our therapeutic candidates for any or all targeted indications. Treatment-related side effects could also
affect patient recruitment, or the ability of enrolled subjects to continue treatment under the trial or result in potential product
liability claims. In addition, some side effects may be difficult to detect, diagnose or manage in clinical practice. Any of these occurrences
may harm our business, financial condition and prospects significantly.
If we and/or our potential
commercialization partners are unable to obtain FDA and/or other foreign regulatory authority approval for our therapeutic candidates,
we and/or our potential commercialization partners will be unable to commercialize our therapeutic candidates.
To date, we have not marketed,
distributed or sold any oncology drug product. Our oncology therapeutic candidates are each subject to extensive governmental laws, regulations
and guidelines relating to their development, preclinical and clinical testing, manufacturing, and commercialization. We may not be able
to obtain regulatory approval for marketing of any of our therapeutic candidates in a timely manner or at all.
Any material delay in obtaining,
or the failure to obtain, required regulatory approvals for marketing will increase our costs and materially and adversely affect our
ability to generate future revenues. Any regulatory approval to market a therapeutic candidate may be subject to restrictive conditions
of use, including cautionary information, thereby limiting the size of the market for the therapeutic candidate. We are, and will continue
to be, subject to numerous regulatory requirements administered by the FDA and foreign regulatory agencies that govern the conduct of
preclinical and clinical testing, manufacturing, marketing authorization, pricing, and third-party reimbursement. Moreover, approval
by one regulatory authority does not necessarily ensure approval by other regulatory authorities in separate jurisdictions. Each jurisdiction
may have different approval processes and may impose additional testing requirements for our therapeutic candidates than other jurisdictions.
Additionally, the FDA or other foreign regulatory bodies may change their marketing approval requirements or adopt new laws, regulations
or guidelines in a manner that delays or impairs our ability to obtain the necessary regulatory approvals to commercialize our therapeutic
candidates.
5
Preclinical studies,
CMC, and clinical trials may involve a lengthy and expensive process with an uncertain outcome, and the results of earlier studies and
trials may not be predictive of future results. We and/or our potential commercialization partners will not be able to commercialize
our therapeutic candidates unless we satisfactorily meet the requirements set by regulatory agencies for CMC, preclinical and clinical
studies, and obtain regulatory approval for marketing therapeutic candidates.
Establishing manufacturing
processes and controls and planning and conducting preclinical studies and clinical trials are expensive, complex, can take many years
to complete and have uncertain outcomes. We cannot predict whether we, independently or through third parties, will encounter problems
with any of the completed, ongoing or planned CMC activities, preclinical studies and/or clinical trials that will cause delays, including
suspension of preclinical studies and/or clinical trials, delays in recruiting patients into clinical trials, or delay of data analysis
in our preclinical studies or clinical studies. Development and validation of manufacturing processes and controls, as well as the planning
and conduct of preclinical studies and clinical trials of our therapeutic candidates may take significantly longer to complete than estimated.
Failure can occur at any stage of development, validation and testing, and we may experience numerous unforeseen events during, or as
a result of, CMC development or validation, the preclinical studies and/or clinical trials that could delay or prevent commercialization
of our current or future therapeutic candidates.
In connection with CMC development
and validation, preclinical studies and clinical trials for our therapeutic candidates and other therapeutic candidates that we may seek
to develop in the future, either on our own or through licensing or partnering agreements, we face various risks, including but not limited
to:
● delays in conducting preclinical studies;
● delays in manufacturing the drug substance and drug product for preclinical studies and clinical trials;
● delays in manufacturing the drug substance and drug product following NDA or BLA approval, if we receive such approval at all;
● delays in securing clinical investigators or trial sites for clinical trials that must be completed for us to obtain any approval that we seek;
● delays in receiving import or other government approvals to ensure appropriate drug supply, and shortages of combination drugs used in our clinical studies;
● delays in obtaining institutional review board (human ethics committee) and other regulatory approvals to commence a clinical trial;
● negative or inconclusive results from preclinical and/or clinical trials;
● the FDA or other foreign regulatory authorities may disagree with the number, design, size, conduct or implementation of our clinical studies and may not approve initiation of certain clinical trials;
● the clinical trials may be delayed or not completed due to the failure to recruit suitable participants or if there is a lower rate of suitable participants than anticipated or if there is a delay in recruiting suitable participants;
● Low investigator or patient compliance with clinical trial protocols;
● a therapeutic candidate may not prove safe or efficacious;
● there may be unexpected or even serious adverse events from the use of a therapeutic candidate;
● the results clinical trials with a therapeutic candidate may not confirm the positive results from earlier preclinical studies or clinical trials;
● the results of a clinical trial may not meet the targeted statistical significance required by the FDA or foreign regulatory authorities;
6
● the results of a clinical trial may lead to limited and/or restrictive approved uses, including the inclusion of warnings and/or contraindications, which could significantly limit the marketability and profitability of the therapeutic candidate;
● our therapeutic candidates may not be reimbursed under different healthcare programs such as Medicare, Medicaid or private health insurance programs;
● changes to the current regulatory requirements related to manufacturing, preclinical or clinical trials which can delay, hinder receipt of a regulatory approval for marketing the therapeutic candidate and also lead to unexpected additional costs in connection with receiving the regulatory approvals; and
● the availability of other drugs that provide alternative and/or superior treatments to our drugs and therapeutic candidates.
A number of companies in
the pharmaceutical and biotechnology industries, including those with greater resources and experience than us, have suffered significant
setbacks in advanced clinical trials, even after observing promising results in earlier preclinical studies and/or clinical trials. Accordingly,
we cannot assure that clinical trials we may conduct will demonstrate sufficient efficacy and safety to obtain regulatory approval to
market our therapeutic candidates. If the results of our preclinical studies and/or clinical trials pertaining to our therapeutic candidates
are not favorable or sufficient to support regulatory approvals, our ability to obtain regulatory approval may be adversely impacted,
which could have a material adverse effect on our business, financial condition and results of operations.
If we do not establish
collaborations for our oncology therapeutic candidates or any other therapeutic candidates that we may develop or acquire in the future,
and/or commercialize such therapeutic candidates, or otherwise raise substantial additional capital, we will likely need to alter our
development and any commercialization plans.
Our drug development programs
and the potential commercialization of our oncology therapeutic candidates, or any other therapeutic candidates that we may develop or
acquire in the future, will require additional cash to fund expenses. As such, our strategy includes selectively partnering or collaborating
with multiple pharmaceutical and biotechnology companies (including by way of out-licensing) to assist us in furthering development and
potential commercialization of our therapeutic candidates, in some or all jurisdictions. For example, further development of CM24 and
NT219 is planned upon partnering or obtaining sufficient investment to perform the next study. We may not be successful in such collaborations
with such third parties on acceptable terms, or at all. In addition, if we fail to negotiate and maintain suitable development or commercialization
agreements (such as out-licensing agreements), we may have to limit the size or scope of our activities or we may have to delay one or
more of our development or commercialization programs. Any failure to enter into or maintain development or commercialization agreements
with respect to the development, marketing and commercialization of our therapeutic candidates, or any other therapeutic candidates that
we may develop or acquire in the future, or failure to develop or acquire, market and commercialize such therapeutic candidates, will
have an adverse effect on our business, financial condition and results of operation.
Any collaborative arrangements
that we establish may not be successful or we may otherwise not realize the anticipated benefits from these collaborations. We do not
control third parties with whom we have or may have collaborative arrangements, and we rely on them to achieve results which may be significant
to us. In addition, any future collaboration arrangements may place the development, manufacturing and commercialization of our oncology
therapeutic candidates or any other therapeutic candidates that we may develop or acquire in the future, outside our control, and may
require us to relinquish important rights or may otherwise be on terms unfavorable to us.
Our collaborative arrangements
require us to rely on external consultants, advisors, experts and service providers for assistance in several key functions, including
preclinical and clinical development, manufacturing, regulatory, market research, and intellectual property. We do not control these
third parties, but we rely on them to achieve results, which may be significant to us. Our collaborative arrangements may not be successful,
or we may otherwise not realize the anticipated benefits from these collaborations. Additionally, we are responsible for any quality
or regulatory issue that a collaborator may have that affects one or more of our therapeutic candidates. Relying upon collaborative arrangements
to develop and/or commercialize our oncology therapeutic candidates or any other therapeutic candidates that we may develop or acquire
in the future subjects us to a number of risks, including:
● we may not be able to control the amount and timing of resources that our collaborators may devote to our drug product or therapeutic candidates;
7
● we may be held liable should a collaborator fail to comply with applicable laws, rules, or regulations when performing services for us;
● our collaborators may experience financial difficulties or changes in business focus;
● our collaborators may experience quality or regulatory issues that negatively affect our therapeutic candidates;
● our collaborators may fail to secure adequate commercial supplies in a timely manner for our drug products upon marketing approval, if at all;
● we may suffer losses due to our collaborators’ failure to perform their duties and we may not be able to be reimbursed by our collaborators for such losses;
● our collaborators may have a shortage of qualified personnel;
● we may be required to relinquish important rights, such as local trademark, marketing and distribution rights;
● business combinations or significant changes in a collaborator’s business strategy may adversely affect a collaborator’s willingness or ability to complete its obligations under any arrangement;
● under certain circumstances, a collaborator could move forward with a competing therapeutic candidate developed either independently or in collaboration with others, including our competitors; and
● collaborative arrangements are often terminated or allowed to expire, which could delay and increase the cost of development of our therapeutic candidates, or our collaborators may not deliver assignments on schedule, which could delay the development of our therapeutic candidates.
If any of these or other
scenarios materialize, they could have an adverse effect on our business, financial condition or results of operations.
Our current and past
business models are based largely upon the development or acquisition and commercialization of new combination products and new therapeutic
candidates that may have not yet been administered to humans or have limited history of treatment with humans. Unexpected difficulties
or delays in successfully developing, acquiring or commercializing such combination and new drugs could have an adverse effect on our
business, financial condition and results of operations.
We currently have a preclinical
platform, CAPTN-3, with its leading therapeutic candidates, IM1240 and IM1305, and two other oncology therapeutic candidates that are
in the clinical trial phase, CM24 and NT219. Despite the past and future performance of numerous clinical studies with these therapeutic
candidates, patients as a monotherapy and in combination with other drugs, we cannot be certain whether any of our therapeutic candidates
will be safe and efficacious when used in either monotherapy settings or in combination with the current or other known cancer treatments.
Developing combination products
with existing drugs or therapies currently on the market brings additional risks to seeking regulatory approval. Even if an existing
drug or therapy is currently approved as safe and effective by the FDA, such drug or therapy may be removed from the market or otherwise
become unavailable for continued use, which could hinder our ability to complete our clinical trials and/or obtain regulatory approval.
8
In addition, we cannot be
certain that the FDA or any foreign regulatory body will consider our oncology therapeutic candidates, whether alone or combined with
other cancer treatments, or any other therapeutic candidate that we may develop or acquire in the future to be sufficiently safe and
effective to support acceptance of a marketing application. Any delays in perfecting the combination, the production of the combination,
or in market acceptance of the combination or new therapeutic candidates could have an adverse effect on our business, financial condition
and results of operations.
Further, as part of our strategy
for growth, we may consider the acquisition of additional therapeutic candidates at various stages of development and in a variety of
therapeutic areas, and we may consider the acquisition or marketing rights of approved drug products as well. However, we may not be
able to identify suitable acquisition candidates, complete acquisitions or integrate acquisitions successfully into our business. In
this regard, acquisitions involve numerous risks, including difficulties in the integration of the acquired therapeutic candidates and/or
drug product and the diversion of management’s attention from other business concerns. Although we will endeavor to evaluate the
risks inherent in any particular transaction, there can be no assurance that we will properly ascertain all such risks. In addition,
acquisitions could result in the incurrence of substantial additional indebtedness and other expenses or in potentially dilutive issuances
of equity securities. There can be no assurance that difficulties encountered with acquisitions will not have a material adverse effect
on our business, financial condition and results of operations.
We rely mainly on third
parties to conduct our CMC, research and development, preclinical studies and clinical trials, and those third parties may not perform
satisfactorily, including, but not limited to, failing to conform quality standards for our therapeutic candidates, which may endanger
our clinical trial participants, and/or fail to meet established deadlines for the completion of such studies and trials.
We do not have the ability
independently to conduct CMC, research and development, preclinical studies or clinical trials for our product candidates, and to a large
degree we rely on third parties, such as contract manufacturing organizations, CROs, medical institutions, contract laboratories, current
and potential development or commercialization partners, clinical investigators and independent study monitors, to perform these functions.
Our reliance on these third parties for development activities reduces our control over these activities.
Furthermore, these third
parties may also have relationships with other entities, some of which may be our competitors. Although we have, in the ordinary course
of business, entered into agreements with these third parties, we continue to be responsible for confirming that each of our preclinical
studies and clinical trials is conducted in accordance with its general investigational plan and protocol. Moreover, the FDA and other
regulatory agencies require us and our applicable third-party collaborators to comply with regulations and standards, commonly referred
to as current good laboratory practices (cGLP), current good manufacturing practices (cGMP), and current good clinical practices (cGCP),
for manufacturing and conducting, recording and reporting the results of preclinical and clinical trials to assure that data and reported
results are credible and accurate and that the clinical trial participants are adequately protected. We cannot guarantee that our third-party
collaborators will remain compliant with the applicable regulations. If our third-party collaborators are unable to comply with FDA regulations
and standards, including, but not limited to, cGLPs, cGMPs and cGCPs, we may be forced to suspend or delay our clinical trials, which
could significantly delay our ability to achieve marketing approval, if at all. Regulatory authorities in other jurisdictions may have
similar responsibilities and requirements. Our reliance on third parties does not relieve us of these responsibilities and requirements.
To date, we believe our contract
manufacturing organizations, CROs and other third-party entities that support our manufacturing, research and development, preclinical
or clinical practices with which we are working have generally performed well. However, if these third parties do not successfully carry
out their contractual duties or meet expected deadlines, we may not meet our deadlines or we may be required to replace them. Although
we believe that there are a number of other third-party contractors we could engage to continue these activities, finding replacements
may result in a delay of clinical trials and/or commercialization of products and additional costs. Accordingly, we may be delayed in
obtaining regulatory approvals for our oncology therapeutic candidate or any therapeutic candidate that we may develop or acquire in
the future, and we may be delayed in our efforts to successfully commercialize such therapeutic candidates for targeted diseases or fail
to maintain marketing authorization to our drug products.
9
In addition, we rely substantially
on third-party data managers for CMC and the preclinical study and clinical trial data that we present to regulatory authorities in order
to obtain marketing authorizations. Although we attempt to audit and control the quality of third-party data, we cannot guarantee the
authenticity or accuracy of such data, nor can we be certain that such data has not been fraudulently generated. There is no assurance
that these third parties will pass FDA or regulatory audits, which could delay or prevent regulatory approval or cause revocation of
already approved marketing authorization.
If third parties do
not manufacture our current therapeutic candidates or any other therapeutic candidate that we may develop or acquire in the future in
sufficient quantities in the required timeframe, at the required quality standards and at an acceptable cost, preclinical, clinical development
and commercialization of our therapeutic candidates could be delayed.
We do not currently own or
operate manufacturing facilities, and we rely, and expect to continue to rely, on third parties to manufacture preclinical, clinical
and commercial quantities of our oncology therapeutic candidates or any other therapeutic candidate that we may develop or acquire in
the future. Our reliance on third parties includes our reliance on them to develop manufacturing processes and manufacture such therapeutic
candidates at a required standard of quality, including quality assurance related to regulatory compliance. Our current and anticipated
future reliance upon others for the development and manufacture of our oncology therapeutic candidates or any other therapeutic candidate
that we may develop or acquire in the future may adversely affect our future profit margins, if any, and our ability to develop such
therapeutic candidates and commercialize any such therapeutic candidates at a required standard of quality and on a timely and competitive
basis.
We may not be able to maintain
our existing or future third-party manufacturing arrangements on acceptable terms, if at all. If for some reason our existing or future
manufacturers do not perform as agreed or expected, or our existing or future manufacturers otherwise terminate their arrangements with
us, we may be required to replace them. Although we are not entirely dependent upon our existing manufacturing agreements since we could
replace them with other third-party manufacturers, we may incur added costs and delays in identifying, engaging, qualifying and training
any such replacements, and in receiving regulatory approval for such replacements.
We rely on third-party
contract vendors to manufacture and supply us with API and other materials used in the manufacture of a drug product to be compliant
with the International Conference of Harmonization Q7 guidance and other applicable laws and regulations, in the quality and quantities
we require on a timely basis.
We currently do not manufacture
any API ourselves. Instead, we rely on third-party vendors for the manufacture and supply of our APIs and other materials that are used
to manufacture and formulate our oncology therapeutic candidates. While there are many potential API manufacturers and suppliers in the
market, if these manufacturers or suppliers are incapable or unwilling to meet our current or future needs on acceptable terms or at
all, or the current or future demand of the public, if any, we could experience delays in developing or conducting clinical trials for
our current therapeutic candidates, IM1240, IM1305, CM24 and NT219, or any other therapeutic candidate that we may develop or acquire
in the future, and incur additional costs.
While there may be several
alternative manufacturers or suppliers of API in the market, we have not conducted extensive audits and investigations into the quality
or availability of their APIs. In addition, we may acquire therapeutic candidates which already have long term commitments to a specific
API supplier. As a result, we can provide no assurances that supply sources will not be interrupted from time to time. Changing API manufacturers
or suppliers or finding and qualifying new API manufacturers or suppliers can be costly and take a significant amount of time. Many APIs
require significant lead time to manufacture. There can also be challenges in maintaining similar quality or technical standards from
one manufacturing batch to the next.
If we are not able to find
stable, reliable manufacturers or suppliers of our APIs and other materials used in the manufacture of our oncology therapeutic candidates,
we may not be able to produce enough supplies of our oncology therapeutic candidates to meet our needs for further development and/or
to conduct clinical trials, which could affect our business, financial condition and results of operation.
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We anticipate continued
reliance on third-party manufacturers if we are successful in obtaining marketing approval from the FDA and/or other regulatory agencies
for IM1240, IM1305, CM24 and NT219, or any other therapeutic candidates we may develop or acquire in the future.
To date, our therapeutic
candidates have been manufactured in relatively small quantities by third-party manufacturers. Once our oncology therapeutic candidates
and/or any other therapeutic candidate that we may develop or acquire in the future is approved for marketing and commercial sale, if
at all, we still expect that we will continue to rely, at least initially, on third-party manufacturers to produce commercial quantities
of such approved therapeutic candidates. These manufacturers may not be able to successfully increase the manufacturing capacity for
any such therapeutic candidates that may be approved in the future in a timely or economic manner, or at all. Significant scale-up of
manufacturing may require additional validation studies, which the FDA must review and approve. If we are unable to successfully increase
the manufacturing capacity for our oncology therapeutic candidates or any therapeutic candidate that we may develop or acquire in the
future, or we are unable to establish alternative manufacturing capabilities and in a timely manner, the commercial launch of any such
therapeutic candidates that are approved in the future may be delayed or there may be a shortage in supply.
We and our third-party
manufacturers are, and will be, subject to regulations of the FDA and other foreign regulatory authorities.
We and our third-party contract
manufacturers are, and will be, required to adhere to laws, regulations and guidelines of the FDA and other foreign regulatory authorities
setting forth cGMPs. These laws, regulations and guidelines cover all aspects of the manufacturing, testing, quality control and recordkeeping
relating to our oncology therapeutic candidates when we initiate their clinical trials. We and our third-party contract manufacturers
may not be able to comply with applicable laws, regulations and guidelines. We and our third-party contract manufacturers are and will
be subject to unannounced inspections by the FDA, state regulators and similar foreign regulatory authorities outside the U.S. Our failure,
or the failure of our third-party contract manufacturers, to comply with applicable laws, regulations and guidelines could result in
the imposition of sanctions on us, including fines, injunctions, civil penalties, failure of regulatory authorities to grant marketing
approval of our therapeutic candidates, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of our
therapeutic candidates, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect regulatory
approval and supplies of our therapeutic candidates and materially and adversely affect our business, financial condition and results
of operations.
Our oncology therapeutic
candidates and/or any other therapeutic candidate that we may develop or acquire in the future, if approved, will be subject to ongoing
regulatory review. If we fail to comply with continuing U.S. and applicable foreign laws, regulations and guidelines, our clinical trials
may be placed on hold, we could lose the FDA and/or other regulatory agencies’ approval(s) we will obtain (if any), and our business
would be seriously harmed.
If our oncology therapeutic
candidates and/or any other therapeutic candidate that we may develop or acquire in the future receives regulatory approval to commercialize,
such therapeutic candidate will be subject to ongoing post-marketing surveillance programs and regulatory review. We and our commercialization
partners, as applicable, are subject to ongoing reporting obligations, including pharmacovigilance, or drug safety, and our manufacturing
operations, and those of contract manufacturers that we select will be subject to continuing regulatory review, including inspections
by the FDA and other foreign regulatory authorities, if a product is approved for commercialization in such foreign jurisdictions. The
results of this ongoing review may result in the withdrawal of an approved product from the market, the interruption of manufacturing
operations or the imposition of labeling or marketing limitations. In addition, since many more patients are treated with drugs following
their marketing post-approval, unanticipated adverse reactions or serious adverse reactions that were not observed in preclinical and/or
clinical trials may be observed during the commercial marketing of a drug product.
As we move forward with commercializing
drug products, we may also periodically discuss with the FDA and other regulatory authorities certain clinical, regulatory and manufacturing
matters and our views may, at times, differ from those of the FDA and other regulatory authorities. If we are required to conduct additional
clinical trials or other testing of an approved drug product, we may face substantial additional expenses, and/or we may have our approval
to commercialize a drug product revoked by the FDA or a foreign regulatory body, should we obtain approval to commercialize in such foreign
jurisdiction.
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In addition, the manufacturer
and the facilities that we or our commercialization partners use or may use to manufacture drug products in the future will be subject
to periodic and unannounced review and inspection by the FDA and other foreign regulatory authorities. Later discovery of previously
unknown problems with a drug product or a therapeutic candidate, the manufacturer or manufacturing process, or failure to comply with
our post-approval requirements, rules and regulatory requirements, may result in actions such as:
● restrictions on such drug product, therapeutic candidate, manufacturer or manufacturing process;
● issuance of Form 483 inspection observations, untitled letters, warning letters from the FDA or other foreign regulatory authorities;
● withdrawal of the product or therapeutic candidate from the market;
● suspension or withdrawal of regulatory approvals;
● refusal to approve pending applications or supplements to approved applications that we or our potential commercialization partners submit;
● voluntary or mandatory recall;
● refusal to permit the import or export of our therapeutic candidates;
● product seizure or detentions;
● injunctions or the imposition of civil or criminal penalties and fines; or
● adverse publicity or changes to the drug’s labeling.
The FDA or foreign regulatory
authorities’ policies may change, or additional government regulations may be enacted that could prevent, limit or delay regulatory
approval of our oncology therapeutic candidates. If we, or our current or potential commercialization partners, suppliers, third-party
contractors or clinical investigators are slow to adapt, or are unable to adapt, to changes in existing regulatory requirements or the
adoption of new regulatory requirements or policies, we or our potential commercialization partners may lose marketing approval for our
oncology therapeutic candidates or any other therapeutic candidate that we may develop or acquire in the future, that obtain regulatory
approval, resulting in decreased or lost revenue from milestones, product sales or royalties and could also result in other civil or
criminal sanctions, including fines and penalties.
Regulatory approval
of our oncology therapeutic candidates (if any) will be limited by the FDA and similar foreign authorities to those specific indications
and conditions for which clinical safety and efficacy have been demonstrated, and the promotion of such product candidates for off-label
uses, or in a manner that otherwise violates applicable FDA regulations, could adversely affect our business.
Any regulatory approval of
therapeutic candidates is limited to those specific diseases and indications for which such therapeutic candidates have been deemed safe
and effective by the FDA or similar foreign authorities. Marketing or commercializing of therapeutic candidates to treat a new symptom
or indication, that was not approved by the FDA or similar foreign authorities would be considered promotion of off-label, or unapproved
use, and would require us to file a supplemental new drug application and obtain regulatory approval. We will rely on physicians to prescribe
and administer our therapeutic candidates (if approved for marketing by the FDA or similar foreign authorities) or as the product labeling
directs and for the indications described on the labeling. To the extent any physicians prescribe such product to patients for off-label
uses, or the use of such products depart from the approved use, this may increase the risk of injury or other adverse events to the patients
and the risk of filing product liability claims against us. Product liability claims are expensive to defend regardless of merit and
could result in substantial damage awards against us or harm our reputation. Furthermore, any off-label use may not effectively treat
the conditions associated with such use, which could harm our reputation in the marketplace among physicians and patients, adversely
affecting our operations.
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While physicians may choose
to prescribe drugs for uses that are not described in the product’s labeling and for uses that differ from those approved by regulatory
authorities, our ability to promote our therapeutic candidates (if approved for marketing by the FDA or similar foreign authorities)
is limited to those indications that are specifically approved by the FDA or other regulatory authorities. Although regulatory authorities
generally do not regulate the behavior of physicians, they do restrict communications by companies on the subject of off-label use. If
the promotional activities related to our therapeutic candidates fail to comply with these regulations or guidelines, we may be subject
to warnings from, or enforcement action by, the FDA or other regulatory authorities. In addition, failure to follow FDA rules and guidelines
relating to promotion and advertising can lead to other negative consequences that could adversely affect our operations, such as the
suspension or withdrawal of our therapeutic candidates from the market, enforcement letters, and corrective actions. Other regulatory
authorities, including the Department of Justice, may impose separately penalties including, but not limited to, fines, disgorgement
of money, operating restrictions, or criminal prosecution.
The FDA requires that our
and our future distribution partners’ sales and marketing efforts, as well as promotions, comply with various laws and regulations.
Prescription drug promotions must be consistent with and not contrary to labeling, present “fair balance” between risks and
benefits, be truthful and not false or misleading, be adequately substantiated (when required), and include adequate directions for use.
In addition to the requirements applicable to approved drug products, we may also be subject to enforcement action in connection with
any promotion of an investigational new drug. A sponsor or investigator, or any person acting on behalf of a sponsor or investigator,
may not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under
investigation or otherwise promote the drug candidate.
If the FDA investigates the
marketing and promotional materials or other communications for our current or future commercial products and finds that any of our commercial
products are being marketed or promoted in violation of the applicable regulatory restrictions, we and our distribution partners could
be subject to FDA enforcement action, or civil or criminal action taken by the U.S authorities, which may result in substantial monetary
penalties and/or harm to our reputation. Any enforcement action (or related lawsuit, which could follow such action) brought against
us in connection with alleged violations of applicable drug promotion requirements, or prohibitions, could harm our business and our
reputation, as well as the reputation of any approved drug products we may promote or commercialize. Such enforcement actions may
also result in significant monetary damages.
We may encounter substantial
delays in the clinical trials for our therapeutic candidates, or we may not be able to conduct their trials on the timelines we expect,
or we may not be able to complete them at all.
Clinical testing is expensive,
time-consuming, and subject to uncertainty. Currently, two of our therapeutic candidates, CM24 and NT219, are in the clinical trial phase
and we intend to enter into a clinical study with IM1240. Our ability to initiate, continue and complete clinical trials is dependent
upon, among other things, our ability to enter into strategic collaborations and/or obtain sufficient additional financing to fund such
studies. We may be unable to secure such collaborations or financing on acceptable terms, or at all. Accordingly, we cannot assure you
that any current or future clinical studies will be initiated or conducted as planned, or completed on schedule, if at all. Issues may
arise, including factors outside of our control, that could delay or prevent the initiation, progress or completion of clinical trials.
A failure of one or more clinical studies may occur at any stage of testing, and clinical studies for any of our therapeutic candidates
may not be successful. Events that may prevent successful or timely completion of clinical development include:
● Failure to meet the safety requirement in toxicology studies;
● delays in reaching a consensus with regulatory agencies on study design;
● delays in reaching agreement on acceptable terms with prospective contract research organizations, or CROs, and clinical study sites, the terms of which can be subject to extensive negotiation and may vary significantly among different CROs and clinical study sites;
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● delays in obtaining required Institutional Review Board (IRB) approval at each clinical study site;
● the departure of a principal investigator from a clinical site, which could cause delays in conducting the clinical trial at a particular clinical site;
● the shortage of staff in clinical sites;
● imposition of a temporary or permanent clinical hold by regulatory agencies;
● delays in recruiting suitable patients to participate in future clinical studies for IM1240, CM24, NT219 or other therapeutic candidates;
● failure by us or our CROs, or third parties, to adhere to clinical study requirements;
● failure to perform in accordance with the FDA’s cGCPs, requirements, or applicable regulatory guidelines in other countries;
● patients dropping out of a study;
● occurrence of adverse events associated with the product candidate leading to a clinical hold;
● changes in regulatory requirements and guidance that require amending or submitting new clinical protocols;
● changes in the standard of care on which a clinical development plan was based, which may require new or additional trials;
● the cost of clinical studies of any therapeutic candidates being greater than we anticipate;
● management’s decision to allocate internal resources to other projects;
● clinical studies of our current and/or future therapeutic candidates producing negative or inconclusive results, which may result in us deciding, or regulators requiring, conduct of additional clinical studies or abandon product development programs; and
● delays in manufacturing, testing, release, validating, or import/export of sufficient stable quantities of current and/or future therapeutic candidates or approved drugs for use in clinical studies or the inability to do any of the foregoing, including any quality issues associated with contract manufacturers.
We may conduct clinical research
in collaboration with medical centers and investigators who would sponsor these studies. In such cases, we will have limited control
over the performance of the study, its design, the recruitment of patients to the study and its schedule. Such studies may not provide
the adequate data required by the FDA or similar regulatory agencies or provide results that are not sufficient to determine the safety
or efficacy of our therapeutic candidates.
We also may conduct clinical
research in collaboration with other biotechnology and biologics entities in which we combine IM1240, CM24, NT219 and/or other or future
therapeutic candidates with the technologies of such collaborators. Such collaborations may be subject to additional delays because of
the management of the trials or the necessity of obtaining additional approvals for therapeutics used in the combination trials, or a
shortage in the availability of such collaborators’ drug products. These combination therapies will require additional testing
and clinical trials, will require additional FDA regulatory approval, and will increase our future expenses.
In addition, if we make manufacturing
or formulation changes to IM1240, CM24, NT219 and/or other or future therapeutic candidates, we may be required, or may elect, to conduct
additional studies to bridge the modified therapeutic candidates to earlier versions. Clinical study delays could also shorten any periods
during which our products have patent protection and may allow our competitors to bring products to market before we do, which could
impair our ability to commercialize these therapeutic candidates successfully and may harm our business and the results of our operations.
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A number of factors, including
scheduling conflicts with participating clinicians and clinical institutions, and difficulties in identifying and enrolling patients
who meet trial eligibility criteria, may cause significant delays in clinical studies. We may not commence or complete clinical trials
involving any of our therapeutic candidates as projected or may not conduct them successfully.
We expect to rely on medical
institutions, academic institutions, or CROs to conduct, supervise, or monitor some or all aspects of clinical trials involving our therapeutic
candidates. If we fail to commence or complete, or experience delays in, any of its planned clinical trials, we may experience delays
in its clinical development and/or commercialization plans.
If we encounter difficulties
enrolling patients in our clinical trials, our clinical development activities could be delayed or otherwise adversely affected.
The timely completion of
clinical trials in accordance with their protocols depends, among other things, on our ability to enroll a sufficient number of patients
who remain in the trial until its conclusion. We may experience difficulties in patient enrollment in our clinical trials for a variety
of reasons, including:
● the size and nature of the patient population;
● the patient eligibility criteria defined in the protocol;
● the size of the study population required for analysis of the trial’s endpoints;
● the proximity of patients to trial sites;
● the design of the trial;
● our ability to recruit clinical trial investigators with the appropriate competencies and experience;
● competing clinical trials for similar therapies or other new therapeutics;
● clinicians’ and patients’ perceptions of the potential advantages and side effects of the product candidate being studied in relation to other available therapies, including any new drugs or treatments that may be approved for the indications we are investigating;
● our ability to obtain and maintain patient consents;
● the risk that patients enrolled in clinical trials will not complete a clinical trial, will withdraw from a clinical trial, or will withdraw from one arm of the study, which could cause an imbalance between study arms and result in informative censoring, causing the results of a study arm to be uninterpretable; and
● the effect of epidemics, endemics or pandemics on the ability of patients to visit the testing sites and the effect of the disease on potential patients who contracted the disease.
Our clinical trials will
compete with other clinical trials for therapeutic candidates that are in the same therapeutic areas as our therapeutic candidates, and
this competition may reduce the number and types of patients available to us, because some patients who might have opted to enroll in
our clinical trials may instead opt to enroll in a trial being conducted by one of our competitors. Accordingly, we cannot guarantee
that the trials will progress as planned or as scheduled. Delays in patient enrollment may result in increased costs or may affect the
timing or outcome of our ongoing clinical trial and planned clinical trials, which could prevent completion of these trials and adversely
affect our ability to advance the development of our therapeutic candidates.
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Even if we can enroll a sufficient
number of patients in our clinical trials, delays in patient enrollment may result in increased costs or may affect the timing or outcome
of the planned clinical trials, which could prevent completion of these trials and adversely affect our ability to advance the development
of our therapeutic candidates.
We may depend on a
partner to conduct clinical trials with CM24, NT219 and/or other therapeutic candidates, and we may enter into future collaboration agreements
with collaboration partners to develop and conduct clinical trials with, obtain regulatory approvals for, and to market and sell our
therapeutic candidates. If such collaboration fails to perform as expected, our clinical trials and/or development plans will be delayed,
and we will be required to seek other partners, which we may not be able to engage in a timely manner, if at all, and which may delay
our development plans and therefore the potential for us to generate future revenue from our therapeutic candidates would be significantly
reduced and our business would be significantly harmed.
We entered into a clinical
collaboration and supply agreement with Bristol Myers Squibb Company (NYSE:BMY) for the phase 1/2 study of CM24 in combination with a
programmed cell death protein 1 (PD-1) antibody nivolumab, and an expansion study to also evaluate CM24 and nivolumab, together with
nab-paclitaxel, in patients with pancreatic cancer. We initiated the phase 1b/2 portion of the phase 1/2 study in March 2021 and in December
2024, we reported the final data for the study. We plan to initiate a Phase 2b study targeting patients based on these potential biomarkers
upon partnering or obtaining sufficient investment to perform this study. We entered into a research agreement with the University of
Colorado for an investigator-initiated Phase 2 study evaluating NT219 in patients with recurrent/metastatic squamous cell carcinoma of
the head and neck, which was initiated in June 2025. We rely and may in the future continue to rely on our collaboration partners to
develop, supply, conduct clinical trials, and/or commercialize our therapeutic candidates and approved products we may market in the
future, if any. We may also enter into collaboration agreements with other parties in the future relating to any current and/or future
therapeutic candidates. Ultimately, if such therapeutic candidates are advanced through clinical trials, certain of the collaboration
partners may have certain rights in connection with the commercialization of the therapeutic candidate, such as rights of first offer
to be responsible for commercialization of these therapeutic candidates. If these collaboration partners do not perform in the manner
we expect or fail to fulfill their responsibilities in a timely manner or at all, if the agreements with them terminate or if the quality
or accuracy of the clinical data they obtain is compromised, the clinical development, regulatory approval and commercialization efforts
related to our therapeutic candidates could be delayed or terminated, and it could become necessary for us to assume the responsibility
at our own expense for the clinical development of such therapeutic candidates and seek replacement collaboration and/or development
partners. In that event, we would likely be required to limit the size and scope of efforts for the development and commercialization
of such product candidate; we would likely be required to seek additional financing to fund further development or identify alternative
strategic collaboration partners; our potential to obtain regulatory approval for, and to generate future revenue from, such therapeutic
candidates would be significantly reduced or delayed; and it could have a material adverse effect on our business, financial position,
results of operations and future growth prospects.
Collaborations involving
our therapeutic candidates pose a number of risks, including the following:
● collaboration partners have significant discretion in determining the efforts and resources that they will apply to these partnerships;
● collaboration partners may have limited supply of products, such as a PD-1 antibody, which we require for the development of our therapeutic candidates;
● collaboration partners may not perform their obligations as expected;
● collaboration partners may not pursue development of our therapeutic candidates or may elect not to continue or renew development programs, based on clinical trial results, changes in the collaboration partners’ strategic focus or available funding or external factors, such as an acquisition, that divert resources or create competing priorities;
● collaboration partners may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing;
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● collaboration partners may have or could independently develop, or develop with third parties, products that compete directly or indirectly with our out-licensed therapeutic candidates;
● disagreements with collaboration partners, including disagreements over proprietary rights, contract interpretation or the conduct of product research, development or commercialization programs, may cause delays or lead to termination of such programs, or require us to assume unplanned expenditures, responsibilities or liabilities with respect to therapeutic candidates we have out licensed, or may result in costly and time-consuming litigation or arbitration;
● collaboration partners may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; and
● collaboration agreements may be terminated and, if terminated, may result in a need for additional capital to pursue further development or commercialization of the applicable therapeutic candidates.
In addition, collaboration
agreements may provide the collaboration partners with rights to terminate such agreements and licenses granted under such agreements
under various conditions, which, if exercised, would adversely affect our product development efforts, could make it difficult for us
to attract new collaboration partners and may adversely affect our reputation. Any such termination of any current or future agreement
with a collaboration partner could have a material adverse effect on our business, financial position and results of operations.
The manufacture of
our therapeutic candidates is complex, and we may encounter difficulties in production, particularly with respect to process development
or scaling-up of our manufacturing capabilities. If we, or any of our third-party manufacturers encounter such difficulties, our ability
to supply drugs for clinical trials or our products (if approved) for patients on a timely basis could be materially delayed or adversely
affected. In addition, this may cause an increase in costs that could result in our inability to maintain a commercially viable cost
structure.
NT219 is a small molecule
chemical compound, and CM24, IM1240 and IM1305 are biologic compounds, and the process of manufacturing each is complex, highly regulated
and subject to multiple risks. Even minor deviations from normal manufacturing processes for each of these therapeutic candidates and/or
any future therapeutic candidate could result in reduced production yields, product defects, and other supply disruptions.
Developing commercially viable
processes is a difficult and uncertain task, and there are risks associated with scaling to the level required for advanced clinical
trials or commercialization, including, among others, cost overruns, potential problems with process scale-up, process reproducibility,
stability issues, lot consistency, and timely availability of raw materials. As a result of these challenges, we may experience delays
in our therapeutic candidates’ preclinical development, clinical development and/or commercialization plans. We may ultimately
be unable to reduce the cost of goods for each of our therapeutic candidates to levels that will allow for an attractive return on investment
if and when those therapeutic candidates are commercialized.
Because each of our
therapeutic candidates represents a novel approach to the treatment of disease, there are many uncertainties regarding the development,
the market acceptance, third-party reimbursement coverage and the commercial potential of these therapeutic candidates.
There is no assurance that
the approaches offered by our therapeutic candidates, CAPTN-3, our tri-specifics platform with its leading therapeutic candidate, IM1240
and IM1305, CM24 or NT219, will gain broad acceptance among physicians or patients, or that governmental agencies or third-party medical
insurers will be willing to provide reimbursement coverage for proposed therapeutic candidates. Since each of our therapeutic candidates,
represents a new approach to treating various conditions, it may be difficult, in any event, to accurately estimate the potential revenues
from these therapeutic candidates. Accordingly, we may spend large amounts of money trying to obtain approval for therapeutic candidates
that have an uncertain commercial market. The market for any products that we may successfully develop utilizing our therapeutics candidates
will also depend on the cost of the product. We do not yet have sufficient information to reliably estimate what it will cost to commercially
manufacture these therapeutic candidates, and the actual cost to manufacture these therapeutic products could materially and adversely
affect the commercial viability of these products. Our goal is to reduce the cost of manufacturing our therapeutic candidates. However,
unless we reduce those costs to an acceptable amount, we may never be able to develop a commercially viable product. If we do not successfully
develop and commercialize our therapeutic candidates based upon this approach or find suitable and economical sources for materials used
in the production of these therapeutic candidates, these therapeutic candidates will not become profitable.
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Our therapeutic candidates
may be provided to patients in combination with other agents provided by third parties. The cost of such combination therapy may increase
the overall cost of our therapeutic candidates’ based therapies and may result in issues regarding the allocation of reimbursements
between our therapeutic candidates and the other agents, all of which may adversely affect the ability to obtain reimbursement coverage
for the combination therapy from third-party medical insurers.
If we fail to comply
with any obligations under our in-license agreements with Yissum and/or THM or any future license agreement or acquisition agreements
of our therapeutic candidates, or disputes arise with respect to those agreements, it could have a negative impact on our intellectual
property rights and we could lose our rights to IM1240, IM1305, NT219 and/or CM24 or any future therapeutic candidate, which could have
a material adverse effect on our business, financial condition and results of operation.
We are a party to a license
agreement with each of Yissum, the technology transfer company of the Hebrew University of Jerusalem, and THM, pursuant to which we license
rights to our therapeutic candidates NT219 and CM24, respectively, and also have financial obligations under the acquisition agreement
for the CAPTN-3 platform. These agreements impose, and any additional licensing arrangements that we may enter into with third parties
may impose, diligence, development and commercialization timelines, milestone payments, royalty payments, insurance and other obligations
on us. Our rights to use the licensed intellectual property are subject to the continuation of, and our compliance with, the terms of
these agreements. Disputes may arise regarding our rights to intellectual property licensed to us from a third party, including but not
limited to:
● the scope of rights granted under the license agreement and other interpretation-related issues;
● the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the licensing agreement;
● the sublicensing of patent and other rights;
● our diligence obligations under the license agreement and what activities satisfy those diligence obligations;
● the ownership of inventions and know-how resulting from the creation or use of intellectual property by us, alone or with our licensors and collaborators;
● the scope and duration of our payment obligations;
● our ability to further license the technology to third parties;
● our rights upon termination of such agreement; and
● the scope and duration of exclusivity obligations of each party to the agreement.
If disputes over intellectual
property and other rights that we have licensed or acquired from third parties prevent or impair our ability to maintain our current
licensing arrangements on acceptable terms, we may be unable to successfully develop and commercialize the affected therapeutic candidates.
If we fail to comply with our obligations under current or future agreements or if other events occur that are not within our control,
these agreements may be terminated or the scope of our rights under them may be reduced, we could lose the rights to our current therapeutic
candidates and/or any other therapeutic candidate we license or acquire, and we might be unable to develop, manufacture or market any
product that is licensed or acquired under these agreements, could experience delays in developing or commercializing these therapeutic
candidates or incur additional costs, any of which could have a material adverse effect on our business, financial condition and results
of operations.
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In addition, we may have
disputes over intellectual property rights related to our therapeutic candidates developed under service agreements or material transfer
agreements with third parties. Such third parties may claim rights to certain know-how or intellectual property that may require us to
enter into license agreements with such parties and pay royalties for such rights or to engage in legal proceedings with these parties.
Our shareholders may
not realize a benefit from our acquisitions of therapeutic candidates commensurate with the ownership dilution they experienced in connection
with the transactions.
If we are unable to realize
the strategic and financial benefits anticipated from an acquisition (through the acquisition of a company or a company’s assets),
or in-licensing of therapeutic candidates, our shareholders may have experienced substantial dilution of their ownership interest without
receiving any commensurate benefit. Due to the substantial number of the ADSs (including ADSs issuable upon exercise of the warrants
to purchase ADSs) which were issued to shareholders in the acquisitions and the private placements we completed and may complete in the
future in order to acquire our therapeutic candidates, the ownership stake and relative voting power of each ordinary share held by our
previous shareholders was and may in the future be significantly reduced. Significant management attention and resources will be required
to integrate and operate any acquired company or new product. Delays in this process could adversely affect our business, financial results,
financial condition and price of our ordinary shares and/or ADSs following any acquisition or in-licensing agreement.
Any impairment in the
value of our intangible assets, including goodwill, could negatively affect our operating results and total capitalization.
Even if we are able to integrate
the acquired business operations successfully, there can be no assurance that its integration will result in the realization of the full
benefits of synergies, innovation, and operational efficiencies that may be possible from such integration and that the benefits will
be achieved within a reasonable period of time. As part of prior acquisitions, we acquired substantial intangible assets, including goodwill.
We may be required to recognize impairment charges on goodwill or other intangible assets acquired through our past or future acquisitions
of therapeutic candidates if expected benefits from these acquisitions fail to materialize and such assets’ carrying values exceed
their fair values, which could adversely affect our business, financial condition and results of operations. We review our intangible
assets for impairment when events or changes in circumstances indicate the carrying value may not be recoverable. For example, as of
December 31, 2025, we recognized impairment charges of $20.5 million for the in-process research and development related to CM24 (acquired
in connection with the acquisition of FameWave in 2020) and NT219 (acquired in connection with the acquisition of the majority shareholdings
of TyrNovo in 2017), mainly due to the write-off of the carrying value of such assets. Factors that may lead to an impairment determination
include: (1) the performance of an acquired commercial product; (2) anticipated loss of exclusivity of an acquired commercial product;
and (3) changes in the future outlook of acquired products. Future impairment reviews could result in additional impairment charges,
which could materially adversely affect our financial results for the periods in which they are recorded.
Further, given the challenges
involved with the development of a biological product and the financial challenges, we may not be able to realize the anticipated benefits
of the acquisition of the Immunorizon technology platform that we acquired in February 2023, which may materially adversely affect our
growth and future operating results as well as our financial condition.
We may be required to record
a significant charge in our consolidated financial statements during the period in which any impairment of our goodwill or other intangible
assets is determined, negatively affecting our results of operations and equity book value, the effect of which could be material.
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We depend on our ability
to identify and acquire or in-license therapeutic candidates to achieve commercial success.
We own the rights to our
therapeutic candidates, each of which was acquired by us from a third-party: NT219 (acquired in connection with the acquisition of the
majority shareholdings of TyrNovo in 2017), CM24 (acquired in connection with the acquisition of FameWave in 2020) and CAPTN-3, our tri-specific
platform (acquired in connection with the acquisition of Immunorizon in February 2023). We evaluate internally and with external consultants
each potential therapeutic candidate. However, there can be no assurance as to our ability to accurately or consistently select therapeutic
candidates that have the highest likelihood of achieving commercial success.
Our business could
suffer if we are unable to attract and retain key personnel.
The loss of the services
of members of senior management or other key personnel could delay or otherwise adversely impact the successful completion of our planned
CMC, research and development, preclinical studies and/or clinical trials or the commercialization of our therapeutic candidates or otherwise
affect our ability to manage our company effectively and to carry out our business plan and raise necessary funds to continue our development
plans. In March 2026, our Chief Executive Officer, Gil Efron, announced his intention to step down from his role as Chief Executive Officer
in August 2026, due to health considerations. The Board of Directors has initiated a formal search process to appoint a new Chief Executive
Officer. Management transitions may create uncertainty and involve a diversion of resources and management attention, be disruptive to
our daily operations or impact public or market perception, any of which could negatively impact our ability to operate effectively or
execute our strategies.
High demand exists for senior
management and other key personnel in the pharmaceutical industry. There can be no assurance that we will be able to continue to retain
and attract such personnel, including a new Chief Executive Officer. Although we have entered into employment or consultancy agreements
with every member of our senior management team, members of our senior management team may resign at any time. We do not maintain key-person
life insurance for any of our personnel.
Our growth and success also
depend on our ability to attract and retain additional highly qualified scientific, technical, business development, marketing, managerial
and finance personnel. If we expand our research and clinical development or purchase or in-license new products or product candidates,
we may need to expand our qualified personnel to advance the development and commercialization of our products. In addition, if we elect
to independently commercialize any therapeutic candidate, we will need to expand our marketing and sales capabilities. We experience
intense competition for qualified personnel, and the existence of non-competition agreements between prospective employees and their
former employers may prevent us from hiring those individuals or subject us to liability from their former employers. While we attempt
to provide competitive compensation packages to attract and retain key personnel, many of our competitors are likely to have greater
resources and more experience than we have, making it difficult for us to compete successfully for key personnel. Compensation packages
for our senior officers are subject to approval of our compensation committee and board of directors (the “Board”) and, in
certain instances, our shareholders. We may not be able to achieve the required corporate approvals for proposed compensation packages,
further making it difficult for us to compete successfully with other companies to attract and retain key personnel. If we cannot attract
and retain sufficiently qualified technical employees on acceptable terms, we may not be able to develop and commercialize competitive
therapeutic candidates. Further, any failure to effectively integrate new personnel could prevent our business from successfully growing.
We are an international
business, and we are exposed to various global and local risks that could have an adverse effect on our business.
We operate our business in
multiple international jurisdictions. Such operations could be affected by changes in foreign exchange rates, capital and exchange controls,
travel restrictions, public health restrictions, expropriation and other restrictive government actions, changes in intellectual property
legal protections and remedies, taxation regimes, trade regulations and procedures and actions affecting approval, production, export
and import of pharmaceutical products, pricing, and marketing of, reimbursement for and access to, our products, as well as by political
unrest, unstable governments and legal systems and inter-governmental disputes. Any of these changes could adversely affect our business.
In addition, there is current uncertainty about the future relationship between the United States and other countries with respect to
trade policies, taxes, government regulations and tariffs and we cannot predict whether, and to what extent, U.S. trade policies will
change in the future. If the conditions in the global economies remain uncertain or continue to be volatile, or if they deteriorate,
including as a result of the impact of military conflict, terrorism or other geopolitical events, such as military or political instability
in Israel or the region or changes in U.S. relations with other countries, our business, operating results and financial condition may
be materially adversely affected.
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Our subsidiary, TyrNovo,
has received Israeli governmental grants to assist in the funding of its research and development activities. The IIA grants which TyrNovo’s
technology, including NT219, has received for research and development expenditures restrict its ability to manufacture products and
transfer (including by way of license for R&D purposes) know-how outside of Israel and require it to satisfy specified conditions.
In addition, we may encounter difficulties partnering TyrNovo’s therapeutic candidates with entities outside of Israel due to certain
restrictions regarding manufacturing and transferring of know-how (including by a way of license for R&D purposes) outside of Israel
imposed due to the receipt of the IIA grants. We may also apply to other governmental non-dilutive funding sources, which if granted,
may impose limitation on our intellectual property or other restrictions
TyrNovo’s technologies,
including NT219, were developed, in part, with grants from the Israel Innovation Authority, or IIA (formerly known as the Office of the
Chief Scientist of the Ministry of Economy and Industry) in the aggregate amount of approximately NIS 5.5 million (or approximately $1.72
million). As of December 31, 2025, TyrNovo had not paid any royalties to the IIA. The requirements and restrictions for such grants are set forth in the Encouragement of Research, Development
and Technological Innovation in Industry Law, 5744-1984, or the Innovation Law, the IIA’s rules and guidelines and the terms of
these grants.
In general, the recipients
of IIA grants are obligated to pay the IIA royalties from the revenues generated from the sale of products and related services developed
as a result of a research and development program funded, in whole or in part, by the IIA, at rates which are determined under the IIA’s
rules and guidelines (generally of 3% to 6% on sales of IIA-funded products or related services, which rates may be increased under certain
circumstances) up to the aggregate amount of the total grants received by the IIA (which may be increased under certain circumstances,
as described below), plus annual interest (as determined in the IIA’s rules and guidelines). Following the full payment of such
royalties and interest, there is generally no further liability for royalty payments; however, other restrictions under the Innovation
Law continue to apply, as described below.
Under the IIA’s rules
and guidelines, TyrNovo is generally prohibited from manufacturing products developed using the IIA funding outside of the State of Israel
without the prior approval of the IIA (except for the transfer of less than 10% of the manufacturing capacity in the aggregate which
requires only a notice) and subject to payment of increased royalties (up to 300% of the grant amount plus accrued interest, depending
on the manufacturing volume that is performed outside of Israel). TyrNovo received the IIA’s approval for the production of NT219’s
API and final product by certain third-party manufacturers outside of Israel in consideration for (among other things) the future payment
of increased royalties as stipulated under the IIA’s rules and guidelines. Additionally, under the IIA’s rules and guidelines,
TyrNovo is prohibited from transferring the IIA-funded know-how and related intellectual property rights outside of the State of Israel,
except under limited circumstances and only with the prior approval of the IIA. TyrNovo may not receive the required approvals for any
proposed transfer, and even if received, TyrNovo may be required to pay the IIA a redemption fee of up to 600% of the grant amounts (less
paid royalties, if any, and depreciation, but no less than the total grants received) plus accrued interest. Approval of the transfer
of know-how to an Israeli company is also required, and may be granted if the recipient assumes all of our responsibilities towards the
IIA, including the restrictions on the transfer of know-how and the manufacturing rights outside of Israel and the obligation to pay
royalties, and, although such transfer will not be subject to the payment of a redemption fee, there will be an obligation to pay royalties
to the IIA from the income of such sale transaction as part of the royalty payment obligation. No assurance can be given that approval
for any such transfer, if requested, will be granted.
These restrictions may impair
our ability to perform or outsource manufacturing outside of Israel or otherwise transfer or sell TyrNovo’s IIA funded know-how
outside of Israel. Furthermore, the consideration available to TyrNovo’s and/or our shareholders in a transaction involving the
transfer outside of Israel of know-how developed with IIA funding (such as a merger or similar transaction) may be reduced by any amounts
that TyrNovo is required to pay to the IIA. If TyrNovo fails to comply with the requirements of the Innovation Law and the IIA’s
rules and guidelines, TyrNovo may be required to return certain grants previously received along with interest and penalties and may
become subject to criminal proceedings.
In addition, we may apply
in the future to other governmental non-dilutive funding sources which may involve certain restrictions on our future business conduct,
including but not limited to the transfer of intellectual property rights and/or the refund of grants or loans.
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We have in the past,
and may in the future, become subject to litigation or claims arising in or outside the ordinary course of business that could negatively
affect our business operations and financial condition.
We have in the past, and
may in the future, become subject to litigation or claims arising in or outside the ordinary course of business (other than intellectual
property infringement actions) that could negatively affect our business operations and financial condition, including securities class
actions and shareholder derivative actions, both of which are typically expensive to defend. Such claims and litigation proceedings may
be brought by third parties, including our competitors, advisors, service providers, partners or collaborators, employees, and governmental
or regulatory bodies. For information on past legal proceedings, please see “Item 8. Financial Information – A. Consolidated
Statements and Other Financial Information – Legal Proceedings.” Any claims and lawsuits, and the disposition of such claims
and lawsuits, could be time-consuming and expensive to resolve, divert management attention and resources, and lead to attempts on the
part of other parties to pursue similar claims. We may not be able to determine the amount of any potential losses and other costs we
may incur due to the inherent uncertainties of litigation and settlement negotiations. In the event we are required or decide to pay
amounts in connection with any claims or lawsuits, such amounts could be significant and could have a material adverse impact on our
liquidity, business, financial condition and results of operations. In addition, depending on the nature and timing of any such dispute,
a resolution of a legal matter could materially affect our future operating results, our cash flows or both. Additionally, we may be
unable to maintain our existing directors’ and officers’ liability insurance in the future at satisfactory rates or adequate
coverage amounts and may incur significant increases in insurance costs.
Risks Related to Our Industry
Even if our oncology
therapeutic candidates or any other therapeutic candidate that we develop or in-license in the future receive regulatory approval, they
may not become or remain commercially viable products.
In the event that our oncology
therapeutic candidates and/or any other therapeutic candidate that we may develop or acquire in the future are approved for commercialization
by the FDA or a foreign authority, they may not be commercially viable products. For example, if we or our potential commercialization
partners receive regulatory approval to market a therapeutic candidate, approval may be subject to limitations on the indicated uses
or subject to labeling or marketing restrictions which could materially and adversely affect the marketability and profitability of the
therapeutic candidate. In addition, a new therapeutic candidate may appear promising at an early stage of development or after preclinical
studies and/or clinical trials but never reach the market, or it may reach the market but not result in sufficient product sales, if
any. A therapeutic candidate may not result in commercial success for various reasons, including:
● difficulty in large-scale manufacturing, including yield and quality;
● low market acceptance by physicians, healthcare payers, patients and the medical community as a result of lower demonstrated clinical safety or efficacy compared to other products, prevalence and severity of adverse side effects, or other potential disadvantages relative to alternative treatment methods;
● insufficient or unfavorable levels of reimbursement from government or third-party payers, such as insurance companies, health maintenance organizations and other health plan administrators;
● infringement on proprietary rights of others for which we or our potential commercialization partners have not received licenses;
● incompatibility with other therapeutic candidates;
● other potential advantages of alternative treatment methods and competitive forces that may make it more difficult for us to penetrate a particular market segment;
● ineffective marketing and distribution support;
● lack of significant competitive advantages over existing products on the market;
● lack of cost-effectiveness; or
● timing of market introduction of competitive products.
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If we are unable, either
on our own or through third parties, to manufacture, commercialize and market our oncology therapeutic candidates or any other therapeutic
candidates that we may develop or acquire in the future when planned, or develop or acquire commercially viable therapeutic candidates,
we may not achieve any market acceptance or generate revenue.
The markets for our
oncology therapeutic candidates are rapidly changing and competitive, and new drug delivery mechanisms, drug delivery technologies, new
drugs and new treatments which may be developed by others could impair our ability to maintain and grow our business and remain competitive.
The pharmaceutical and biotechnology
industry is highly competitive, and we face significant competition from many pharmaceutical, biopharmaceutical and biotechnology companies
that are researching and marketing products designed to address the indications treated by our oncology therapeutic candidates. There
are various other companies that currently market or are in the process of developing products that address all of the indications or
diseases treated by our therapeutic candidates, some of them are in a more progressed stage of development than us and may reach the
market before we do.
New drug delivery mechanisms,
drug delivery technologies, new drugs and new treatments that have been developed or that are in the process of being developed by others
may render our oncology therapeutic candidates noncompetitive or obsolete, or we may be unable to keep pace with technological developments
or other market factors. Some of these technologies may have an entirely different platform or means of treating the same indications
as CAPTN-3, our tri-specific platform with its leading therapeutic candidates, IM1240 and IM1305, CM24 and NT219, or other therapeutic
candidates that we may develop or in-license in the future. Technological competition from pharmaceutical and biotechnology companies,
universities, governmental entities and others, is intense and is expected to increase. Many of these entities have significantly greater
research and development capabilities, human resources and budgets than we do, as well as substantially more marketing, manufacturing,
financial and managerial resources. These entities represent significant competition for us. Acquisitions of, or investments in, competing
pharmaceutical or biotechnology companies by large corporations could increase such competitors’ financial, marketing, manufacturing
and other resources.
The potential widespread
acceptance of therapies that are alternatives to ours may limit market acceptance of our formulations or therapeutic candidates, even
if commercialized. Many of our targeted diseases and conditions can also be treated by other medications or drug delivery technologies.
These treatments may be widely accepted in medical communities and have a longer history of use. The established use of these competitive
drugs may limit the potential for our oncology therapeutic candidates to receive widespread acceptance.
Third-party payers
may not adequately reimburse customers for our oncology therapeutic candidates, if approved for marketing in the United States or other
markets, and such oncology therapeutic candidates might not be purchased or used, which may result in our revenues and profits not developing
or increasing.
Our revenues and profits
will depend heavily upon the availability of adequate coverage and reimbursement for the use of our oncology therapeutic candidates,
if approved, from governmental and/or other third-party payers, both in the U.S. and in foreign markets. There may be significant delays
in obtaining coverage for newly approved therapeutic candidates. Moreover, eligibility for coverage does not necessarily signify that
an approved product will be reimbursed in all cases or at a sufficient rate, including one that covers our costs, such as research, development,
manufacture, sale, and distribution costs. Accordingly, even if we succeed in bringing one or more of our therapeutic candidates to the
market, they may not be considered cost-effective, and the amount reimbursed may be insufficient to allow us to sell our approved products
on a competitive basis. Reimbursement by a third-party payer may depend upon a number of factors, including the third-party payer’s
determination that the use of an approved product is, among others:
● a covered benefit under its health plan;
● safe, effective and medically necessary;
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● appropriate for the specific patient;
● cost-effective, including compared to approved alternate therapies; and
● neither experimental nor investigational.
Obtaining reimbursement approval
for an approved product from each government or other third-party payer is a time-consuming and costly process that could require us
or our current or potential development and commercialization partners to provide supporting scientific, clinical and cost-effectiveness
data for the use of an approved product to each payer. Even when a payer determines that an approved product is eligible for reimbursement,
the payer may impose coverage limitations that preclude or restrict payment for some uses that are approved by the FDA or other foreign
regulatory authorities. Reimbursement rates may vary according to the use of the approved product and the clinical setting in which it
is used, may be based on payments allowed for lower-cost products that are already reimbursed, may be incorporated into existing payments
for other products or services, and may reflect budgetary constraints or imperfections in Medicare, Medicaid or other data used to calculate
these rates.
Increasingly, the third-party
payers who reimburse patients or healthcare providers, such as government and private insurance plans, are seeking greater upfront discounts,
additional rebates, and other concessions to reduce the prices for approved products. If the price we are able to charge for any approved
product, or the reimbursement provided for such approved product, is inadequate or becomes inadequate in light of our development and
other costs, our return on investment could be adversely affected.
In the U.S., there have been,
and we expect that there will continue to be, federal and state proposals to constrain expenditures for medical products and services
which may affect payments for our oncology therapeutic candidates, if approved. We believe that legislation that reduces reimbursement
for our oncology therapeutic candidates, if approved, could adversely impact how much or under what circumstances healthcare providers
will prescribe or administer our oncology therapeutic candidates, if approved. This could materially and adversely impact our business
by reducing our ability to generate revenue, raise capital, obtain additional collaborators and market our oncology therapeutic candidates,
if approved. At this stage, we are unable to estimate the extent of the direct or indirect impact of any such federal and state proposals.
Further, coverage and reimbursement
policies are subject to change and are not always consistent across different payers or even federal healthcare programs. For example,
the Centers for Medicare and Medicaid Services (CMS) frequently change product descriptors, coverage policies, product and service codes,
payment methodologies and reimbursement values which may be revised or interpreted in ways that could significantly affect our business
and products. Government and private third-party payers often follow Medicare coverage policy and payment limitations in setting their
own reimbursement rates. Moreover, both CMS and other third-party payers may have sufficient market power to demand significant price
reductions. Such price reductions and/or other significant coverage policies or payment limitations could materially and adversely affect
our business, financial condition and results of operations.
Legislative or regulatory
reform of the healthcare system in the United States may harm our business.
In the United States, there
have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other
things, impact our business and any of our therapeutic candidates or any other therapeutic candidate that we may develop or acquire in
the future. We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in
more rigorous coverage criteria, additional downward pressure on the price, and/or unfavorable reimbursement rates that we, or any future
collaborators, may receive for any product candidates we obtain marketing approval for and our business could be materially harmed.
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On March 23, 2010, President
Obama signed the “Patient Protection and Affordable Care Act” (P.L. 111-148) (the “ACA”) and on March 30, 2010,
he signed the “Health Care and Education Reconciliation Act” (P.L. 111-152), collectively commonly referred to as the “Healthcare
Reform Law.” The Healthcare Reform Law included a number of new rules regarding health insurance, the provision of healthcare,
conditions to reimbursement for healthcare services provided to Medicare and Medicaid patients, and other healthcare policy reforms.
Through the law-making process, substantial changes have been and continue to be made to the current system for paying for healthcare
in the U.S., including changes made to extend medical benefits to certain Americans who lacked insurance coverage and to contain or reduce
healthcare costs (such as by reducing or conditioning reimbursement amounts for healthcare services and drugs, and imposing additional
taxes, fees, and rebate obligations on pharmaceutical and medical device companies). This legislation was one of the most comprehensive
and significant reforms ever experienced by the U.S. in the healthcare industry and has significantly changed the way healthcare is financed
by both governmental and private insurers. This legislation has impacted the scope of healthcare insurance and incentives for consumers
and insurance companies, among others. Additionally, the Healthcare Reform Law’s provisions were designed to encourage providers
to find cost savings in their clinical operations. Pharmaceuticals represent a significant portion of the cost of providing care. This
environment has caused changes in the purchasing habits of consumers and providers and resulted in specific attention to the pricing
negotiation, product selection and utilization review surrounding pharmaceuticals which could result in lower pricing and/or reduced
market acceptance for any drug products we may commercialize in the U.S. in the future. At this stage, it is difficult to estimate the
full extent of the direct or indirect impact of the Healthcare Reform Law on us.
The healthcare regulatory
environment has seen significant changes in recent years and is still in flux. Legislative initiatives to modify, limit, replace,
or repeal the ACA and judicial challenges have continued for over a decade. However, as of the Supreme Court’s ruling ordering
the dismissal of, arguably, the most promising case challenging the ACA to-date on June 17, 2021, it appears that the ACA will remain
in-effect in its current form for the foreseeable future; however, we cannot predict what additional challenges may arise in the future,
the outcome thereof, or the impact any such actions may have on our business. Further, the current Trump administration has taken several
measures focusing on healthcare and drug pricing and access in particular. For example, President Trump has signed multiple executive
orders addressing drug pricing including: on April 15, 2025, outlining several actions the Secretary of the Department of HHS must take
to optimize healthcare regulations that will provide access to prescription drugs at lower costs; on May 5, 2025, aiming to promote domestic
production of critical medicines; and on May 12, 2025, aiming to establish a most-favored-nation (“MFN”) drug pricing policy
that would tie U.S. drug prices to the prices paid for drugs in other countries. On November 6, 2025, CMS announced a new voluntary payment
initiative called the GENEROUS Model (GENErating cost Reductions for U.S. Medicaid Model) where drug manufacturers may voluntarily offer
supplemental rebates to participating state Medicaid programs that are intended to provide such Medicaid programs with a MFN price for
participating manufacturers’ products. On December 23, 2025, CMS published two proposed rules that would incorporate MFN pricing
principles into federal reimbursement for prescription drugs. The first proposal, the GLOBE Model (Global Benchmark for Efficient Drug
Pricing Model) for Medicare Part B, would require manufacturers of specified single source drugs and sole source biologics to pay incremental
rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and eligibility
criteria. The second proposal, the GUARD Model (Guarding U.S. Medicare Against Rising Drug Costs) for Medicare Part D, would similarly
mandate manufacturer rebates for qualifying sole source drugs where the Medicare net price exceeds an MFN benchmark derived from international
reference pricing methodologies. On February 5, 2026, the Trump administration launched the TrumpRx platform designed to allow consumers
to purchase certain drugs at reduced prices as negotiated between the drug manufacturers and the Trump administration.
On the legislative front,
the American Rescue Plan Act of 2021 was signed into law on March 11, 2021, which, in relevant part, eliminates the statutory Medicaid
drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source drugs and innovator multiple source
drugs, beginning January 1, 2024. And, in July 2021, the Biden administration released an executive order entitled, “Promoting
Competition in the American Economy,” with multiple provisions aimed at prescription drugs. In response, on September 9, 2021,
HHS released a “Comprehensive Plan for Addressing High Drug Prices” that outlines principles for drug pricing reform and
sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take
to advance these principles. And, in August 2022, the Inflation Reduction Act (“IRA”) was signed into law, which will, among
other things, allow U.S. Department of Health and Human Services (“HHS”) to negotiate the selling price of certain drugs
and biologics that the Centers for Medicare & Medicaid Services (“CMS”) reimburses under Medicare Part B and
Part D, although only high-expenditure single-source drugs that have been approved for at least 7 years (11 years for
biologics) can be selected by CMS for negotiation, with the negotiated price taking effect two years after the selection year.
The negotiated prices, which first became effective in 2026, will be capped at a statutory ceiling price. Beginning in October 2023,
the IRA also began penalizing drug manufacturers that increase prices of Medicare Part B and Part D drugs at a rate greater
than the rate of inflation. The IRA permits the Secretary of HHS to implement many of these provisions through guidance, as opposed to
regulation, for the initial years. Manufacturers that fail to comply with the IRA may be subject to various penalties, including
civil monetary penalties. On July 4, 2025, President Trump signed the One Big Beautiful Bill Act into law which, among other things,
is expected to reduce funding to federal healthcare programs, imposes additional requirements to be eligible for healthcare, and clarifies
exclusions for orphan drugs under IRA’s Drug Price Negotiation Program. On January 15, 2026, President Trump called on Congress
to enact “The Great Healthcare Plan,” to, among other things, codify and expand MFN pricing, lower government subsidies to
private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase,
and enact restrictions on pharmacy benefit managers. These actions and policies may significantly reduce U.S. drug prices, potentially
impacting manufacturers’ global pricing strategies and profitability, while increasing their operational costs and compliance risks.
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At the state level, individual
states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical pricing, including
price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency
measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. A number of states, for example,
require drug manufacturers and other entities in the drug supply chain, including health carriers, pharmacy benefit managers, wholesale
distributors, to disclose information about pricing of pharmaceuticals, including, but not limited to, information in connection with
new product launches that exceed certain levels as identified in the relevant statutes. For example, in June 2016 Vermont became the
first state to pass legislation requiring certain drug companies to disclose information relating to justification of certain price increases,
and many other states have since followed suit. These efforts and any other such legislation requiring publication of drug costs could
materially and adversely impact our business, financial condition, and results of operations by promoting a reduction in drug prices
or encouraging purchasers to use other low-cost, established drugs or therapies.
There is uncertainty as to
what healthcare programs and regulations may be implemented or changed at the federal and/or state level in the U.S. or the effect of
any future legislation or regulation on us. Furthermore, we cannot fully assess the impact that President Trump’s second term will
have on healthcare programs and regulations or the pharmaceutical industry in general. However, it is possible that such initiatives
could have an adverse effect on our ability to obtain approval and/or successfully commercialize products in the U.S. in the future,
as applicable.
We are subject to additional
federal and state healthcare laws and regulations relating to our business, and our failure to comply with those laws could have a material
adverse effect on our results of operations and financial conditions.
Healthcare providers, physicians,
and third-party payers play a primary role in the recommendation and prescription of any therapeutic candidates for which we obtain marketing
approval. Our current or future arrangements with healthcare providers, physicians, marketers or sales personnel, third-party payers,
patients, and others in a position to refer, recommend, purchase, or use our products may expose us to broadly applicable U.S. federal
and state fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships
through which we market, sell and distribute any product candidates for which we obtain FDA approval. The applicable healthcare laws
to which we have been and/or may be subject include, but are not limited to, the following:
● the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, in exchange for or to induce either the referral of an individual for, or the purchase, order or recommendation of, any good or service for which payment may be made under government healthcare programs such as the Medicare and Medicaid programs;
● the federal Anti-Inducement Law (also known as the Civil Monetary Penalties Law), which prohibits a person from offering or transferring remuneration to a Medicare or State healthcare program beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular provider, practitioner or supplier of any item or service for which payment may be made, in whole or in part, by Medicare or a State healthcare program;
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● the Ethics in Patient Referrals Act of 1989, commonly referred to as the Stark Law, which prohibits physicians from referring Medicare or Medicaid patients for certain designated health services where that physician or family member has a financial relationship with the entity providing the designated health service, unless an exception applies;
● federal false claims laws that prohibit, among other things, individuals or entities from knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid or other government healthcare programs that are false or fraudulent;
● the so-called federal “Sunshine Act”, which requires certain pharmaceutical and medical device companies to monitor and report certain payments and other transfers of value to physicians, as defined by such law, certain other healthcare professionals, and teaching hospitals and ownership and investment interests held by physicians and their immediate family members to CMS for disclosure to the public;
● the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) and its implementing regulations, which impose obligations on certain covered entities and their business associates with respect to safeguarding the privacy, security, and transmission of individually identifiable health information, and require notification to affected individuals, regulatory authorities, and potentially the media of certain breaches of security of individually identifiable health information;
● HIPAA’s fraud and abuse provisions, which impose criminal and civil liability for executing a scheme to defraud any healthcare benefit program, or knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services;
● the federal Food, Drug, and Cosmetic Act, which, among other things, strictly regulate drug product and medical device marketing, prohibits manufacturers from marketing such products for off-label use, and regulates the distribution of samples;
● federal criminal laws that prohibit executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters; and
● state law equivalents of each of the above federal laws, such as anti-kickback, false claims, transparency and reporting laws which may apply to items or services reimbursed by any third-party payer, including commercial insurers, many of which differ from each other in significant ways, thus complicating compliance efforts.
Additionally, there has been
a trend of increased federal and state regulation of payments made to physicians or others in a position to refer, purchase, or recommend
drug products. For example, some states impose a legal obligation on companies to adhere to voluntary industry codes of behavior (e.g.,
the PhRMA Code), which apply to pharmaceutical companies’ interactions with healthcare providers, some mandate implementation of
corporate compliance programs, along with the tracking and reporting of gifts, compensation, and other remuneration to physicians, and
some states limit or prohibit such gifts. Further, the Healthcare Reform Law, among other things, amended the intent requirement of the
federal Anti-Kickback Statute so that a person or entity can now be found guilty of fraud or an anti-kickback violation without actual
knowledge of the statute or specific intent to violate it. In addition, the Healthcare Reform Law provides that the government may assert
that a claim including items or services resulting from a violation of the federal Anti-Kickback Statue constitutes a false or fraudulent
claim for purposes of the False Claims Act.
The scope and enforcement
of federal and state healthcare laws are broad and often uncertain and subject to change in the current environment of healthcare reform,
especially in light of the lack of applicable precedent and guidance in many areas. Compliance efforts may involve substantial costs
and resources and federal or state regulatory authorities may review and challenge our prior, current, and/or future activities under
these laws. Any action against us for an alleged or suspected violation, regardless of the outcome or success of our defense against
such actions, could have a material adverse effect on our reputation, business, results of operations, and financial condition including
causing us to incur significant legal expenses and divert our management’s attention from the operation of our business. If our
operations or business arrangements are found to be in violation of any such requirements, we may be subject to penalties, including
civil or criminal penalties, monetary damages, the curtailment or restructuring of our operations, or exclusion from participation in
government contracting, healthcare reimbursement or other government programs, including Medicare and Medicaid, any of which could adversely
affect our financial results.
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We could be exposed
to significant drug product liability claims, which could be time consuming and costly to defend, divert management attention and adversely
impact our ability to obtain and maintain insurance coverage.
The clinical trials that
we conduct, conducted or may have to conduct, and the testing, manufacturing, marketing and commercial sale of our oncology therapeutic
candidates or any other therapeutic candidates that we may develop or acquire in the future, involve and will involve an inherent risk
that significant liability claims may be asserted against us. Should we decide to seek additional insurance against such risks before
we initiate clinical trials or commence our product sales, there is a risk that such insurance will be unavailable to us, or if it can
be obtained at such time, that it will be available only at an unaffordable cost. Even if we obtain insurance, it may prove inadequate
to cover claims or litigation costs, especially in the case of wrongful death claims. Product liability claims or other claims related
to our therapeutic candidates or any other therapeutic candidate that we may develop or acquire in the future, regardless of their outcome
and merit, could require us to spend significant time and money in litigation or to pay significant settlement amounts or judgments.
Any successful product liability or other claim may prevent us from obtaining adequate liability insurance in the future on commercially
desirable or reasonable terms. An inability to obtain sufficient insurance coverage at an acceptable cost or otherwise to protect against
potential product liability claims could prevent or inhibit the commercialization of our therapeutic candidates or any other therapeutic
candidates that we may develop or acquire in the future. A product liability claim could also significantly harm our reputation and delay
market acceptance of our therapeutic candidates or any other therapeutic candidate that we may develop or acquire in the future.
Our business involves
risks related to handling regulated substances which could severely affect our ability to conduct research and development of our therapeutic
candidates.
In connection with our current
or potential development and commercialization partners’ research and clinical development activities, as well as the manufacture
of materials and therapeutic candidates, we and our current or potential development and commercialization partners are subject to foreign,
federal, state and local laws, rules, regulations and policies governing the use, generation, manufacture, storage, air emission, effluent
discharge, handling and disposal of certain materials, biological specimens and wastes. We and our current or potential development and
commercialization partners may be required to incur significant costs to comply with environmental and health and safety regulations
in the future. Our research and clinical development, as well as the activities of our manufacturing and current or potential development
and commercialization partners, both now and in the future, may involve the controlled use of hazardous materials, including but not
limited to certain hazardous chemicals. We cannot eliminate the risk of accidental contamination or injury from these materials. In the
event of such an occurrence, we could be held liable for any damages that result, and any such liability could exceed our resources.
Unfavorable macroeconomic
conditions and other adverse macroeconomic factors could adversely affect our business, financial condition, cash flow or results of
operations.
Unfavorable macroeconomic
conditions and other adverse macroeconomic factors have resulted, among other matters, in tightening in the debt and equity markets,
and high levels of inflation. For example, the tightening of the equity markets makes it more difficult to raise capital at a reasonable
valuation, or at all. In addition, the U.S. Bureau of Labor Statistics has reported for the period from January 2023 to January 2024,
the Consumer Price Index for All Urban Consumers rose 3.1 percent, from January 2024 to January 2025, the Consumer Price Index for All
Urban Consumers rose 3.0 percent. If the inflationary pressure continues for a prolonged period, it may continue to result in increased
costs of labor, cost of clinical trials, and costs of manufacturing which could adversely affect our results of operations. Furthermore,
in recent years, there has been a significant increase in interest rates that impacted the cost of debt, liquidity and valuations of
companies and other assets.
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Our
results of operations could be adversely affected by general conditions in the global and local macroeconomic economic conditions affecting
the financial markets. An economic downturn could result in a variety of risks to our business, including weakened demand for our therapeutic
candidates and our inability to raise additional capital when needed on acceptable terms, if at all. A weak or declining economy could
also strain our partners and suppliers, possibly resulting in supply disruption, or cause future customers to delay making payments for
our products.
Trade
disputes, trade restrictions, tariffs and other geopolitical tensions between the United States and other countries, including Israel,
may also exacerbate unfavorable macroeconomic conditions, including inflationary pressures, foreign exchange volatility, financial market
instability, and economic recessions or downturns in the United States, Israel, or globally, which may limit our access to capital, or
otherwise negatively impact our business and operations.
Any
of the foregoing could harm our business and we cannot anticipate all of the ways in which the current economic climate and financial
market conditions could adversely impact our business.
Our
business and operations may be materially adversely affected in the event of computer system failures or security or breaches due to
cyber-attacks or cyber intrusions, including ransomware, phishing attacks and other malicious intrusions.
In
recent years, cybersecurity threats have become a greater risk and focus for companies. In particular, ransomware attacks, where a hacker
locks and threatens to delete or disclose the victim’s data unless a ransom is paid, has become a major risk. We and those of our
third-party contract manufacturers and other third parties on which we rely are at risk of cyber-attacks or cyber intrusions via the
Internet, computer viruses, break-ins, malware, ransomware, phishing attacks, hacking, denial-of-service attacks or other attacks and
similar disruptions from unauthorized use of, or access to, computer systems (including from internal and external sources). These types
of incidents continue to be prevalent and pervasive across industries, including in our industry. In addition, we expect information
security risks to continue to increase due to the proliferation of new technologies and the increased sophistication and activities of
organized crime, hackers, terrorists and other external parties, including foreign state actors.
Despite
the implementation of security measures, our internal computer systems, and those of our third-party contract manufacturers and other
third parties on which we rely, are vulnerable to damage from computer viruses, unauthorized access, cyber-attacks, cyber intrusions,
natural disasters, fire, terrorism, war, and telecommunication and electrical failures. If such an event were to occur and interrupt
our operations, it could result in a material disruption of our drug development programs. For example, the loss of clinical trial data
from ongoing or planned clinical trials could result in delays in our regulatory approval efforts and significantly increase our costs
to recover or reproduce the data. To the extent that any disruption or security breach results in a loss of or damage to our data or
applications, loss of trade secrets or inappropriate disclosure of confidential or proprietary information, including protected health
information or personal data of employees or former employees, access to our clinical data, we could incur liability and the further
development of our therapeutic candidates could be delayed.
Scrutiny
of sustainability and environmental, social, and governance (“ESG”) initiatives could increase our costs or otherwise adversely
impact our business.
In
recent years, attention has been given to corporate activities related to ESG practices from investors and other stakeholders with various
views on these topics. For example, certain institutional and individual investors have requested ESG-related information and disclosures
in order to incorporate ESG criteria into their investment and voting decisions. Such requests may result in increased costs, enhanced
compliance or disclosure obligations, or other adverse impacts on our business, financial condition or results of operations. If our
ESG practices and reporting do not meet investor or other stakeholder expectations, we may be subject to investor or regulator engagement
regarding such matters. In addition, our failure to comply with any applicable sustainability rules or regulations that could lead to
penalties and adversely impact our reputation, access to capital and employee retention. Such ESG matters may also impact our third-party
contract manufacturers and other third parties on which we rely, which may augment or cause additional impacts on our business, financial
condition, or results of operations.
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The
rapid development of artificial intelligence may negatively affect our business.
The
rapid development and increasing use of artificial intelligence (“AI”) technologies across the pharmaceutical and biotechnology
industries may create risks and uncertainties that could affect our business. Competitors, collaborators, CROs, and other third parties
may adopt AI-enabled tools that improve the speed, cost, or effectiveness of drug discovery, development, or other operations, potentially
placing us at a competitive disadvantage. In addition, the use of AI technologies by third parties with whom we interact may introduce
risks relating to data integrity, cybersecurity, confidentiality, intellectual property ownership, or regulatory compliance. The legal
and regulatory landscape governing AI technologies is evolving and may impose additional obligations or costs on industry participants.
Although the use of AI technologies are still evolving in our industry, the broader proliferation of AI may indirectly affect our business,
financial condition, results of operations, or competitive position.
Risks Related to Intellectual Property
Third-party
claims of intellectual property infringement and other legal challenges may require us to spend substantial time and money and could
prevent us from or delay us in developing or commercializing our therapeutic candidates. An adverse result in any infringement claims
or other legal challenges could have a material adverse effect on our business, results of operations and on our financial condition.
The development, manufacture,
use, offer for sale, sale or importation of our therapeutic candidates may infringe on the claims of third-party patents or other intellectual
property rights. The nature of claims contained in unpublished patent filings around the world is unknown to us, and it is impossible
to know which countries patent holders may choose for the extension of their filings under the Patent Cooperation Treaty, or other mechanisms.
We may not have identified all patents, published applications or published literature that may affect our business either by blocking
our ability to commercialize our products or potential products, by preventing the patentability of one or more aspects of our products
or potential products, or by covering the same or similar technologies that may affect our ability to market our products and potential
products. For example, we may not have conducted a patent clearance search sufficient to identify potentially obstructing third party
patent rights. Because patent applications in Europe, the United States and many other foreign jurisdictions are typically not published
until 18 months after filing, and publications in the scientific literature often lag behind actual discoveries, we cannot be certain
that others have not filed patent applications that may contain claims covering in part or in full our technologies, our product candidates
or the use of our product candidates. In certain limited circumstances, patent applications may remain confidential in the U.S. Patent
and Trademark Office, or the USPTO, until they issue as a U.S. patent. We cannot be certain that we or our licensors were the first to
file patent applications covering our product candidates. We also may not know whether our competitors filed patent applications for
technology covered by our pending applications. Competitors may have filed patent applications or received patents and may obtain additional
patents and proprietary rights that may block or compete in part or in full with our patents.
Additionally,
pending patent applications which have been published can, subject to certain limitations, be later amended in a manner that could cover
our technologies, our product candidates or the use of our product candidates. As a result, we may become party to, or threatened with,
future adversarial proceedings or litigation regarding patents with respect to our product candidates and technology. The scope of a
patent claim is determined by an interpretation of the law, the written disclosure in a patent and the patent’s prosecution history.
Our interpretation of the relevance or the scope of a patent or a pending application may be incorrect, which may negatively impact our
ability to market our drug candidates. We may incorrectly determine that our product candidates are not covered by a third-party patent
or may incorrectly predict whether a third party’s pending application will issue with claims of relevant scope. Our determination
of the expiration date of any patent in the United States or abroad that we consider relevant may be incorrect, which may negatively
impact our ability to develop and market our drug candidates. Our failure to identify and correctly interpret relevant patents may negatively
impact our ability to develop and market our drug candidates.
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Third
parties may assert that we are employing their proprietary technology without authorization. There may be third-party patents or patent
applications with claims to materials, formulations, methods of manufacture, or methods of treatment related to the use or manufacture
of our commercial products or drug product candidates. We cannot guarantee that any of our search and review is sufficiently complete
and thorough, nor can we be sure that we have identified each and every patent and pending application in the United States and abroad
that is relevant or necessary to the commercialization of our commercial products or drug product candidates. Because patent applications
can take many years to issue, there may be currently pending patent applications that may later result in issued patents that our commercial
products or drug product candidates may infringe. In addition, third parties may obtain patents in the future and claim that use of our
technologies infringes upon these patents. If any third-party patents were held by a court of competent jurisdiction to cover the manufacturing
process of any of our commercial products or drug product candidates, any molecules formed during the manufacturing process or any final
product itself, the holders of any such patents may be able to block our ability to import or otherwise continue commercialization of
such commercial product or to commercialize such drug product candidate unless we obtained a license under the applicable patents, or
until such patents expire or are finally determined to be invalid or unenforceable. Similarly, if any third-party patents were held by
a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture, or methods of use, the holders of
any such patents may be able to block our ability to continue the commercialization of our commercial products or to develop and commercialize
the applicable drug product candidate unless we obtained a license or until such patent expires or is finally determined to be invalid
or unenforceable.
In
the event of patent infringement claims, or to avoid potential claims, we may choose or be required to seek a license from a third-party
and would most likely be required to pay license fees or royalties or both. These licenses may not be available on acceptable terms,
or at all. Even if we were able to obtain a license, the rights may be non-exclusive, which could potentially limit our competitive advantage.
Ultimately, we could be prevented from commercializing a therapeutic candidate or be forced to cease some aspect of our business operations
if, as a result of actual or threatened patent infringement or other claims, we are unable to enter into licenses on acceptable terms.
Parties
making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further commercialize
our commercial products or develop and commercialize one or more of our drug product candidates. Defense of these claims, regardless
of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from our business.
In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys’
fees for willful infringement, pay royalties, redesign our infringing products or obtain one or more licenses from third parties, which
may be impossible or require substantial time and monetary expenditure.
The
cost to us of any intellectual property litigation or other infringement proceeding, even if resolved in our favor, could be substantial.
Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively because of their substantially
greater financial resources. Uncertainties resulting from the initiation and continuation or defense of intellectual property litigation
or other legal proceedings or litigation could have a material adverse effect on our ability to compete in the marketplace. Intellectual
property litigation and other proceedings may also absorb significant cash resources and management attention and time. Consequently,
we are unable to guarantee that we will be able to manufacture, use, offer for sale, sell or import our therapeutic candidates in the
event of an infringement action.
We
may be unable to adequately protect or enforce our rights to intellectual property, causing us to lose valuable rights. Loss of any of
our intellectual property rights may lead us to lose market share and could have an adverse effect on our business, results of operations
and financial condition.
Our
success depends, in part, on our ability, and the ability of our potential development and commercialization partners to obtain patent
protection for our therapeutic candidates, maintain the confidentiality of our trade secrets and know-how, operate without infringing
on the proprietary rights of others and prevent others from infringing our proprietary rights. We may become involved in proceedings,
including oppositions, post grant reviews, interferences, derivation proceedings, inter parties’ reviews, patent nullification
proceedings, or re-examinations challenging our patent rights or the patent rights of others, and the outcome of any such proceedings
are uncertain. An adverse determination in any such proceeding could reduce the scope of, or invalidate, important patent rights, allow
third parties to commercialize our technology, products and/or product candidates and compete directly with us without being obligated
to make any payments to us, or result in our inability to manufacture or commercialize products and/or product candidates without infringing
third-party patent rights. Litigation or other proceedings may fail and, even if successful, may result in substantial costs and distract
our management and other employees.
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In
addition, if the breadth or strength of protection provided by our patents and patent applications is threatened, it could dissuade companies
from collaborating with us to license, develop or commercialize current or future product candidates. Even if our patent applications
are successfully issued as patents, they may not be issued in a form that will provide us with any meaningful protection, prevent competitors
from competing with us, or otherwise provide us with any competitive advantage. Our competitors may be able to circumvent our patents
by developing similar or alternative technologies or products in a non-infringing manner.
Furthermore,
because of the substantial amount of discovery required in connection with intellectual property litigations in general, there is a risk
that some of our confidential information could be compromised by disclosure during intellectual property litigation or proceeding. Such
litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities
or any future sales, marketing or distribution activities. We may not have sufficient financial or other resources to conduct such litigation
or proceedings adequately. Most of our competitors are larger than we are and have substantially greater resources. They are, therefore,
likely to be able to sustain the costs of complex intellectual property litigation or proceedings more effectively than we can because
of their greater financial resources and more mature and developed intellectual property portfolios. Accordingly, despite our efforts,
we may not be able to prevent third parties from infringing, misappropriating or otherwise violating our intellectual property.
We
try to protect our proprietary position by, among other things, filing U.S. and other patent applications related to our therapeutic
candidates, inventions and improvements that may be important to the continuing development of our therapeutic candidates. Because the
patent position of pharmaceutical companies involves complex legal and factual questions, we cannot predict the validity and enforceability
of any patents we may obtain with certainty. The patent applications that we own or in-license may fail to result in issued patents with
claims that cover our product candidates in the United States or in other foreign countries. Publications of discoveries in the scientific
literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions remain confidential
for a period of time after filing, and some remain so until issued. We cannot be certain that we were the first to file any patent application
related to our product candidates, or whether we were the first to make the inventions claimed in our owned patents or pending patent
applications, nor can we know whether those from whom we license patents were the first to make the inventions claimed or were the first
to file. As a result, the issuance, scope, validity, enforceability and commercial value of our patent rights are highly uncertain. There
is no assurance that all potentially relevant prior art relating to our patents and patent applications has been found, which can invalidate
a patent or prevent a patent from issuing from a pending patent application. Even if patents do successfully issue, and even if such
patents cover our product candidates, third parties may challenge their validity, enforceability, or scope, which may result in such
patents being narrowed, found unenforceable or invalidated, which could allow third parties to commercialize our technology or products
and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing
third party patent rights. Furthermore, even if they are unchallenged, our patents and patent applications may not adequately protect
our intellectual property, provide exclusivity for commercial products or drug product candidates, prevent others from designing around
our claims or provide us with a competitive advantage. Any of these outcomes could impair our ability to prevent competition from third
parties, which may have a material adverse impact on our business.
Moreover,
the issuance of a patent, while presumed valid and enforceable, is not conclusive as to its validity or its enforceability and it may
not provide us with adequate proprietary protection or competitive advantages against competitors with similar products. Competitors
may also be able to design around our patents. Other parties may develop and obtain patent protection for more effective technologies,
designs or methods. We may not be able to prevent the unauthorized disclosure or use of our technical knowledge or trade secrets by consultants,
vendors, former employees and current employees.
Our
competitors may independently develop products similar to ours or design around or otherwise circumvent any patents that may be issued
to or licensed by us. Our pending patent applications, and those that we may file in the future or those we may license from third parties
may not result in patents being issued. If these patents are issued, they may not provide us with proprietary protection or competitive
advantages. The degree of future protection to be afforded by our proprietary rights is uncertain because legal means afford only limited
protection and may not adequately protect our rights or permit us to gain or keep our competitive advantage.
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Furthermore,
our ability to enforce our patent rights depends on our ability to detect infringement. It is difficult to detect infringers who do not
advertise the components that are used in their products. Moreover, it may be difficult or impossible to obtain evidence of infringement
in a competitor’s or potential competitor’s product, particularly in litigation in countries other than the U.S. that do
not provide an extensive discovery procedure. Any litigation to enforce or defend our patent rights, if any, even if we were to prevail,
could be costly and time-consuming and would divert the attention of our management and key personnel from its business operations. We
may not prevail in any lawsuits that we initiate and the damages or other remedies awarded if it were to prevail may not be commercially
meaningful.
Patent
rights are territorial; thus, the patent protection we have sought will only extend, if issued, to those countries, if any, in which
we will be issued patents. Even so, the laws of certain countries do not protect our intellectual property rights to the same extent
as do the laws of the United States. Competitors may successfully challenge any of our patents, produce similar drugs or products that
do not infringe such patents, or produce drugs in countries where we have not applied for patent protection or that do not respect such
patents. Furthermore, it is not possible to ascertain the scope of claims that will be allowed in published applications or which claims
of granted patents, if any, will be deemed enforceable in a court of law.
Filing,
prosecuting, and defending patents in all countries throughout the world would be prohibitively expensive, and our intellectual property
rights in some countries outside the United States can be less extensive than those in the United States. Consequently, we may not be
able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing
products made using our inventions in and into the United States or other jurisdictions. As part of ordinary course prosecution and maintenance
activities, we determine whether to seek patent protection outside the U.S. and in which countries. This also applies to patents we have
acquired or in-licensed from third parties. In some cases, this means that we, or our predecessors in interest or licensors of patents
within our portfolio, have sought patent protection in a limited number of countries for patents covering our product candidates. Competitors
may use our technologies in jurisdictions where we have not obtained or are unable to adequately enforce patent protection to develop
their own products and further, may export otherwise infringing products to territories where we have patent protection, but enforcement
is not as strong as that in the United States. These products may compete with our products, and our patents or other intellectual property
rights may not be effective or sufficient to prevent them from competing.
Many
companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The
legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets,
and other intellectual property protection, particularly those relating to pharmaceutical products, which could make it difficult for
us to stop the infringement of our patents, the reproduction of our manufacturing or other know-how or marketing of competing products
in violation of our proprietary rights generally. Proceedings to enforce our patent rights in foreign jurisdictions, whether or not successful,
could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk
of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert
claims against us. We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be
commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the world may be inadequate to obtain
a significant commercial advantage from the intellectual property that we develop or license.
After
the completion of development and registration of any future patents, third parties may still act to manufacture or market our therapeutic
candidates in infringement of our patent protected rights. Such manufacture or marketing of our therapeutic candidates in infringement
of any patent-protected rights is likely to cause us damage and lead to a reduction in the prices of our therapeutic candidates, thereby
reducing our potential profits.
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We
may invest a significant amount of time and expense in the development of our therapeutic candidates only to be subject to significant
delay and patent litigation before they may be commercialized. In addition, due to the extensive time needed to develop, test and obtain
regulatory approval for our therapeutic candidates, any patents that may be issued that protect our therapeutic candidates may expire
early during commercialization. This may reduce or eliminate any market advantages that such patents may give us. Patents have a limited
lifespan. In the United States, if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years from
its earliest U.S. non-provisional filing date. Various extensions may be available, but the life of a patent, and the protection it affords,
is limited. Even if patents covering our product candidates are obtained, once the patent life has expired for a product candidate, we
may be open to competition from competitive medications. Following patent expiration, we may face increased competition through the entry
of generic products into the market and a subsequent decline in market share and profits.
We
are developing some of our therapeutic candidates in collaboration with academic and other research institutes and biopharmaceutical
companies. While we attempt to ensure that our intellectual property is protected under the terms of our collaboration agreements with
such institutes, these institutes may have claims to our intellectual property.
We do not have patent
protection in certain countries, and we may not be able to effectively enforce our intellectual property rights in certain countries,
which could significantly erode the market for our product candidates.
We intend to seek regulatory
approval to market our oncology therapeutic candidates in a number of foreign countries. Our oncology therapeutic candidates are not
protected by patents in certain countries, which means that competitors may be free to sell products that incorporate the same technology
that is used in our products in those countries. In addition, the laws and practices in some foreign countries may not protect intellectual
property rights to the same extent as in the United States. We or our licensors may not be able to effectively obtain, maintain or enforce
rights with respect to the intellectual property relating to our oncology product candidates in those countries. In that regard, we believe
that although China is one of the largest potential markets for some of our products under development, some of our product candidates
are less protected by patents in China than in the U.S., and it may be difficult to enforce intellectual property rights in China. Our
lack of patent protection in one or more countries, or the inability to obtain, maintain or enforce intellectual property rights in one
or more countries, could adversely affect our ability to commercialize our products in those countries and could otherwise have a material
adverse effect on our business.
If
we are unable to protect the confidentiality of our trade secrets or know-how, such proprietary information may be used by others to
compete against us.
In
addition to filing patents, we generally try to protect our trade secrets, know-how and technology by entering into confidentiality or
non-disclosure agreements with parties that have access to it, such as our current or potential development and commercialization partners,
employees, contractors and consultants. We also enter into agreements that purport to require the disclosure and assignment to us of
all, or certain, rights to the ideas, developments, discoveries and inventions of our employees, advisors, research collaborators, contractors
and consultants while we employ or engage them. However, these agreements can be difficult and costly to enforce or may not provide adequate
remedies. Any of these parties may breach the confidentiality agreements and willfully or unintentionally disclose our confidential information,
or our competitors might learn of the information in some other way. The disclosure to, or independent development by, a competitor of
any trade secret, know-how or other technology not protected by a patent could materially adversely affect any competitive advantage
we may have over any such competitor. In addition, monitoring infringement of intellectual property rights is difficult, and we cannot
be certain that the steps we have taken will prevent unauthorized use of our know-how, particularly in China and other countries in which
the laws may not protect our proprietary rights as fully as the laws of the United States. Accordingly, other parties, including competitors,
may improperly duplicate our products using our proprietary technologies. Pursuing legal remedies against persons infringing our patents
or otherwise improperly using our proprietary information is a costly and time-consuming process that would divert management’s
attention and other resources from the conduct of our normal business.
Although
we expect all of our employees and consultants to assign their inventions to us, and all of our employees, consultants, advisors, and
any third parties who have access to our proprietary know-how, information or technology to enter into confidentiality agreements, we
cannot provide any assurances that all such agreements have been duly executed or that our trade secrets and other confidential proprietary
information will not be disclosed or that competitors will not otherwise gain access to our trade secrets or independently develop substantially
equivalent information and techniques. Misappropriation or unauthorized disclosure of our trade secrets could impair our competitive
position and may have a material adverse effect on our business. Additionally, if the steps taken to maintain our trade secrets are deemed
inadequate, we may have insufficient recourse against third parties for misappropriating such trade secrets. In addition, others may
independently discover our trade secrets and proprietary information.
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To
the extent that any of our employees, advisors, research collaborators, contractors or consultants independently develop, or use independently
developed, intellectual property in connection with any of our projects, disputes may arise as to the proprietary rights to this type
of information. If a dispute arises with respect to any proprietary right, enforcement of our rights can be costly and unpredictable,
and a court may determine that the right belongs to a third-party.
We
may be subject to other patent-related litigation or proceedings that could be costly to defend and uncertain in their outcome.
In
addition to infringement claims against us, we may in the future become a party to other patent litigation or proceedings before regulatory
agencies, including interference or re-examination proceedings filed with the USPTO or opposition proceedings in other foreign patent
offices regarding intellectual property rights with respect to our therapeutic candidates, as well as other disputes regarding intellectual
property rights with our current and potential development and commercialization partners, or others with whom we have contractual or
other business relationships. Post-issuance oppositions are not uncommon, and we and our current and potential development and commercialization
partners will be required to defend these opposition procedures as a matter of course. Opposition procedures may be costly, and there
is a risk that we may not prevail.
In
particular, we may be subject to a third-party pre-issuance submission of prior art or become involved in opposition, derivation, reexamination,
inter partes review, post-grant review or interference proceedings challenging our patent rights or the patent rights of others.
The costs of defending our patents or enforcing our proprietary rights in post-issuance administrative proceedings and litigation can
be substantial and the outcome can be uncertain. An adverse determination in any such submission, proceeding or litigation could reduce
the scope of, or invalidate, our patent rights, allow third parties to commercialize our technology or products and compete directly
with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing third-party patent
rights. In addition, if the breadth or strength of protection provided by our patents and patent applications is threatened, it could
dissuade companies from collaborating with us to license, develop or commercialize current or future product candidates.
Obtaining
and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements
imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
Periodic
maintenance fees on any issued patent are due to be paid to the USPTO and foreign patent agencies in several stages over the lifetime
of the patent. The USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary,
fee payment and other similar provisions during the patent application process. While an inadvertent lapse can in many cases be cured
by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result
in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.
Non-compliance events that could result in abandonment or lapse of a patent or patent application include, but are not limited to, failure
to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal
documents. In such an event, our competitors might be able to enter the market, which would have a material adverse effect on our business.
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We
may be subject to claims that our employees, consultants, or independent contractors have wrongfully used or disclosed confidential information
of third parties, such as trade secrets of their former employers.
We
may also be subject to claims based on the actions of employees and consultants with respect to the usage or disclosure of intellectual
property learned at other employers. We employ and utilize the services of individuals who were previously employed or provided services
to universities or other biotechnology or pharmaceutical companies. Although we try to ensure that our employees, consultants, and independent
contractors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or
our employees, consultants, or independent contractors have inadvertently or otherwise used or disclosed intellectual property, including
trade secrets or other proprietary information, of any of our employee’s, consultant’s or independent contractor’s
former employer or other third parties. Litigation may be necessary to defend against these claims. If we fail in defending any such
claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel, which could materially
adversely impact our business. Even if we are successful in defending against such claims, litigation could result in substantial costs
and be a distraction to management and other employees.
Moreover,
we may be subject to claims that former employees, collaborators or other third parties have an interest in our patents or other intellectual
property as an inventor or co-inventor. For example, we may have inventorship disputes arise from conflicting obligations of consultants
or others who are involved in developing our drug product candidates. Litigation may be necessary to defend against these and other claims
challenging inventorship or our ownership of our patents or other intellectual property. If we fail in defending any such claims, in
addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use,
valuable intellectual property. Such an outcome could have a material adverse effect on our business. Even if we are successful in defending
against such claims, litigation could result in substantial costs and be a distraction to management and other employees.
We may not have sufficient patent terms
to effectively protect our products and business.
Patents have a limited lifespan.
In the United States, the natural expiration of a patent is generally 20 years after it is filed. Although various extensions may be
available, the life of a patent, and the protection it affords, is limited. Given the amount of time required for the development, testing
and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates
are commercialized. As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others
from commercializing products similar or identical to ours or otherwise provide us with a competitive advantage. Even if patents covering
our product candidates are obtained, once the patent life has expired for a product, we may be open to competition from generic medications.
While patent term extensions
under the Hatch-Waxman Act in the United States and under Supplementary Protection Certificates (SPCs) in Europe, for example, may be
available to extend the patent exclusivity term for patents covering our drug product candidates, we cannot provide any assurances that
any such patent term extension will be obtained and, if so, for how long. In addition, upon issuance in the United States, any patent
term can be adjusted downward or upward based on certain prosecution delays caused by the applicant(s) or the U.S. Patent and Trademark
Office, or USPTO. For example, a patent term can be reduced based on certain delays caused by the patent applicant during patent prosecution
or due to a terminal disclaimer required for allowance.
Risks Related to our Operations in Israel
We conduct our operations
in Israel and therefore, political, economic and military instability in Israel and its region may adversely affect our business, results
of operations, and financial condition.
Because we are incorporated
under the laws of the state of Israel and our operations are conducted in Israel, our business and operations are directly affected by
economic, political, geopolitical and military conditions in Israel. Any hostilities involving Israel, or the interruption or curtailment
of trade within Israel or between Israel and its trading partners could adversely affect our operations and results of operations and
could make it more difficult for us to raise capital. Since the establishment of the State of Israel in 1948, a number of armed conflicts
have occurred between Israel and its neighboring countries and terrorist organizations active in the region, including Hamas (an Islamist
militia and political group in the Gaza Strip) and Hezbollah (an Islamist militia and political group in Lebanon), which have involved
missile strikes, hostile infiltrations, terrorism against civilian targets in various parts of Israel, and abductions of soldiers and
citizens.
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On October 7, 2023, Hamas
terrorists infiltrated Israel’s border from the Gaza Strip and conducted a series of attacks on civilian and military targets.
Hamas also launched extensive rocket attacks on Israeli population and industrial centers. These attacks resulted in extensive deaths,
injuries, and the kidnapping of civilians and soldiers. Following the attacks, Israel’s security cabinet declared war against Hamas
and, as a result of attacks by Hezbollah along Israel’s northern border with Lebanon that commenced following the commencement
of the war with Hamas, launched attacks against Hezbollah in Lebanon. Additionally, the Houthi movement, which controls parts of Yemen,
launched a number of attacks on marine vessels traversing the Gulf of Aden and Red Sea, causing supply chain disruptions, and also launched
drone and missile attacks on Israel. In addition, Iran launched direct drone and missile attacks on military and civilian targets within
Israel.
In June 2025, in light of
continued nuclear threats and intelligence assessments, Israel launched a military operation directly targeting military and nuclear
infrastructure inside Iran, aimed at disrupting Iran’s capacity to coordinate or launch further hostilities against Israel and to degrade
its nuclear program. In response, Iran launched multiple waves of drones and ballistic missiles at Israeli cities. While most of these
attacks were intercepted, several caused civilian deaths and casualties, as well as some damage to infrastructure and property. A ceasefire
was declared between Israel and Iran in June 2025 after 12 days of hostilities.
In
October 2025, a ceasefire in the conflict with Hamas came into effect; however, the situation remains fragile, with isolated incidents
of fighting.
On February 28, 2026, Israel
and the United States commenced coordinated military strikes against targets in Iran, including military and strategic infrastructure
in response to ongoing regional tensions and recent escalations involving Iran’s nuclear and military activities. In response,
Iran launched a series of retaliatory attacks against Israel, targeting major cities and strategic sites. While most of these attacks
have been intercepted to date, some resulted in civilian casualties and damage to property. Subsequently, Hezbollah launched attacks
against Israel in retaliation for the killing of Ali Hosseini Khamenei, the former Supreme Leader of Iran, and in response, Israel launched
attacks against Lebanon and Israeli ground forces have entered into Southern Lebanon, and hostilities between Israel and Hezbollah are
ongoing. Iran subsequently began launching retaliatory strikes against U.S. and other targets in the Gulf region. The Israeli government
has raised its alert level nationwide, and the situation remains highly unstable, with ongoing exchanges of fire and heightened risk
of further escalation. Regional and international responses are ongoing, and the risk of broader conflict in the Middle East has increased.
Since the war broke out in
October 2023 and through the ongoing conflicts to date, our operations have not been adversely affected in a material manner, and we
have not experienced material disruptions to our business operations. We do not currently have active clinical studies in Israel and
out therapeutic candidates are manufactured by service providers outside of Israel. Most of our research and development work is being
conducted by third-party entities outside of Israel. However, a prolonged and/or heightened conflict or further deterioration of regional
conditions could have an adverse effect on our business, financial condition and results of operation.
Our commercial insurance
does not cover losses that may occur as a result of an event associated with the security situation in the Middle East. Although the
Israeli government is currently committed to covering the reinstatement value of direct damages that are caused by terrorist attacks
or acts of war, we cannot assure you that this government coverage will be maintained, or if maintained, will be sufficient to compensate
us fully for damages incurred. Any losses or damages incurred by us could have a material adverse effect on our business.
The global perception of
Israel and Israeli companies, influenced by actions taken by international judicial bodies, may lead to increased sanctions and other
negative measures against Israel and Israeli companies, including boycotts of Israeli goods and services or restrictions on business
with Israel and Israeli companies. In addition, the political and security situation in Israel could also result in parties with whom
we have agreements involving performance in Israel claiming that they are not obligated to perform their commitments under those agreements
pursuant to force majeure provisions in such agreements. These restrictive laws and policies, along with any future rulings from international
tribunals against Israel, may have an adverse impact on our operating results, financial condition or our business.
In
connection with the Israeli security cabinet’s declaration of war against Hamas in October 2023 and hostilities with other organizations,
several hundred thousand Israeli military reservists were drafted to perform immediate military service. As of March 18, 2026,
none of our current employees in Israel are currently on active military duty. However, military service call ups that result in absences
of personnel for extended periods may materially and adversely affect our business, prospects, financial condition and results of operations.
37
Prior to the October 2023 war,
the Israeli government pursued extensive changes to Israel’s judicial system and has recently renewed its efforts to effect such
changes. In response to the foregoing developments, certain individuals, organizations, and institutions, both within and outside of Israel,
voiced concerns that such proposed changes, if adopted, may negatively impact the business environment in Israel. Such proposed changes
may also lead to political instability or civil unrest.
Actual or perceived political
instability in Israel or the region or any negative changes in the political environment, may individually or in the aggregate adversely
affect the Israeli economy and, in turn, our business, financial condition, results of operations and the market price of our shares,
as well as our ability to raise additional capital.
It
may be difficult to enforce a U.S. judgment against us and our officers and directors in Israel or the United States, to assert U.S.
securities laws claims in Israel or to serve process on our officers and directors.
We
are incorporated in Israel. All of our executive officers and most of our directors reside outside of the United States, and all of our
assets and most of the assets of our executive officers and directors are located outside of the United States. Therefore, a judgment
obtained in the United States against us or such executive officers and our directors, including one based on the civil liability provisions
of the U.S. federal securities laws, may not be collectible in the United States, and it may be difficult for you to affect service of
process on these persons in the United States. In addition, it may be difficult to assert U.S. securities law claims in original actions
instituted in Israel or obtain a judgment in Israel based on the civil liability provisions of U.S. federal securities laws. Israeli
courts may refuse to hear a claim based on an alleged violation of U.S. securities laws against us or our non-U.S. officers and directors
on the grounds that Israel is not the most appropriate forum to bring such a claim. In addition, even if an Israeli court agrees to hear
such a claim, it may determine that Israeli law and not U.S. law is applicable to the claim. If U.S. law is found to be applicable, the
content of applicable U.S. law must be proven as a fact by expert witnesses, which can be a time consuming and costly process. Certain
matters of procedure will also be governed by Israeli law. There is little binding case law in Israel that addresses the matters described
above.
Additionally,
Israeli courts might not enforce judgments obtained in the United States against us or our non-U.S. directors and executive officers,
which may make it difficult to collect on judgments rendered against us or our non-U.S. officers and directors by either a U.S. or foreign
court. Moreover, an Israeli court will not enforce a non-Israeli judgment if it was given in a state whose laws do not provide for the
enforcement of judgments of Israeli courts (subject to exceptional cases), if its enforcement is likely to prejudice the sovereignty
or security of the State of Israel, if it was obtained by fraud or in the absence of due process, if it is at variance with another valid
judgment that was given in the same matter between the same parties, or if a suit in the same matter between the same parties was pending
before a court or tribunal in Israel at the time the foreign action was brought.
Claims
for indemnification by our directors and officers may reduce our available funds to satisfy successful shareholder claims against us
and may reduce the amount of money available to us.
The
Companies Law and our amended and restated articles of association permit us to indemnify our directors and officers for acts performed
by them in their capacity as directors and officers. The Companies Law and our amended and restated articles of association provide that
a company may not exempt or indemnify a director or an office holder nor enter into an insurance contract, which would provide coverage
for any monetary liability incurred as a result of (a) a breach by the director or officer of his duty of loyalty, except for insurance
and indemnification where the director or officer acted in good faith and had a reasonable basis to believe that the act would not prejudice
the company; (b) a breach by the director or officer of his duty of care if the breach was done intentionally or recklessly, except if
the breach was solely as a result of negligence; (c) any act or omission done with the intent to derive an illegal personal benefit;
or (d) any fine, civil fine, monetary sanctions, or forfeit imposed on the officer or director.
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We have issued letters of
indemnification to our directors and officers, pursuant to which we have agreed to indemnify them in advance for any liability or expense
imposed on or incurred by them in connection with acts they perform in their capacity as a director or officer, to the fullest extent
permitted by applicable law, to the extent that these liabilities are not covered by insurance. The total amount of the indemnity will
not exceed 25% of our then consolidated shareholders’ equity, per our most recent audited or reviewed consolidated financial statements.
Our indemnification obligations
limit the personal liability of our directors and officers for monetary damages for breach of their duties as directors by shifting the
burden of such losses and expenses to us. Although we have obtained directors’ and officers’ liability insurance, certain
liabilities or expenses covered by our indemnification obligations may not be covered by such insurance or the coverage limitation amounts
may be exceeded.
As a result of the Atzmon
Claim described in “Item 8. Financial Information – A. Consolidated Statements and Other Financial Information – Legal
Proceedings”, or other claims which may be filed against our directors and officers, we may need to use a significant amount of
our funds to satisfy our indemnification obligations, which could severely harm our business and financial condition and limit the funds
available to shareholders who may choose to bring a claim against our company. See the risk factor titled “Third-party claims
of intellectual property infringement and other legal challenges may require us to spend substantial time and money and could prevent
us from or delay us in developing or commercializing our therapeutic candidates. An adverse result in any infringement claims or other
legal challenges could have a material adverse effect on our business, results of operations and on our financial condition,”
under the risk factor section titled “Risks Related to Intellectual Property”.
These
provisions and resultant costs may also discourage us from bringing a lawsuit against directors and officers for breaches of their duties
and may similarly discourage the filing of derivative litigation by our shareholders against the directors and officers even though such
actions, if successful, might otherwise benefit our shareholders.
Provisions
of Israeli law and our amended and restated articles of association may delay, prevent or otherwise impede a merger with, or an acquisition
of the Company, or an acquisition of a significant portion of our shares, which could prevent a change of control, and negatively affect
the market price of our ordinary shares.
Israeli
corporate law regulates mergers, requires tender offers for acquisitions of shares above specified thresholds, requires special approvals
for certain transactions involving directors, officers or significant shareholders and regulates other matters that may be relevant to
these types of transactions. These provisions of Israeli law may delay, prevent or make difficult an acquisition of us, which could prevent
a change of control and therefore depress the price of our shares.
39
Furthermore,
Israeli tax considerations may make potential transactions unappealing to us or to our shareholders, especially for those shareholders
whose country of residence does not have a tax treaty with Israel which exempts such shareholders from Israeli tax. For example, Israeli
tax law does not recognize tax-free share exchanges to the same extent as U.S. tax law. With respect to mergers, Israeli tax law allows
for tax deferral in certain circumstances but makes the deferral contingent on the fulfillment of a number of conditions, including,
in some cases, a holding period of two years from the date of the transaction during which sales and dispositions of shares of the participating
companies are subject to certain restrictions. Moreover, with respect to certain share exchange transactions, the tax deferral is limited
in time, and when such time expires, the tax becomes payable even if no disposition of the shares has occurred.
In
addition, our amended and restated articles of association also contain provisions that could delay or prevent changes in control. These
provisions include matters in connection with the election and removal of directors, such as our staggered Board, the right of our Board
to appoint additional directors to fill vacancies on the Board, the size of our Board, the terms of office of our directors and the special
majority required to amend such provision in our amended and restated articles of association.
Further,
under our amended and restated articles of association, we have 50,000,000 shares of authorized non-voting senior preferred shares, which
can be issued by our Board, which contain superior liquidation and dividend rights, and may contain other rights, including conversion,
redemption, optional and other special rights, qualifications, limitations or restrictions, equivalent or superior to our ordinary shares,
without further action by our shareholders, unless shareholder approval is otherwise required by applicable law, the rules of any exchange
or other market on which our securities may then be listed or traded, our articles of association then in effect, or any other applicable
rules and regulations. Furthermore, in a merger between Israeli companies, if the non-surviving entity has more than one class of shares,
the merger may need to be approved by each class of shareholders, including any classes of otherwise non-voting shares, such as our authorized
non-voting senior preferred shares. See “We can issue non-voting senior preferred shares without shareholder approval, which
could adversely affect the rights of holders of ordinary shares.”
These
and other similar provisions could delay, prevent or impede an acquisition of us by a third-party or our merger with another company,
or an acquisition of a significant portion of our shares, and may make it more difficult for our shareholders to elect different individuals
to our Board, even if doing so would be considered to be beneficial by some of our shareholders, and may limit the price that investors
may be willing to pay in the future for our ordinary shares.
Because
a certain portion of our expenses is incurred in currencies other than the U.S. dollar, our results of operations may be harmed by currency
fluctuations and inflation.
Our
reporting and functional currency is the U.S. dollar. Most of the royalty payments from potential development and commercialization partners
are expected to be payable in U.S. dollars, and we expect our revenues from future sales or licensing agreements to be denominated mainly
in U.S. dollars. We pay a portion of our expenses in U.S. dollars; however, a portion of our expenses, related to salaries of our employees
in Israel, our office lease and payment to part of the service providers in Israel, are paid in NIS and in other currencies, such as
euro to our suppliers in Europe. In addition, a portion of our financial assets is held from time to time in NIS. As a result, we are
exposed to currency fluctuation risks and inflation. For example, if the NIS appreciates against the U.S. dollar, our NIS expenses as
reported in U.S. dollars may be higher than anticipated. In addition, if the NIS depreciates against the U.S. dollar, the U.S. dollar
value of our financial assets held in NIS will decline.
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Your
rights and responsibilities as a shareholder are governed by Israeli law, which may differ in some respects from the rights and responsibilities
of shareholders of U.S. companies. Israeli law may impose obligations and responsibilities on a shareholder of an Israeli company that
are not imposed upon shareholders of corporations in the U.S.
We
are incorporated under Israeli law. The rights and responsibilities of the holders of our ordinary shares are governed by our amended
and restated articles of association and Israeli law. These rights and responsibilities differ in some respects from the rights and responsibilities
of shareholders in typical U.S.-based corporations. In particular, a shareholder of an Israeli company has a duty to act in good faith
and in a customary manner in exercising its rights and fulfilling its obligations toward the company and other shareholders and to refrain
from abusing its power in the company, including, among other things, in voting at the general meeting of shareholders on matters such
as amendments to a company’s articles of association, increases in a company’s authorized share capital, mergers and acquisitions
and related party transactions requiring shareholder approval under the Companies Law. In addition, a controlling shareholder of an Israeli
company or a shareholder who knows that it possesses the power to determine the outcome of a shareholder vote or who has the power to
appoint or prevent the appointment of a director or executive officer in the company or has other powers toward the company has a duty
of fairness toward the company. There is limited case law available to assist us in understanding the implications of these provisions
that govern shareholders’ actions. These provisions may be interpreted to impose additional obligations and responsibilities on
holders of our ordinary shares and/or ADSs that are not typically imposed on shareholders of U.S. corporations.
Our
amended and restated articles of association designate courts located either within the State of Israel, or the Federal District Courts
of the United States, as the exclusive forum for certain litigation that may be initiated by our shareholders, which could limit our
shareholders’ ability to bring a favorable or convenient judicial forum for disputes with us.
Our
amended and restated articles of association provide that, unless we consent in writing to the selection of an alternative forum, the
Tel Aviv District Court (Economic Division in the State of Israel (or, if the Tel Aviv District Court does not have jurisdiction, and
no other Israeli court has jurisdiction, the federal district court for the District of New York) shall be the sole and exclusive forum
for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of breach of a fiduciary duty owed
by any of our directors, officers or other employees to us or our shareholders, and (3) any action asserting a claim arising pursuant
to any provision of the Companies Law or the Israeli Securities Law 5728-1968, in all cases subject to the court’s having personal
jurisdiction over the indispensable parties named as defendants. In addition, other than with respect to plaintiffs or a class of plaintiffs
which may be entitled to assert a cause of action arising under the Securities Act in the courts of the State of Israel, the federal
district courts of the United States for the District of New York shall otherwise be the exclusive forum for any complaint asserting
a cause of action arising under the Securities Act. Any person or entity purchasing or otherwise acquiring any interest in our shares
or ADSs shall be deemed to have notice of and consented to these provisions. This forum selection provision limits shareholders’
choice in selecting a judicial forum for disputes with us that it finds favorable or convenient and may have the effect of discouraging
lawsuits against us or our directors and officers.
Risks
Primarily Related to the ADSs and Our Ordinary Shares
The
market price of our ordinary shares and ADSs is subject to fluctuation, which could result in substantial losses by investors.
The
stock market in general, and the market price of our ordinary shares on the TASE and ADSs on NASDAQ, are subject to fluctuation, and
changes in the price of our listed securities may be unrelated to our operating performance. The market prices of our ordinary shares
on the TASE and ADSs on NASDAQ have fluctuated in the past, and we expect it will continue to do so. The market price of our ordinary
shares and ADSs is and will be subject to a number of factors, including:
● announcements of technological innovations or new therapeutic candidates by us or by others;
● announcements by us of significant acquisitions, strategic partnerships, in-licensing, out-licensing, joint ventures or capital commitments;
41
● announcement by us of preclinical and clinical results;
● our need to raise additional capital;
● expiration or terminations of licenses, research contracts or other development or commercialization agreements;
● public concern as to the safety of drugs that we, our current or potential development and commercialization partners or others develop;
● the volatility of market prices for shares of biotechnology companies generally;
● success or failure of research and development projects;
● departure of key personnel;
● developments concerning intellectual property rights or regulatory approvals;
● variations in our and our competitors’ results of operations;
● changes in earnings estimates or recommendations by securities analysts;
● the outcome of any litigation and other legal proceedings;
● changes in government regulations or patent decisions;
● developments by our current or potential development and commercialization partners; and
● general economic, political, market and security conditions and other factors, including factors unrelated to our operating performance and including the impact of the security situation in Israel and the region.
These
factors and any corresponding price fluctuations may materially and adversely affect the market price of our ordinary shares and ADSs
and result in substantial losses by investors.
Additionally,
market prices for listed securities of biotechnology and pharmaceutical companies have been very volatile and have experienced significant
price and volume fluctuations for reasons often unrelated to the operating performance of any one company. These fluctuations may be
attributed, among other reasons, to the general global economic environment and the instability in markets. In the past, following periods
of market volatility, shareholders have often instituted securities class action litigation. If we were involved in securities litigation,
it could have a substantial cost and divert resources and attention of management from our business, even if we are successful. See “Third-party
claims of intellectual property infringement and other legal challenges may require us to spend substantial time and money and could
prevent us from or delay us in developing or commercializing our therapeutic candidates. An adverse result in any infringement claims
or other legal challenges could have a material adverse effect on our business, results of operations and on our financial condition”.
A
continuation or worsening of the levels of market disruption and volatility seen in the recent past could have an adverse effect on our
ability to access capital, on our business, results of operations and financial condition, and on the market price of the ADSs or our
ordinary shares.
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Future sales of our
ordinary shares or ADSs, or securities convertible into our ordinary shares or ADSs, or the perception that future sales may occur, could
reduce the market price of our ordinary shares and ADSs.
As of March 18, 2026, we had an aggregate of 1,858,911,801 issued and
outstanding ordinary shares (including 1 dormant ordinary share held in treasury), no issued and outstanding non-voting senior preferred
shares, outstanding non-listed warrants to purchase 1,273,129 ADSs (representing 2,545,449,780 ordinary shares) issued to investors, underwriters
and placement agents as part of a number of public and registered direct offerings by us and 75,414 outstanding options and restricted
share units (“RSUs”). In the future, we may issue additional ordinary shares, ADSs or other equity or debt securities exercisable
or convertible into ordinary shares or ADSs, including under our 2025 Sales Agreement that we entered into with Wainwright on September
19, 2025, for the offer and sale, from time to time, of ADSs through ATM program and/or under our Form F-3 shelf registration statement
filed with the SEC in December 2022, as amended. As of March 18, 2026, we had not sold any ADSs under the 2025 Sales Agreement.
On
December 8, 2022, we filed a registration statement on Form F-3 with the SEC utilizing a “shelf” registration process, under
which we may offer and sell, from time to time in one or more offerings, up to an aggregate of $200,000,000 of ADSs (representing our
ordinary shares), ordinary shares, preferred shares, warrants, overallotment purchase rights, subscription rights, units and/or capital
notes.
Any
future sales by us or our shareholders of a substantial number of our ordinary shares or ADSs, or equity or debt securities convertible
or exercisable into our ordinary shares or ADSs, or the perception that such sales may occur in the future, including sales of ordinary
shares or ADSs issuable upon the exercise of warrants or options, the vesting or RSUs or the conversion of convertible securities, may
cause the market price of our ordinary shares or ADSs or other listed securities to decline.
We
may not meet the continued listing requirements of NASDAQ, which could result in a delisting of the ADSs from NASDAQ.
The
ADSs are listed on NASDAQ. We have in the past, and may in the future, be unable to comply with certain of the listing standards that
we are required to meet to maintain the listing of the ADSs on NASDAQ.
On October 16, 2025, we received
a letter from the Listings Qualifications Department of The Nasdaq Stock Market LLC notifying the Company that it is not in compliance
with the minimum bid price requirement set forth in NASDAQ Listing Rules for continued listing on the Nasdaq Capital Market, as the closing
bid price of the ADSs had been below the minimum $1.00 per share requirement under NASDAQ Listing Rule 5550(a)(2) for 30 consecutive trading
days. In accordance with NASDAQ Listing Rule 5810(c)(3)(A), the Company had an initial period of 180 calendar days from the date of the
notification letter from The Nasdaq Stock Market LLC, or until April 14, 2026, to regain compliance with the minimum bid price requirement.
If at any time before April 14, 2026, the closing bid price of the Company’s ADSs is USD $1.00 or more for a minimum of ten consecutive
business days, the Company would be deemed to have regained compliance with the minimum bid price requirement. On March 2, 2026, we effected
a change in the ratio of the ADSs to our ordinary shares, from one (1) ADS representing two hundred (200) ordinary shares, to a new ADS
ratio of one (1) ADS representing two thousand (2,000) ordinary shares. Between March 2, 2026 and March 13, 2026, the closing price of
the ADSs was above $1.00 per ADS. On March 16, 2026, the Company received from NASDAQ a written confirmation of compliance, and the matter
is closed.
The
change in ratio of the ADSs to our ordinary shares has the same effect as a reverse split of the ADSs. There can be no assurance
that the ADS ratio change will result in a sustained increased in the trading price of the ADSs. In addition, a decline in the market
price of the ADSs after the ratio change may result in a greater percentage decline than would occur in the absence of a ratio change.
There may also be a decrease in liquidity of the ADSs and an increase in volatility of the ADS trading price. Reverse splits can be negatively
perceived by market participants and thus may adversely affect investor confidence in our company. There can be no assurance that we
will be able to implement additional ADS ratio changes or reverse splits in the future, whether due to shareholder approval requirements,
market conditions, or other factors as needed to maintain compliance with NASDAQ listing requirements.
43
Nasdaq has adopted a series
of rule changes in the recent past to expedite the delisting of securities of companies struggling to maintain the required minimum share
price. Under the amended rule, when a company has been given a second 180-day compliance period and does not regain compliance with the
price criteria for 10 consecutive business days prior to the end of the second period, a request for a hearing no longer stays the suspension
and delisting of its security pending the Nasdaq Hearing Panel’s decision. After the second 180-day period expires, trading of
the company’s security is automatically suspended, and the security will move to the over-the-counter market while the appeal is
pending. In addition, under the amended rule, a listed company is not eligible for any cure period to address a deficiency in the minimum
bid price requirement if it effected a reverse stock split in the prior year. Accordingly, if we fall out of compliance with the minimum
bid price requirement within one year of having conducted the most recent ratio change, we will be issued a delisting decision rather
than being granted any cure period. In addition, companies that fall out of compliance with the minimum bid price requirement are issued a
delisting decision without being granted any cure period if they have effectuated one or more reverse stock splits within a two-year
period with a cumulative ratio of 250 shares or more to one.
Moreover, NASDAQ has proposed new rule changes in January 2026 to adopt as a continued listing requirement market value of listed securities
(“MVLS”) of at least $5 million. Under the proposed rule changes, companies that fail to comply with the MVLS requirement
would be subject to trading suspension and immediate delisting from NASDAQ, and the review by the Nasdaq Listing Qualifications Hearings
Panel (the Hearings Panel) would be limited solely to factual errors.
If
in the future we fail to meet the continued NASDAQ listing requirements, as a result of which NASDAQ delists the ADSs from trading on
its exchange, an investor would likely find it significantly more difficult to dispose of or obtain ADSs, and our ability to raise future
capital through the sale of ADSs could be severely limited. We additionally may not be able to list ADSs on another national securities
exchange, which could result in our securities being quoted on an over-the-counter market. If this were to occur, our shareholders could
face significant material adverse consequences, including limited availability of market quotations for ADSs and reduced liquidity for
the trading of our securities. In addition, we could experience a decreased ability to issue additional securities and obtain additional
financing in the future. There can be no assurance that an active trading market for ADSs will develop or be sustained. As a result of
these factors, if the ADSs are delisted from NASDAQ, the price of the ADSs is likely to decline. The delisting of the ADSs from NASDAQ
could also have other negative results, including the potential loss of confidence by employees, the loss of institutional investor interest
and fewer business development opportunities.
If
the ADSs are delisted from NASDAQ, we would remain a publicly traded company on the TASE and revert to being subject to full Israeli
securities laws and disclosure requirements. Accordingly, we will need to comply with U.S. and Israeli disclosure requirements, and we
expect that these additional reporting requirements would increase our legal and financial compliance costs and require significant management
time.
In
the event that the ADSs are delisted from NASDAQ, U.S. broker-dealers may be discouraged from effecting transactions in the ADSs because
they may be considered penny stocks and thus be subject to the penny stock rules.
The
SEC has adopted a number of rules to regulate “penny stock” that restrict transactions involving stock which is deemed to
be penny stock. Such rules include Rules 3a51-1, 15g-1, 15g-2, 15g-3, 15g-4, 15g-5, 15g-6, 15g-7, and 15g-9 under the Securities and
Exchange Act of 1934, as amended (the “Exchange Act”). These rules may have the effect of reducing the liquidity of penny
stocks. “Penny stocks” generally are equity securities with a price of less than $5.00 per share (other than securities registered
on certain national securities exchanges or quoted on NASDAQ if current price and volume information with respect to transactions in
such securities is provided by the exchange or system). Following a delisting from NASDAQ, the ADSs may constitute “penny stock”
within the meaning of these rules. The additional sales practice and disclosure requirements imposed upon U.S. broker-dealers may discourage
such broker-dealers from effecting transactions involving the ADSs, which could severely limit the market liquidity of the ADSs and impede
their sale in the secondary market.
A
U.S. broker-dealer selling penny stock to anyone other than an established customer or “accredited investor” (generally,
an individual with net worth in excess of $1,000,000 or an annual income exceeding $200,000, or $300,000 together with his or her spouse)
must make a special suitability determination for the purchaser and must receive the purchaser’s written consent to the transaction
prior to sale, unless the broker-dealer or the transaction is otherwise exempt. In addition, the “penny stock” regulations
require the U.S. broker-dealer to deliver, prior to any transaction involving a “penny stock”, a disclosure schedule prepared
in accordance with SEC standards relating to the “penny stock” market, unless the broker-dealer or the transaction is otherwise
exempt. A U.S. broker-dealer is also required to disclose commissions payable to the U.S. broker-dealer and the registered representative
and current quotations for the securities. Finally, a U.S. broker-dealer is required to submit monthly statements disclosing recent price
information with respect to the “penny stock” held in a customer’s account and information with respect to the limited
market in “penny stocks”.
44
Securities
holders should be aware that, according to the SEC, the market for “penny stocks” has suffered in recent years from patterns
of fraud and abuse. Such patterns include (i) control of the market for the security by one or a few broker-dealers that are often related
to the promoter or issuer; (ii) manipulation of prices through prearranged matching of purchases and sales and false and misleading press
releases; (iii) “boiler room” practices involving high-pressure sales tactics and unrealistic price projections by inexperienced
sales persons; (iv) excessive and undisclosed bid-ask differentials and markups by selling broker-dealers; and (v) the wholesale dumping
of the same securities by promoters and broker-dealers after prices have been manipulated to a desired level, resulting in investor losses.
We
incur increased costs and risks as a result of operating as a public company in the U.S. and Israel, and our management is and will continue
to be required to devote substantial time to compliance initiatives.
The
ADSs have been traded on NASDAQ since November 20, 2015, and prior to that our ordinary shares traded on the TASE, where they continue
to trade. As a public company whose securities are listed in the United States and Israel, we incur accounting, legal and other expenses,
including costs associated with our reporting requirements under the Exchange Act and the Israeli Securities Law. We also incur costs
associated with corporate governance requirements, including requirements under Section 404 and other provisions of the Sarbanes-Oxley
Act, as well as rules implemented by the SEC and NASDAQ, and provisions of Israeli corporate and securities laws applicable to public
companies. Certain aspects of Israeli securities laws are different than U.S. securities law, and our dual listing on TASE exposes us
and our management to differing regulatory regimes which may involve increased regulatory risk.
Pursuant
to Section 404 of the Sarbanes-Oxley Act and the related rules adopted by the SEC and the Public Company Accounting Oversight Board,
our management is required to report on the effectiveness of our internal control over financial reporting. In addition, if we become
an “accelerated filer” or a “large accelerated filer” as those terms are defined under Rule 12b-2 of the Exchange
Act, our independent registered public accounting firm will be required to attest to our evaluation of internal controls over financial
reporting. Unless we successfully design and implement changes to our internal controls and management systems, or if we fail to maintain
the adequacy of these controls as such standards are modified or amended from time to time, we may not be able to comply with Section
404. As a result, our auditors may be unable to attest to the effectiveness of our internal controls over financial reporting. This could
subject us to regulatory scrutiny and result in a loss of public confidence in our management, which could, among other things, adversely
affect the price of our ordinary shares and our ability to raise additional capital.
The
process of determining whether our existing internal controls over financial reporting systems are compliant with Section 404 and whether
there are any material weaknesses or significant deficiencies in our existing internal controls, requires the investment of substantial
time and resources, including by our chief executive officer, chief financial officer and other members of our senior management. As
a result, this process may divert internal resources and take a significant amount of time and effort to complete.
We
cannot predict the outcome of evaluations we will conduct in the future, and whether we will need to implement additional remedial actions
in order to implement effective controls over financial reporting. The determination and any remedial actions required could result in
us incurring additional costs that we did not anticipate, including the hiring of outside consultants. Irrespective of compliance with
Section 404, any failure of our internal controls could have a material adverse effect on our stated results of operations and harm our
reputation. As a result, we may experience higher than anticipated operating expenses, as well as higher independent auditor fees during
and after the implementation of these changes. If we are unable to implement any of the required changes to our internal control over
financial reporting effectively or efficiently, it could adversely affect our operations, financial reporting and/or results of operations
and could result in an adverse opinion on internal controls from our independent auditors and cause the market price of our ordinary
shares and ADSs to decline.
Changes
in the laws and regulations affecting public companies may result in increased costs to us as we respond to their requirements. These
laws and regulations could make it more difficult or costlier for us to obtain certain types of insurance, including director and officer
liability insurance, and we may be forced to accept reduced policy limits and coverage or incur substantially higher costs to obtain
the same or similar coverage. The impact of these requirements could also make it more difficult for us to attract and retain qualified
persons to serve on our Board, our board committees or as executive officers. We cannot predict or estimate the amount or timing of additional
costs we may incur in order to comply with such requirements.
45
We
are a non-accelerated filer, and we cannot be certain if the reduced disclosure requirements applicable to us will make the ADSs less
attractive to investors.
We
are currently a “non-accelerated filer”, as that term is defined in the Securities Act. Accordingly, we take advantage of
certain exemptions from various reporting requirements that are applicable to other public companies that are not a “non-accelerated
filers,” in particular, reduced disclosure obligations regarding exemptions from the provisions of Section 404(b) of the Sarbanes-Oxley
Act of 2002 requiring that independent registered public accounting firms provide an attestation report on the effectiveness of internal
control over financial reporting. Decreased disclosures in our SEC filings due to our status as a “non-accelerated filer”
may make it harder for investors to analyze our results of operations and financial prospects.
We
cannot predict if investors will find the ADSs less attractive if we rely on exemptions applicable to smaller reporting companies and
non-accelerated filers. If some investors find the ADSs less attractive as a result, there may be a less active trading market for the
ADSs and our ordinary share price may be more volatile.
We
may be classified as a Passive Foreign Investment Company, or PFIC, for U.S. federal income tax purposes in 2025 and may continue to
be, or become, a PFIC in future years, which may have negative tax consequences for U.S. investors.
We
will be treated as a PFIC for U.S. federal income tax purposes in any taxable year in which either (i) at least 75% of our gross income
is “passive income” or (ii) on average at least 50% of our assets by value produce passive income or are held for the production
of passive income. Based on our estimated gross income, the average value of our gross assets, and the nature of our business, we may
be treated as a PFIC for the 2025 tax year and we may also be classified as a PFIC in future years. If we are treated as a PFIC for any
taxable year during which a U.S. investor held the ADSs, certain adverse U.S. federal income tax consequences could apply to the U.S.
investor.
As
a foreign private issuer, we are permitted to follow certain home country corporate governance practices instead of applicable NASDAQ
requirements, which may result in less protection than is accorded to investors under rules applicable to U.S. domestic issuers.
As
a foreign private issuer, we are permitted to follow certain home country corporate governance practices instead of those otherwise required
under the NASDAQ Listing Rules for U.S. domestic issuers. We follow home country practice in Israel with regard to (among other things)
director nomination procedures, quorum requirement at shareholder meetings and approval of related party transactions and executive compensation.
In addition, we follow our home country law, instead of the NASDAQ Listing Rules, which require that we obtain shareholder approval for
certain dilutive events, such as for the establishment or amendment of certain equity-based compensation plans, an issuance that will
result in a change of control of the company, certain transactions other than a public offering involving issuances of a 20% or more
interest in the Company and certain acquisitions of the stock or assets of another company. In the future we may elect to follow additional
home country corporate governance practices instead of those otherwise required under the NASDAQ Listing Rules for U.S. domestic issuers.
Following our home country governance practices as opposed to the requirements that would otherwise apply to a U.S. company listed on
NASDAQ may provide less protection than is accorded to investors under the NASDAQ Listing Rules applicable to domestic issuers. See “Item
16G. Corporate Governance.”
We
are a “foreign private issuer” and have disclosure obligations that are different from those of U.S. domestic reporting companies.
As a result, we may not provide you the same information as U.S. domestic reporting companies or we may provide information at different
times, which may make it more difficult for you to evaluate our performance and prospects.
We
are a foreign private issuer and, as a result, are not subject to the same requirements as U.S. domestic issuers. Under the Exchange
Act, we are subject to reporting obligations that, in certain respects, are less detailed and/or less frequent than those of U.S. domestic
reporting companies. For example, as a foreign private issuer, we are exempt from the rules and regulations under the Exchange Act, related
to the furnishing and content of proxy statements. While our officers and directors are, effective March 18, 2026, required to make insider
reports under Section 16(a) of the Exchange Act, our principal shareholders are exempt from the reporting under Section 16(a) of the
Exchange Act, and our directors, officers and principal shareholders continue to be exempt from the short-swing profit recovery provisions
contained in Section 16(b) of the Exchange Act. In addition, we are not required under the Exchange Act to file annual, quarterly and
current reports and financial statements with the SEC as frequently or as promptly as domestic companies whose securities are registered
under the Exchange Act.
46
We
intend to file with the SEC, within 120 days after the end of each fiscal year ending December 31, an annual report on Form 20-F containing
financial statements which will be examined and reported on, with an opinion expressed, by an independent registered public accounting
firm. In accordance with NASDAQ Listing Rules, as a foreign private issuer, we are required to submit on Form 6-K an interim balance
sheet and income statement as of the end of the second quarter of each fiscal year.
Foreign
private issuers are also exempt from Regulation FD, which is intended to prevent issuers from making selective disclosures of material
information. As a result of all of the above, you may not have the same protections afforded to shareholders of a company that is not
a foreign private issuer.
We
may lose our foreign private issuer status in the future, which could result in significant additional costs and expenses.
As
discussed above, we are a foreign private issuer, and therefore, we are not required to comply with all of the periodic disclosure and
current reporting requirements of the Exchange Act. The determination of foreign private issuer status is made annually on the last business
day of an issuer’s most recently completed second fiscal quarter, and, accordingly, the next determination will be made with respect
to us on June 30, 2026. In the future, we would lose our foreign private issuer status if (1) more than 50% of our outstanding voting
securities continue to be owned by U.S. residents and (2) a majority of our directors or executive officers are U.S. citizens or residents,
or we fail to meet additional requirements necessary to avoid loss of foreign private issuer status. If we lose our foreign private issuer
status, we will be required to file with the SEC periodic reports and registration statements on U.S. domestic issuer forms, which are
more detailed and extensive than the forms available to a foreign private issuer. We will also have to mandatorily comply with U.S. federal
proxy requirements, and our officers, directors and principal shareholders will become subject to the short-swing profit disclosure and
recovery provisions of Section 16 of the Exchange Act. In addition, we will lose our ability to rely upon exemptions from certain corporate
governance requirements under the NASDAQ Listing Rules. As a U.S. listed public company that is not a foreign private issuer, we will
incur significant additional legal, accounting and other expenses that we do not incur as a foreign private issuer.
The ADS holders may
not be able to fully exercise their voting rights to the same extent as our ordinary shareholders. The depositary for the ADSs will give
us a discretionary proxy to vote our ordinary shares underlying ADSs if a holder of the ADSs does not provide voting instructions, except
in limited circumstances, which could adversely affect their interests.
The
ADS holders may instruct the depositary how to vote the number of deposited ordinary shares their ADSs represent. Except by instructing
the depositary, you will not be able to exercise voting rights unless you surrender your ADSs and withdraw the shares. However, you may
not know about the meeting enough in advance to withdraw the shares. We cannot assure you that you will receive the voting materials
in time to ensure that you can instruct the depositary to vote your shares. In addition, the depositary and its agents are not responsible
for failing to carry out voting instructions or for the manner of carrying out voting instructions. This means that you may not be able
to exercise voting rights and there may be nothing you can do if your shares are not voted as you requested, and you cannot vote in person
at meetings as a holder of ADSs.
Under
the deposit agreement for the ADSs, the depositary will give us a discretionary proxy to vote our ordinary shares underlying ADSs at
shareholders’ meetings if a holder of the ADSs does not provide voting instructions, unless we notify the depositary that:
● we do not wish to receive a discretionary proxy;
● there is substantial shareholder opposition to the particular question; or
● the particular question would have an adverse impact on our shareholders’ rights.
47
The
effect of this discretionary proxy is that a holder of the ADSs cannot prevent our ordinary shares underlying such ADSs from being voted,
absent the situations described above, and it may make it more difficult for shareholders to influence the management of our company.
Holders of our ordinary shares listed for trading on the TASE are not subject to this discretionary proxy.
We
currently do not anticipate paying cash dividends, and accordingly, shareholders must rely on the appreciation in our ordinary shares
and ADSs for any return on their investment.
We
currently anticipate that we will retain future earnings, if any, for the development, operation and expansion of our business and do
not anticipate declaring or paying any cash dividends for the foreseeable future. The ability of an Israeli company to pay dividends
is governed by Israeli law, which provides that unless otherwise approved by a court, distributions, including cash dividends, may be
made only out of retained earnings as determined for statutory purposes, and only if there is no reasonable concern that the dividend
distribution will prevent us from meeting our existing and foreseeable obligations, as they become due. Subject to the foregoing, payment
of future dividends, if any, will be at the discretion of our Board and will depend on various factors, such as our financial condition,
operating results, current and anticipated cash needs and other business and economic factors that our Board may deem relevant. Since
we do not have earnings, we currently do not have any ability to pay dividends or repurchase our shares, absent court approval. Therefore,
the success of an investment in our ordinary shares and ADSs will depend upon any future appreciation in their value. There is no guarantee
that our ordinary shares and ADSs will appreciate in value or even maintain the price at which our holders have purchased their shares
and ADSs.
Investors
in the ADSs may not receive the same distributions or dividends as those we make to the holders of our ordinary shares, and, in some
limited circumstances, investors in the ADSs may not receive any value for them, if it is illegal or impractical to make them available
to investors in the ADSs.
The
depositary for the ADSs has agreed to pay investors in the ADSs the cash dividends or other distributions it or the custodian receives
on ordinary shares or other deposited securities underlying the ADSs, after deducting its fees and expenses. Investors in the ADSs will
receive these distributions in proportion to the number of ordinary shares their ADSs represent. However, the depositary is not responsible
if it decides that it is unlawful or impractical to make a distribution available to any holders of ADSs. For example, it would be unlawful
to make a distribution to a holder of ADSs if it consists of securities that require registration under the Securities Act, but that
are not properly registered or distributed under an applicable exemption from registration. In addition, conversion into U.S. dollars
from foreign currency that was part of a dividend which was distributed in foreign currency made in respect of deposited ordinary shares
may require the approval or license of, or a filing with, any government or agency thereof, which may be unobtainable. In these cases,
the depositary may determine not to distribute such property and hold it as “deposited securities” or may seek to affect
a substitute dividend or distribution, including net cash proceeds from the sale of the dividends that the depositary deems an equitable
and practicable substitute. We have no obligation to register under U.S. securities laws any ADSs, ordinary shares, rights or other securities
received through such distributions. We also have no obligation to take any other action to permit the distribution of ADSs, ordinary
shares, rights or anything else to holders of ADSs. In addition, the depositary may withhold from such dividends or distributions its
fees and an amount on account of taxes or other governmental charges to the extent the depositary believes it is required to make such
withholding. This means that investors in the ADSs may not receive the same distributions or dividends as those we make to the holders
of our ordinary shares, and, in some limited circumstances, investors in the ADSs may not receive any value for such distributions or
dividends if it is illegal or impractical for us to make them available to investors in the ADSs. These restrictions may cause a material
decline in the value of the ADSs.
48
Holders of ADSs must
act through the depositary to exercise rights of shareholders of our company.
Holders
of the ADSs do not have the same rights as our shareholders and may only exercise the voting rights with respect to the underlying ordinary
shares in accordance with the provisions of the deposit agreement for the ADSs. Under Israeli law, the minimum notice period required
to convene a shareholders’ meeting is no less than 35 or 21 calendar days, depending on the proposals on the agenda for the shareholders’
meeting. When a shareholder meeting is convened, holders of the ADSs may not receive sufficient notice of the meeting to permit them
to withdraw their ordinary shares to allow them to cast their vote with respect to any specific matter. In addition, the depositary and
its agents may not be able to send notice to holders of the ADSs or carry out their voting instructions in a timely manner. We will make
all reasonable efforts to cause the depositary to extend voting rights to holders of the ADSs in a timely manner, but we cannot assure
holders that they will receive the voting materials in time to ensure that they can instruct the depositary to vote the ordinary shares
underlying their ADSs. Furthermore, the depositary and its agents will not be responsible for any failure to carry out any instructions
to vote, for the manner in which any vote is cast or for the effect of any such vote. As a result, holders of the ADSs may not be able
to exercise their right to vote and they may lack recourse if the ordinary shares underlying their ADSs are not voted as they requested.
In addition, ADS holders will not be able to call a shareholders’ meeting unless they first withdraw their ordinary shares from
the ADS program and receive delivery of the underlying ordinary shares held in the Israeli market in order to allow them to submit to
us a request to call a meeting with respect to any specific matter, in accordance with the applicable provisions of the Companies Law
and our amended and restated articles of association.
Our
ordinary shares and the ADSs are traded on different markets and this may result in price variations.
Our
ordinary shares trade on the TASE, and the ADSs trade on NASDAQ. Trading on these markets take place in different currencies (U.S. dollars
on NASDAQ and NIS on the TASE), and at different times (resulting from different time zones and different public holidays in the U.S.
and Israel). The trading prices of our securities on these two markets may differ due to these and other factors. Any decrease in the
price of our securities on one of these markets could cause a decrease in the trading price of our securities on the other market.
The
ADSs have relatively limited trading volume, which may limit the ability of our investors to sell their ADSs in the U.S.
The
ADSs have been traded at low volumes in the past and may be traded at low volumes in the future for reasons related or unrelated to our
performance. This low trading volume may result in lesser liquidity and lower than expected market prices for ADSs, and our investors
may not be able to resell their ADSs for more than they paid for them.
We
can issue non-voting senior preferred shares without shareholder approval, which could adversely affect the rights of holders of ordinary
shares.
Our
amended and restated articles of association permit us to establish the rights, privileges, preferences and restrictions of future series
of our non-voting senior preferred shares, which contain superior liquidation and dividend rights, and may contain other rights, including
conversion, redemption, optional and other special rights, qualifications, limitations or restrictions, equivalent or superior to our
ordinary shares and to issue such non-voting senior preferred shares without further approval from our shareholders. The rights of holders
of our ordinary shares and ADSs may suffer as a result of the rights granted to holders of non-voting senior preferred shares that we
may issue in the future. In addition, we could issue non-voting senior preferred shares containing rights that prevent a change in control
or merger, thereby depriving holders of our ordinary shares and ADSs of an opportunity to sell their shares at a price in excess of the
prevailing market price.
If
equity research analysts do not publish research or reports about our business or if they issue unfavorable commentary or downgrade our
ordinary shares or ADSs, the price of our ordinary shares and ADSs could decline.
The
trading market for our ordinary shares and ADSs will rely in part on the research and reports that equity research analysts publish about
us and our business. The price of our ordinary shares and ADSs could decline if such research or reports are not published or if one
or more securities analysts downgrade the ADSs or if those analysts issue other unfavorable commentary or cease publishing reports about
us or our business.
49
We
have broad discretion as to the use of the net proceeds from our previous offerings and may not use them effectively.
We
currently intend to use the net proceeds from our previous offerings, including under our ATM programs, to expand our clinical development
program, expand our clinical development pipeline for additional drug products, including by way of possible acquisitions, expand our
pre-clinical development activity and for general corporate purposes, including working capital requirements. However, our management
will have broad discretion in the application of the net proceeds from our previous offerings. Our shareholders may not agree with the
manner in which our management chooses to allocate the net proceeds from our previous offerings. The failure by our management to apply
these funds effectively could have a material adverse effect on our business, financial condition and results of operations. Pending
their use, we may invest the net proceeds from our previous offerings in a manner that does not produce income. The decisions made by
our management may not result in positive returns on any investment by shareholders and shareholders will not have an opportunity to
evaluate the economic, financial or other information upon which our management bases its decisions.
ITEM
4. INFORMATION ON THE COMPANY
A. History and Development of the Company
We
were incorporated under the laws of the State of Israel (under a previous name) on August 12, 1968. Our ordinary shares were originally
listed for trading on the TASE in 1978 and the ADSs have been traded on NASDAQ since November 2015. Our ordinary shares are currently
traded on the TASE under the symbol “PPBT”, and the ADSs are currently traded on NASDAQ under the symbol “PPBT”.
The Company is headquartered in Rehovot, Israel and our telephone number is +972-3-933-3121. Our website address is www.purple-biotech.com.
Information contained on, or that can be accessed through, our website does not constitute a part of this Annual Report and is not incorporated
by reference herein. We have included our website address in this Annual Report solely for informational purposes. The SEC maintains
an Internet site that contains reports, proxy and information statements, and other information regarding issuers, such as us, that file
electronically with the SEC at www.sec.gov.
In
October 2012, the District Court in Lod, Israel approved the creditors arrangement in accordance with Section 350 of the Companies Law
in order to effectuate the sale by our company (then known as Mainrom Line Logistics Ltd.) of all its activities, assets, rights, obligations
and liabilities to a private company held by its then controlling shareholders, and all rights of our creditors against us were extinguished.
From the completion of these transactions until the completion of the acquisition of Kitov Pharmaceuticals described below, Purple Biotech
(then known as Kitov Pharma) did not conduct any business activities and was a public shell company listed on the TASE with no assets,
debt and/or liabilities.
On
July 11, 2013, we acquired Kitov Pharmaceuticals, which, prior to the completion of its merger with and into our company in December
2017, together with our company, was engaged in the research and development of Consensi. As part of the acquisition, Mainrom Line Logistics
Ltd. changed its name to Kitov Pharmaceuticals Holdings Ltd., which was subsequently changed in January 2018 to Kitov Pharma Ltd.
On
January 13, 2017, we announced that we had acquired a majority equity stake in TyrNovo, a privately held developer of novel small molecules
in the oncology therapeutic field, whose main asset is NT219.
On
April 25, 2017, the boards of directors of each of Kitov Pharma and Kitov Pharmaceuticals approved a merger between the two entities,
with Kitov Pharma remaining as the surviving entity. The merger was completed in December 2017. Kitov Pharmaceuticals was dissolved upon
the merger, and Kitov Pharma remained as the surviving entity.
In
January 2020, we completed the acquisition of FameWave, a privately held biopharmaceutical company, whose main asset is CM24, a clinical
stage humanized monoclonal antibody in the oncology therapeutic field.
On
December 7, 2020, we changed our name to Purple Biotech Ltd.
In
December 2021, we decided to discontinue the manufacturing and distribution of Consensi.
In
February 2023, we completed the acquisition of Immunorizon, a privately held biotechnology company developing multi-specific antibodies
as oncology therapies that selectively activate the immune response within the tumor microenvironment (TME). For information regarding
the Immunorizon acquisition, see “Item 10 – Additional Information – C. Material Contracts – Immunorizon Acquisition.”
50
For
a description of our principal capital expenditures for the three years ended December 31, 2025, see “Item 5. Operating and
Financial Review and Prospects.”
B. Business Overview
We are a clinical-stage company
developing a next-generation immunotherapy platform designed to maximize anti-cancer potency while minimizing toxicity. We are focused
on advancing our lead program, CAPTN-3 - a platform of masked tri-specific antibodies that simultaneously target tumors while engaging
both T cells and NK cells. Capping technology confines immune activation to the TME, significantly expanding the therapeutic window versus
unmasked T-cell engagers. The platform’s lead candidate, IM1240, is advancing toward the clinic and its second candidate, IM1305,
is in preclinical development. Our pipeline also includes additional clinical-stage assets, for which further development is pending
partnering of investment, including CM24, a CEACAM1-blocking antibody that demonstrated improved outcomes across all efficacy endpoints
in a Phase 2 study for the treatment of pancreatic ductal adenocarcinoma, and NT219, a dual IRS1/2 and STAT3 inhibitor in a Phase 2 study
for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.
● CAPTN-3: A platform of masked tri-specific antibodies that simultaneously target tumor-associated antigens while engaging both T cells and NK cells. The capping technology confines immune activation to the TME by masking the CD3-binding arm in circulation and activating it only at the tumor site, significantly expanding the therapeutic window versus unmasked T-cell engagers. This technology presents a novel mechanism of action by unleashing both innate and adaptive immune responses at the TME to induce an optimal anti-tumor immune response. The platform’s lead candidates, IM1240 (capped-CD3x5T4xNKG2A) and IM1305 (capped-CD3xTROP2xNKG2A), are in preclinical development. IM1240 targets the 5T4 tumor-associated antigen, which is expressed in a variety of solid tumors and is associated with advanced disease, increased invasiveness, and poor clinical outcomes. Preclinical studies have shown sustained tumor regression in a triple-negative breast cancer in-vivo model and pronounced anti-tumor effects in non-small cell lung cancer and head and neck cancer patient-derived explants (PDEs). A toxicology study demonstrated an improved safety and pharmacokinetic profile for IM1240. In-vivo and in-vitro data demonstrated the platform’s plug-and-play capability and a potentially beneficial safety profile. During 2024, we held a pre-IND meeting with the FDA that provided a clear path forward for our development plan through Phase 1, and we expect to submit an IND application to the FDA for IM1240 during 2026 and plan to initiate a first-in-human study thereafter. IM1305 targets the TROP2 tumor-associated antigen.
● CM24: CM24, is a humanized monoclonal antibody designed to block the interactions of Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1), a glycoprotein that plays a key role in immune regulation, cell adhesion, and tumor progression. CEACAM1 promotes tumor immune evasion and progression through multiple pathways. We have concluded a randomized, controlled, open-label, multicenter, proof-of-concept Phase 2 study for CM24 as a combination therapy with an anti-PD-1 checkpoint inhibitor and chemotherapy for the treatment of second-line pancreatic ductal adenocarcinoma (PDAC). The final data for the study demonstrated consistent improvement across all efficacy endpoints and also identified potentially predictive biomarkers, including pretreatment levels of CEACAM1 and neutrophil extracellular traps (NETs) in the serum and pretreatment levels of CEACAM1 in the tumor. Further development of this asset is planned upon partnering or obtaining sufficient investment to perform the next study.
● NT219: A dual-inhibitor, small molecule that simultaneously targets Insulin Receptor Substrate 1 and 2 (IRS1/2) and Signal Transducer and Activator of Transcription (STAT3), two major survival signal transduction pathways driving the development of cancer drug resistance. We concluded a Phase 1 dose-escalation study evaluating NT219 as a monotherapy and in combination with cetuximab. NT219 demonstrated anti-tumor activity as a second-line treatment for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. We entered into a research agreement with the University of Colorado Anschutz Medical Campus for an investigator-initiated Phase 2 study evaluating NT219 in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck in combination with cetuximab or pembrolizumab, which was initiated in June 2025. Further development of this asset is planned upon partnering or obtaining sufficient investment to perform the next clinical study.
Our
Competitive Strengths
The
pharmaceutical market is characterized by large international pharmaceutical companies that develop a wide range of products, both generic
and innovative, which operate alongside smaller companies, such as ours, that develop a specific drug or a combination of drugs. Therefore,
many small companies enter into agreements with such global companies during the drug development stage in order to continue the development
or marketing of the drug, taking advantage of the financial, marketing and/or other resources available to such global companies. At
the same time, global companies tend to enter into agreements with smaller companies in order to save development time and resources.
The global drug sector is a highly developed market with a turnover of hundreds of billions of U.S. dollars and intense competition.
We
believe there are several advantages to the therapeutic candidates we are developing, as set forth below.
51
CAPTN-3 - IM1240
and IM1305
CAPTN-3, our platform of
tri-specific antibodies, is a multi-valent antibody designed to activate an anti-tumoral immune response against TAA positive tumors
while expanding its therapeutic window through masking of the T cell engager arm.
The two features described
below represent advantages of our tri-specific platform as they are intended to provide specific anti-tumor effects at the tumor site
with reduced side effects, as well as efficient activation of the anti-tumoral immune response.
● Dual activation of T cells and NK cells to induce a stronger specific immune response against cancer cells (Kyrysyuk et al., Annu. Rev. Immunol. 2023. 41:17–38); and
● A cleavable capping system aimed at preventing systemic T cell activation, improving the safety profile and pharmacokinetic properties, and widening the therapeutic index.
The tri-specific platform
is a ‘Plug-and-Play’ platform that allows incorporation of antibodies against various TAAs, and thereby can produce a pipeline of products
that target multiple cancer types expressing these TAAs. It is also versatile in terms of the NK cell targets. In addition, CAPTN-3 incorporates
a human serum albumin (HSA) binding domain designed to extend the molecule’s half-life.
The IM1240 therapeutic
candidate is the platform’s lead candidate targeting the TAA 5T4 (capped CD3x5T4xNKG2A) and has distinctive features that we believe
could allow it to outperform competitors. 5T4 is a well-studied TAA, minimally expressed in healthy tissues and associated with poor
prognosis in multiple cancer types.
IM1240
demonstrated sustained tumor regression in a triple negative breast cancer in-vivo model as well as dose dependent activity and pronounced
anti-tumor effects of the engager arms in non-small cell lung cancer PDEs. IM1240 demonstrated that cytokine release is 5T4-dependent
and suppressed by the conditionally activated capping technology, suggesting a potentially beneficial safety profile of this tri-specific
antibody. A non-human primate toxicology study demonstrated an improved safety and pharmacokinetic profile, supporting the advancement
of IM1240 into IND-enabling development.
The data further demonstrated
additional trispecific antibodies, suggesting CAPTN-3’s plug and play platform capability.
IM1305 is the second tri-specific
antibody generated using the CAPTN-3 platform and is designed to target the tumor-associated antigen TROP2 while simultaneously engaging
CD3 on T cells and NKG2A on NK cells and CD8⁺ T cells. TROP2 is broadly expressed across multiple solid tumors and has been associated
with tumor progression and poor clinical outcomes. In in-vivo studies, IM1305 induced sustained tumor regression in humanized triple-negative
breast cancer mouse models. Similar to IM1240, IM1305 incorporates the CAPTN-3 conditionally activated capping technology and an HSA
moiety.
Transcriptomic analysis
across approximately 11,000 TCGA samples shows NKG2A expression is strongly associated with tumor expression of 5T4 or TROP2, supporting
inclusion of the NKG2A arm in CAPTN-3 designs.
CM24
CEACAM1 is unique among the
CEACAM family members in that it is widely distributed among various species and it has the largest number of splice variants compared
to other members of the family. Moreover, CEACAM1 also has the widest tissue distribution of all characterized family members (source:
Current Opinion in Cell Biology Volume 18, Issue 5, October 2006, Pages 565-571). Accordingly, CM24 may have a competitive advantage
over other CEACAM-targeting agents in that its inhibitory effect may be more general and target several splice variants and more tissues.
Additional
potential advantages of CM24 over other CEACAM-targeting technologies may include:
● As CM24 blocks the homo- as well as the hetero-dimerization, i.e. blocks both CEACAM1-CEACAM1 as well as CEACAM1-CEACAM5 interaction - it has the potential to be more effective in controlling the contact inhibition of cancerous cells with cells of the immune system. CM24 acts as an immune adhesion inhibitor molecule – a mechanism that is central to the immune evasion mechanism of neoplastic cells.
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● In addition to its contribution to tumor suppression, CEACAM1 also has a modulatory role in multiple cell types such as T-cells, NK cells, monocytes and neutrophils.
● CEACAM1 has been proposed to be a ligand for T-cell Immunoglobulin and Mucin domain-3 (TIM-3) – another immune checkpoint inhibitor. By activating TIM-3 with CM24, a synergistic effect may be expected. The relationship between CEACAM1 and TIM-3 has been described as a mechanism that may overcome immune fatigue and T-cell exhaustion (Nature. 2015 Jan 15; 517(7534): 386–390; Acharya N, et al. J Immunotherapy 8:e911-22, 2020).
● CEACAM1 is expressed on NETs which, among other activities, are believed to promote metastatic processes of tumors.
● CEACAM1 has been associated with trophism for cancer cells and the metastatic phenotype manifested through its expression on NETs (Rayes RF, et al. J Immunology. 2020) and our data.
CM24
has been evaluated as monotherapy at escalating doses up to 10mg/kg in a phase 1 clinical trial, where 27 patients with different
cancers in advanced stages were treated with the monoclonal antibody. There were no dose limiting toxicities which were associated
with CM24, nor any drug related mortalities. In a second Phase 1b study, CM24 at 3 dose levels, 10, 15 and 20mg/kg, was administered
in combination with standard dose of nivolumab to a total of 14 patients with PDAC, Colorectal cancer (CRC) and papillary thyroid
cancer. The combination of CM24 and nivolumab was well tolerated and demonstrated initial signals of efficacy. We completed a
randomized, controlled, open label, multicenter Phase 2 study evaluating CM24 in combination with nivolumab and standard of care
chemotherapy in 63 patients with pancreatic ductal adenocarcinoma as a second line treatment as compared to standard of care
chemotherapy was initiated and enrollment was completed during December 2023.
We reported positive
final results from the randomized Phase 2 study, which demonstrate clear and consistent improvement across all efficacy endpoints
for CM24 in combination with nivolumab and Nal-IRI/5FU/LV chemotherapy. A biomarker enriched patient population analysis based on
pretreatment ranges of serum CEACAM1 demonstrated significant improvement in the treatment arm over the control of 79% reduction in
risk of death (HR 0.21, CI 0.04-1.06 P = 0.04) with median OS improvement of 5.1 months and over 90% reduction in risk of
progression or death (HR < 0.1, CI 0-inf, P = 0.003) with median PFS improvement of 2.9 months and improvement in the treatment
arm over the control in ORR of 50% vs. 0%. An additional subgroup analysis of 16 patients, based on a range of pretreatment serum
CEACAM1 between 6,000 pg/mL and 15,000 pg/mL, together with patients with pretreatment tumor CEACAM1 levels of H score 115-275,
demonstrated significant improvement in the treatment arm over the control of 78% reduction in risk of death (HR 0.22; CI
(0.07-0.7); (P 0.006)) with median overall survival (OS) improvement of 3.7 months and 95% reduction in risk of progression or death
(HR 0.05; CI (0.01-0.44); (P 0.0003)) with median PFS improvement of 2.9 months and improvement in the treatment arm over the control in ORR of 37.5%
vs. 0%. An additional subgroup analysis of 24 patients, which comprised 80% of the patients in the study cohort, with a range of
pretreatment serum CEACAM1 between 6,000 pg/mL and 15,000 pg/mL, together with patients with pretreatment serum MPO levels of 200
ng/mL and 600 ng/mL, demonstrated significant improvement in the treatment arm over the control of 61% reduction in risk of death
(HR 0.39; CI (0.16-0.98); (P 0.039)) with median OS improvement of 2.4 months and 72% reduction in risk of progression or death (HR 0.28; CI (0.11-0.73); (P 0.006))
with median PFS improvement of 2.2 months and improvement in the treatment arm over the control in ORR of 30.7% vs. 0%.
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NT219
NT219
is a first-in-class drug candidate and, to the best of our knowledge, currently the only one that inhibits both IRS1/2 and STAT3. The
inhibition of both has been demonstrated to be essential to facilitate a significant anti-tumor effect and overcome drug resistance.
NT219
binds covalently to IRS1 and IRS2 and targets them to degradation, gaining a sustained inhibition of IRS1/2-mediated signaling. Prolonged
inhibition of STAT3 was also demonstrated, long after the drug was washed out.
NT219
inhibits major cancer survival pathways downstream IRS1/2, such as the AKT and the β-catenin, known to be involved in drug resistance,
cancer stem cell renewal, immune evasion, and metastasis.
NT219
is a small molecule, and small molecules are typically less expensive to develop and have less complex CMC as compared to proteins or
antibodies.
In
preclinical development, NT219 demonstrated several advantageous effects in animal models, such as:
● single agent activity in PDX and xenograft models;
● overcoming drug resistance acquired by various cancer types;
● synergistic anti-tumor effects in combination with approved cancer therapies belonging to various classes such as chemotherapy and targeted therapies; and
● suppression of refractory tumors to immune checkpoint inhibitors by the combination of NT219 with anti- Programmed Cell Death Protein 1 (PD1) therapy. The effect on tumor growth was accompanied by the conversion of immunosuppressive TME to immunoreactive (upregulation of cytotoxic T cells and NK cells paralleled with a decrease in T regulatory cells, tumor-associated macrophages and monocytic and granulocytic myeloid-derived suppressor cells (MDSCs).
In
the monotherapy portion of the phase 1/2 dose escalation study of NT219, no dose limiting toxicities (DLTs) have been observed and NT219
has been found to be well tolerated with no treatment-related Grade 4/5 AEs.
In the phase 1/2 dose escalation
study of NT219 in combination with cetuximab, anti-tumor activity was observed in previously treated HPV negative 2L/3L R/M squamous
cell carcinoma of head and neck cancer (SCCHN) patients. Overall, 25 patients were enrolled in the combination arm; 23 patients were
evaluable for efficacy, 8 of which were at the highest dose levels of 50+100 mg/kg that reached or surpassed NT219 target exposure level.
Out of these 8 patients, 2 patients demonstrated confirmed partial response (PR), and 3 patients demonstrated stable disease, representing
ORR of 25% and disease control rate (DCR) of 62.5%. Median follow-up across all dose levels was 9.4 months (95% CI: 3.4-10.0, 8 out
of 15 patients remaining in follow up). Safety profile was well tolerated and manageable up to and including at 100mg/kg. Most common
treatment emergent adverse events (AEs) were infusion related reactions and nausea, and no treatment-related Grade 4/5 AEs were observed.
Pharmacokinetic analysis demonstrated dose dependent increase. Biomarker analysis of biopsies collected from SCCHN patients before treatment
with NT219 (50mg/kg) and cetuximab demonstrated enhanced activation of IGF1R and STAT3 in responders (PR) as compared to non-responding
patients (progressed disease), suggesting these NT219’s targets as potential biomarkers for NT219+cetuximab therapy. Based on the
phase 1/2 dose escalation study, we determined the RP2D for NT219 at 100mg/kg. In February 2025, we entered into a research agreement
with the University of Colorado for an investigator-initiated Phase 2 study of NT219 in patients with recurrent and/or metastatic squamous
cell carcinoma of the head and neck, which was initiated in June 2025 and is expected to conclude in June 2026.
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Our
Strategy
Our
goal is to become a leading player in the development and commercialization of innovative drugs that treat unmet medical needs and can
capitalize on significant market opportunities, focusing on oncology therapeutics.
Key
elements of our strategy are to:
● focus on oncology therapeutic assets for treatment of unmet medical needs, representing a significant market opportunity;
● leverage our expertise in the clinical and regulatory processes in the United States, together with our research and development capabilities and network of professional advisors, to efficiently develop therapeutic candidates in pre-clinical and clinical stages of development and achieve marketing authorization;
● expand our line of therapeutic candidates through the development of new therapeutic candidates based on our platform technology;
● develop new disruptive and innovative technologies in collaboration with third parties, as well as using our in-house capabilities; and
● cooperate with third parties, to both develop and commercialize therapeutic candidates in order to share costs and leverage the expertise of others.
Our oncology therapeutic
candidates, CAPTN-3, our tri-specific platform with its leading therapeutic candidates, IM1240 and IM1305, CM24 and NT219, are further
described below.
Our
Development Programs
CAPTN-3 Tri-specific Platform
Background
For
decades, cancer research has been heavily focused on therapeutic modalities directly targeting cancer cells such as radio- or chemotherapy.
Despite providing significant improvement of patient outcome, these treatments have significant limitations related to poor tolerability
and acquired resistance mechanisms. More recently, further to a better understanding of tumor escape mechanisms, the rise of immuno-oncology
approaches opened new horizons. Immune checkpoint inhibitors designed to release effector immune cells from inhibitory signals delivered
by cancer cells and the TME have become the backbone therapy in numerous oncology indications and new strategies have been explored to
redirect immune cells towards malignant cancer cells.
T
cell engagers is an emerging therapeutic modality that consists in linking tumor infiltrating T cells to target tumor cells via antibody-derived
products. By binding to a TAA with one arm and to the CD3 molecule associated with the T cell receptor (TCR) with the other arm, T cell
engagers promote the formation of a cytolytic synapse between T cells and cancer cells leading to destruction of the tumor. Conceptually,
any cytotoxic immune effector cell can be engaged by this modality including CD8+ T cells, gamma-delta T cells, NK and NKT cells. In
this context, T-cell engagement is independent of the specific recognition of a peptide-MHC complex and in principle, every tumor infiltrating
T cell with cytotoxic potential is expected to be activated by T cell engagers. The first success with this new approach came from blinatumomab,
a CD19/CD3 bispecific that achieved 40% complete response in patients with acute lymphocytic leukemia (ALL) leading to accelerated approval
by the FDA in 2018. Based on our knowledge, multiple T cell engagers are currently being explored in advanced clinical trials.
The
increase in T cell engagers or more generally immuno-engagers that are in development is directly related to the progress in protein
engineering technologies allowing to derive new antibody-based compounds with distinctive features. Compared to monospecific monoclonal
antibodies, multi-specific constructs potentiate antibody-mediated effects, for example they can be used to “crosslink” immune
cells and cancer cells expressing specific TAAs, they can bind two epitopes on the same target to avoid resistance or they can interact
with several TAAs or several immune cells. Numerous formats of bispecific antibody-based therapeutic candidates are being investigated
in clinical studies and the possibilities are further increasing with the emergence of tri- and multi-specific compounds some of which
have already shown potential promising data and are entering clinical testing. The main field for all of these compounds is oncology,
and in general, at least one of the specificities is intended to redirect T- or NK cells. Based on new research and clinical insights,
the rationale for dual engagement of T and NK cells is attaining stronger recognition and this is one of the main features of our tri-specific
platform.
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CAPTN-3
Tri-specific Platform Description
Our
CAPTN-3 tri-specific platform is comprised of conditionally activated tri-specific antibodies that engage both T cells and NK cells and
a specific TAA to induce a strong, localized immune response within the TME. A cleavable capping technology confines the compound’s
therapeutic activity to the local TME, which increases the anticipated therapeutic window in patients. This technology presents a novel
mechanism of action by unleashing both innate and adaptive immune responses at the TME to induce an optimal anti-tumor immune response.
T
cell engagement is achieved through binding CD3 using a commercially validated antibody fragment. CD3 is a protein complex associated
with the T cell receptor on the surface of both CD4+ and CD8+ T cells. Agonistic binding to CD3ε triggers
T cell activation that is mediated by Lck/Zap70 and leads to downstream activation of multiple signaling pathways such as NK-kB or NF-AT.
Anti-CD3 is the backbone of the vast majority of bispecific T cell engagers (BiTE). Three products were already approved by the US FDA
(Blinatumomab, CD3×CD19 in 2014 for acute lymphoblastic leukemia, Tebentafusp, CD3×IMCgp100 in 2022 for Uveal Melanoma, teclistamab,
CD3xBCMA in 2022 for Multiple Myeloma and Tarlatamab CD3xDLL3 in 2024 for SCLC) and a large number other BiTE are currently in clinical
development.
The
NK cell mediated activity is manifested by the NK cell engager arms of NKG2A or NKG2D. The NKG2A arm of the tri-specific blocks the interaction
between NKG2A, an inhibitory receptor expressed on NK cells or CD8+ T-cells, and the HLA-E ligand expressed on cancer cells. Blockage
of the inhibitory effect of NKG2A-HLA-E interaction allows NK and T-cell activation and thereby, promotes tumor suppression, and consequently
induces cell killing. The NKG2D of the tri-specific arm inhibits the interaction between NKG2D, an activating receptor expressed on NK
cells and CD8+ T-cells, and its ligands expressed on cancer cells, eliciting cytotoxicity of NK and T cells against the tumor. This activation
of NKG2D triggers cellular proliferation, cytokine production, and cancer cell killing.
In
addition to its unique combination of the TAA, CD3 and NK cells binding arms, our CAPTN-3 tri-specific platform is also differentiated
from competing products with a cleavable cap, which limits the compound’s therapeutic activity to the local TME. This cap is attached
to the anti-CD3 moiety and blocks its interaction with circulating CD3 positive T cells thereby impeding potential off-tumor adverse
reactions. The cap is designed to be cleaved-off by multiple TME-specific proteases, which increase the likelihood for cleavage
by many tumor types. Upon removal of this cap, the anti-CD3 moiety of the molecule is freed to bind and activate T lymphocytes via CD3.
In addition, the cap design incorporates a human serum albumin (HSA) binding domain designed to extend the molecule’s half-life.
Our lead tri-specific antibodies
in preclinical development are IM1240, which targets 5T4 expressing tumors, and IM1305, which targets TROP2 expressing tumors.
IM1240:
IM1240, our lead CAPTN-3 tri-specific antibody, targets the novel tumor associated antigen 5T4, which is expressed in a variety of solid
tumors and is associated with advanced disease, increased invasiveness and poor clinical outcome. IM1240 is directed towards 5T4 (also
known as trophoblast glycoprotein (TPBG)), using a proprietary set of complementarity-determining regions (CDRs). 5T4 is an oncofetal
surface protein that is not found on adult healthy tissues but is abnormally expressed in several cancer types. This specific expression
pattern as well as the correlation with poor prognosis in different cancer diseases such as lung, gastric, head and neck and other cancers
makes it an ideal TAA for various therapeutic approaches.
Preclinical data
IM1240 is the outcome of
significant lead optimization work to maximize the compounds properties in terms of affinity, efficacy and safety. The different tribodies
demonstrated high affinity for 5T4, CD3 and NK cell inhibitory receptor and efficient anti-tumor responses in in vitro killing assays.
The
benefit of the dual T cell/ NK cell activation was demonstrated in cytotoxicity assays against various 5T4+ cancer cells lines,
and in an autologous patient-derived non-small cell lung cancer (NSCLC) explant study, where the 5T4xCD3xNK tri-specific was more potent
than either the 5T4xCD3 or the 5T4xNK variants. In terms of specificity no cytotoxicity was observed in 5T4 negative cancer cells.
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The
relevance and robustness of the cleavable capping system was investigated in xenograft models using immune-competent mice. Sustained
tumor regression was achieved with the tri-specific harboring a cleavable cap. The effect was superior to a variant with no cap, illustrating
the detrimental effect of peripheral engagement of tumor-irrelevant T cells. The efficacy was completely lost using a variant with non-cleavable
cap in which the CD3 arm of the tri-specific remained blocked.
Additional preclinical data
for IM1240 demonstrated that:
● IM1240, demonstrated high affinity binding towards CD3 & NKG2A proteins and CD3 & NKG2A expressing cells, while no binding was detected using the mutated versions of the tri-specific, indicating specificity. The synergistic effects of the aCD3 and aNKG2A arms in suppressing 5T4+ NSCLC PDEs at 10nM were demonstrated, emphasizing CAPTN-3’s potential advantage in a clinically relevant biological assay. A dose-dependent effect of IM1240 was shown.
● Sustained tumor regression in triple negative breast cancer humanized mice was demonstrated for the capped tri-specific, which was superior to the uncapped tri-specific. No effect was shown with the non-cleavable capped tri-specific whose CD3 binding function is irreversibly blocked.
● Cytotoxic effect and binding to CD3 was fully recovered following capping cleavage.
● PBMC-mediated cytotoxicity against 5T4+ cancer cells was demonstrated at picomolar EC50 while no effect was observed in 5T4- cancer cells.
● IM1240 and non-capped tri-specific inhibited NKG2A-HLA-E interaction in a dose-dependent manner, while NKG2A mutated tri-specific had no effect.
● NK cell mediated cytotoxicity against HLA-E expressing cancer cells was demonstrated, while NKG2A mutated tri-specific had no effect.
● A cytokine release assay from hPBMC showed a 5T4+ cancer cell dependency and was inhibited by the cap, showing superior safety profile.
● Plug and Play abilities of the platform were demonstrated through different tribodies targeting 5T4 (aCD3xa5T4xaNKG2A), EGFR (aCD3xaEGFRxaNKG2A) and NKG2D (aCD3xa5T4xaNKG2D) which demonstrated low nM and selective binding to cells overexpressing the target, and efficient PBMC and NK mediated cytotoxicity.
In
September 2025, we announced that research by Dr. Amir Horowitz of the Tisch Cancer Institute at the Icahn School of Medicine at Mount
Sinai Dr. Amir Horowitz demonstrated that IM1240 induces tumor cell death in treatment-resistant head and neck cancer biopsies. Using
fresh biopsies of head and neck squamous cell carcinoma (HNSCC) patients who have acquired resistance to anti-PD1 therapy, the results
have shown induction of cancer cell apoptosis by the tri-specific IM1240 (capped-CD3x5T4xNKG2A), while none of the related variant bispecifics,
having either a non-functional CD3 arm (5T4xCD3) or NKG2A arm (5T4xNKG2A), showed an effect. The results correlate with patient-derived
NSCLC tumor explants previously reported and suggest a synergistic effect of the CD3 and the NKG2A arms, a design which is unique to
our CAPTN-3 platform. Additionally, robust data analysis representing of approximately 26,000 human transcriptomes across most solid
tissues suggests that NKG2A expression is consistently accompanied by both HLA-E and 5T4 in solid tissues, but not in blood, supporting
the design of IM1240 that targets 5T4 and potentially reducing safety concerns.
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In
October 2025, we announced that we had achieved a manufacturing and scalability milestone with a commercially viable yield for IM1240.
We have developed a high-efficiency manufacturing and purification process for developing IM1240.
In
December 2025, we reported positive new data preclinical data for IM1240, generated in collaboration with the laboratory of Dr. Amir
Horowitz of the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai:
● IM1240 demonstrated significant anti-tumor activity in three PD1–resistant ex-vivo models, including new results in HNSCC patient-derived biopsies. In these studies, IM1240 induced tumor cell apoptosis, with anti-tumor activity dependent on both CD3 and NKG2A arms.
● IM1240’s immune-mediated anti-tumor activity in PD1-resistant NSCLC patient derived explants was evidenced by a significant increase in IFNγ secretion.
● To discern IM1240’s selectivity, a transcriptomic analysis of ~11,000 TCGA (The Cancer Genome Atlas) human samples showed that NKG2A expression co-occurs with 5T4 in solid tissues, which provides rationale for inclusion of the αNKG2A arm unique to the CAPTN-3 platform.
In
January 2025, we successfully completed a non-human primates toxicology study of IM1240. In the study, IM1240 demonstrated a favorable
safety and tolerability profile, with hematologic findings that align with its expected pharmacodynamic effects on immune activation.
The CD3 capping design of IM1240 showed clear differentiation compared with the non-capped comparator, IM1222, enabling a significant
reduction in immune-related effects, including cytokine release, which remained modest, even at doses up to 300-fold higher than those
of the non-capped antibody. IM1240 demonstrated a favorable pharmacokinetic profile in the study, characterized by increased systemic
exposure and a prolonged circulating half-life. Pharmacokinetic analyses showed dose-dependent and proportional increases in exposure,
as reflected by both AUC and Cmax. In addition, efficacy observed in vivo in tumor-bearing mice occurred at exposures meaningfully
lower than those achieved in the study, further supporting IM1240’s advantageous therapeutic window.
Competitive Oncology Drugs in Development
that Target 5T4
We
face potential competition from companies developing therapies targeting 5T4, as well as those utilizing proteolytically cleaved, conditionally
activated platforms. Several companies are advancing 5T4-targeted therapies, including antibody-drug conjugates (ADCs), bispecific antibodies,
and T-cell engagers, which may directly compete with IM1240. Additionally, several companies are developing conditionally activated biologics
designed to enhance tumor selectivity while minimizing off-tumor toxicity. The potential of our approach differentiates IM1240, we believe,
through its unique mechanism of action and potential clinical benefits.
IM1305: IM1305 (capped-CD3xTROP2xNKG2A),
our second CAPTN-3 tri-specific antibody, contains a masked anti-CD3 arm, as well as an anti-NKG2A arm, and an anti-TROP2 arm. The potent
anti-CD3 arm is masked at the periphery with a cleavable cap, designed to be removed specifically in the TME, which is expected to reduce
the risk of off-target cytokine release and potentially enables higher dosing to achieve increased efficacy.
Encouraging
preclinical results targeting TROP2 have demonstrated sustained tumor regression of human triple negative breast cancer (TNBC) in a mouse
model, with no detectable tumor recurrence following treatment completion. Significant cell death induction was demonstrated in multiple
tumor types, including TNBC, tongue and hypopharyngeal cancers, pancreatic and gastric cancers, at remarkably low doses (EC50 1-5 pM).
TROP2
is broadly expressed across major solid tumors (e.g., breast, lung, gastrointestinal, ovarian) and is associated with poor prognosis.
Supported by prior clinical validation from approved TROP2-directed antibody-drug conjugates (ADCs), the broad potential of targeting
TROP2 makes it a compelling target for the CAPTN-3 platform. Unlike ADCs or monospecific antibodies, CAPTN-3 combines selective TROP2
binding with multi-effector immune recruitment (T and NK cells). This immune synapse–driven cytotoxicity is expected to potentially
be independent of TROP2 density, providing a strong rationale for activity in non-ADC settings and across diverse tumor types.
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Preclinical
data for IM1305 demonstrated that:
● The adaptability of the CAPTN-3 platform and demonstrated high-affinity binding to both TROP2 and NKG2A (EC₅₀ ~2 nM).
● Potent PBMC-mediated tumor cell killing was observed at low concentrations (EC₅₀ 1–5 pM) across multiple tumor types, including triple-negative breast, gastric, pancreatic, and head and neck cancers.
● Like IM1240, IM1305’s anti-cancer activity and CD3 binding were fully restored after cap cleavage, a critical component of CAPTN-3’s conditional activation design.
● In humanized triple-negative breast cancer mouse models, IM1305 induced sustained tumor regression at low doses (p < 0.0001), reinforcing the platform’s broad application potential.
Competitive Oncology Drugs in Development
that Target TROP2
We face potential competition
from companies developing therapies targeting TROP2, as well as those utilizing proteolytically cleaved, conditionally activated platforms.
Several companies are advancing TROP2-targeted therapies, including antibody-drug conjugates (ADCs), bispecific antibodies and T-cell
engagers, which may directly compete with IM1305. In particular, TROP2-targeted ADCs have been approved or are in late-stage clinical
development for multiple solid tumor indications, including sacituzumab govitecan and datopotamab deruxtecan, and additional TROP2-directed
biologics and cell-engaging therapies are being investigated. Additionally, several companies are developing conditionally activated
biologics designed to enhance tumor selectivity while minimizing off-tumor toxicity. The potential of our approach differentiates IM1305,
we believe, by virtue of its multi-specific mechanism of action, which is designed to simultaneously engage tumor cells, T cells and
NK cells while confining immune activation to the tumor microenvironment.
CM24
Background
CM24
is a humanized monoclonal antibody directed against CEACAM1, a multi-faceted membrane protein belonging to the Human CEA protein family
that acts as an immune checkpoint inhibitor, a pro-angiogenic, anti apoptotic agent, and a protein that promotes tumor invasiveness and
metastases. Evidence has shown that CEACAM1 is expressed on tumor infiltrating lymphocytes and its expression is up-regulated in several
cancer types. Moreover, CEACAM1 is associated with mechanisms of trophism and metastases in cancer, manifest through mechanisms such
as neutrophil extracellular traps.
The
technology originated from the laboratory of Dr. Gal Markel from Sheba Medical Center and initially developed by cCAM Biotherapeutics
Ltd. (cCAM), which was acquired by Merck Sharp and Dohme Corp. (MSD), in 2015.
MSD
conducted a phase 1 clinical trial, including patients with metastatic melanoma, non-small cell lung cancer, bladder, gastric, colorectal
and ovarian cancer patients. In this initial Phase 1 dose ranging study of CM24 as single agent, a stable disease rate of approximately
33% among the evaluable patients was noted as best overall response. Despite no known safety risks, MSD discontinued the clinical study
and returned the rights of CM24 to former cCAM shareholders and founders of FameWave. Review of the Phase 1 study results by external
scientific advisors retained by us suggested that while CM24 was generally safe, higher doses of the antibody along with a modified dosing
regimen in a defined patient population would be warranted.
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The
Mechanism of Action
CM24
is a humanized monoclonal antibody directed against CEACAM1, a multi-faceted membrane protein belonging to the Human CEA protein family
that acts as an immune checkpoint inhibitor, a pro-angiogenic, anti apoptotic agent, and a protein that promotes tumor invasiveness and
metastases.
CEACAM1
belongs to the CEA superfamily. CEACAM1 interacts with itself (i.e., hemophilic interaction) and with CEACAM5 (heterophilic interaction),
as well as with various bacterial proteins. Different functions have been attributed to the CEACAM1 protein: anti-proliferative properties
in carcinomas of the colon and prostate, or facilitation of proliferation in melanoma; central involvement in angiogenesis, insulin clearance
and immune-modulation. CEACAM1 is expressed by many types of tumors and is associated with poor prognosis in cutaneous melanoma, uveal
melanoma, hepatocellular carcinoma, cholangiocarcinoma, gastroesophageal adenocarcinoma colorectal adenocarcinoma and lung cancer. In
addition, increased CEACAM1 expression on cancer tissues and peripheral blood lymphocytes and elevated serum CEACAM1 were observed in
patients with melanoma, osteosarcoma and pancreatic carcinoma. These collective observations provide a strong justification for the development
of a therapeutic approach that targets the tumor promoting functions of CEACAM1.
Earlier
preclinical studies revealed CM24 reversed CEACAM1-mediated immune evasion by abrogating CEACAM1-CEACAM1 interactions, restoring Zeta-chain-associated
protein kinase 70 (ZAP70) phosphorylation and TCR-driven effector functions, while maintaining antigen-restricted recognition. This abrogates
the immunosuppressive function of CEACAM1, promoting cell killing by T cells and NK cells.
CM24
is a blocking monoclonal antibody that prevents CEACAM1-CEACAM1 and CEACAM1-CEACAM5 interactions, thus enhancing the cytotoxic activity
of lymphocytes, attenuating metastatic processes, preventing angiogenesis, and promoting tumor apoptosis.
CEACAM1
is also part of the NETs complex. NETs are regarded as an important member of the TME, which contribute to metastatic dissemination and
immune evasion. We have demonstrated direct binding of CM24 to NETs, and inhibition of NET-induced cancer cell migration by CM24. The
effects on NETs demonstrate a novel mechanism of action for CM24, which may support the role of CM24 in controlling immune evasion, metastasis,
NET-related complications and patient’s survival.
CM24
Suppresses Neutrophil Extracellular Trap (NET)-Induced Migration and Metastasis of Cancer Cells
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Preclinical
and Mechanism of Action and Target Validation
Preclinical
studies have shown evidence that CM24 enhances the cytotoxic activity of tumor-infiltrating lymphocytes (TILs) against various CEACAM1-positive
tumor cell lines. Our preclinical studies have shown that CM24 attenuates NET-induced tumor cell migration. CM24 is being developed for
multiple oncological indications according to the expression pattern of its target protein. Additional preclinical studies showed that
a combination of CM24 with PD-1 and PDL-1 antibodies resulted in a synergistic anti-cancer effect. Additional preclinical studies provide
strong justification for CM24’s mechanism of action in activating the immune system through multiple pathways as validated by world
renowned researchers at Harvard Medical School and MIT, in an article published in Nature* as well as by Dr. Gal Markel from
the Tel HaShomer Medical Center**.
* Huang Y-H, et al., (2015) Nature, 517(7534): 386–390. Doi:10.1038/nature13848
** Markel G., et al., (2006) J Immunol., 177:6062-6071; doi: 10.4049/jimmunol.177.9.6062
Clinical
Development
Phase
1 Clinical Trial
MSD
conducted an interventional, Phase 1, first in human, non-randomized, single group assignment, open-label, multi-centered and multiple
escalating doses study to assess the safety, efficacy, pharmacokinetics and tolerability of the CM24 antibody in the
treatment of subjects with selected advanced or recurrent malignancies including melanoma, non-small cell lung adenocarcinoma
(NSCLC) and bladder, gastric, colorectal or ovarian cancer.
The
main objectives of the MSD clinical study were to assess the safety and tolerability of CM24 and to determine the recommended dose for
Phase 2 trials, characterization of the pharmacokinetic profile and immunogenicity of CM24, and to evaluate the preliminary efficacy
of the drug. The trial was conducted at four sites in the U.S. and Israel and was designed as a dose escalation stage that was to be
followed by an expansion stage. The trial was concluded following administration of CM24 to 27 patients and prior to determining the
recommended phase 2 level and reaching the expansion stage.
Main
conclusions by us from the Phase 1 clinical trials results:
● CM24 was found to be generally safe and well tolerated. There were no DLTs up to 10mg/kg and no drug related morbidity.
● Target saturation was not reached up to 10mg/kg. PK was variable across all patients showing slower clearance and higher half-life with increasing dose. PK modeling suggested that full receptor occupancy may likely require doses >10mg/kg to be administered every 2 weeks.
● Treatment related adverse events noted in 17 subjects: 82% Grade 1, 16% Grade 2 and 2.7% Grade 3. Most frequent were increased liver function tests (LFTs) and anorexia. The two Grade 3 events were headache and abdominal pain; there were 2 deaths that occurred within 30 days from the last administration of CM24 due to disease progression.
● A stable disease rate of approximately 33% among the 24 evaluable patients was achieved, mostly in the two highest dose groups, where approximately half of the evaluable patients achieved stable disease.
The
Phase 1 study showed that CM24 was generally well tolerated and resulted in a stable disease rate of approximately 33% in the evaluable
patients. The Phase 1 study was not designed to pre-screen CEACAM-1 levels on tumor tissue. Furthermore, in this Phase 1 study, no PD-1
inhibitor was tested in combination with CM24. As noted, the doses used in the study were below those required to reach target saturation
as determined by pharmacokinetic evaluations.
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Phase
1/2 Clinical Trials
A
Phase 1/2 study that included three parts has been completed. The trial was conducted in clinical collaboration with Bristol Myers Squibb.
The
first part of the study included a dose escalation of CM24 at 10, 15 and 20mg/kg, in combination with standard dose of the PD-1 inhibitor
nivolumab, in patients with selected solid tumors who have received up to 2 prior regimens for their advanced and/or metastatic disease.
The primary objective of this part of the study was to evaluate safety, tolerability, PK and determine the RP2D.
In
June 2021, we reported on the first dose cohort of the dose escalation phase (10mg/kg), where one patient with refractory advanced MSI-S
pancreatic cancer having been previously treated with two previous regimens, had a confirmed partial response to CM24 and nivolumab,
both with respect to imaging and biochemical markers. The responsive patient showed a 40% reduction in tumor size following two cycles
of treatment with CM24 in combination with nivolumab 480mg/kg q1 month. In addition, levels of CA19-9 tumor marker dropped by 56%, compared
to baseline levels. Additionally, there were no dose-limiting toxicities or serious adverse events observed in any of the three patients
enrolled in the first dose cohort of the study.
In
July 2023, we reported clinical data from the first part of the Phase 1/2 study. Fourteen patients were evaluable for efficacy, out of
which 11 were PDAC patients. The best overall response included 1 PR (PDAC) and 2 Stable Disease (SD) (1 PDAC and 1 papillary thyroid
cancer (PTC)). No DLTs were observed across all dose levels; no Grade 4 or higher adverse events (AEs) or treatment related deaths have
been reported. Pharmacokinetic analysis of CM24 shows exposure is dose-proportional across the 3 doses in this study. Median OS of 4.6
months (95% CI 2.0-11.3) for 11 PDAC patients.
The
second part of the study was designed as a safety (primary endpoint) run-in stage, enrolled patients with advanced/metastatic PDAC who
have received up to one prior regimen for their disease. In this part of the study, PDAC patients received CM24 at 20mg/kg plus nivolumab
at 240mg (both q2 weeks) and one of the following two standard of care chemotherapy regimens of either gemcitabine and nab-paclitaxel
or liposomal-irinotecan (Nal-IRI), 5-fluorouracil and leucovorin. A total of 16 PDAC patients were enrolled in this part of the trial,
eight patients per chemotherapy regimen. No DLT were noted by any of the patients.
The
third part of the study was a randomized Phase 2 study. In December 2024, we reported positive final results from the randomized Phase
2 study, which demonstrate clear and consistent improvement across all efficacy endpoints for CM24 in combination with nivolumab and
Nal-IRI/5FU/LV chemotherapy. The primary endpoint of the study is OS and the secondary endpoints include PFS, ORR and DCR. A Bayesian
methodology was used to estimate the magnitude of effect of the experimental arm versus the standard-of-care arm in each chemotherapy
cohort; the study was not powered for hypothesis testing. A total of 63 patients were enrolled, across 18 centers in the United States,
Spain, and Israel in two parallel and independent randomized study cohorts (total of 2 arms per cohort). The experimental arms administered
patients with CM24 plus nivolumab and one of two standard-of-care chemotherapies for second-line PDAC, dependent on prior first line
therapy regimen; either gemcitabine/nab-paclitaxel or liposomal irinotecan (Nal-IRI)/5-fluorouracil (5-FU) and leucovorin (LV) (Nal-IRI/5FU/LV),
while the control arms administered either respective chemotherapy alone. CA19-9 as well as additional exploratory biomarkers were also
evaluated. Of the 63 patients enrolled, 32 were in the gemcitabine/nab-paclitaxel study (experimental and control) and 31 were in the
Nal-IRI/5FU/LV study (experimental and control). The gemcitabine/nab-paclitaxel-based part of the study was impacted by informative censoring
of the control arm that led to an imbalance between the control and experimental arms, rendering this part of the study unsuitable for
analysis; this part of the study has no impact on the CM24+nivolumab+Nal-IRI/5FU/LV portion of the study.
62
The
study’s final efficacy results in the Nal-IRI/5FU/LV intent to treat (ITT) cohort population are summarized in the following table:
Metric CM24 + Nivolumab + Nal/IRI/5FU/LV Arm (n = 16) Nal/IRI/5FU/LV Arm (n = 15)
Hazard ratio for OS 0.81 (95% CI: 0.38-1.71)
Median OS 7.92 months 5.55 months
6 months OS rate 53% 47%
Hazard Ratio for PFS 0.75 (95% CI: 0.35-1.61)
Median PFS 3.9 months 2.0 months
3 months PFS rate 67% 47%
6 months PFS rate 17% 13%
ORR 25% 7%
DCR 63% 47%
A
consistent and continuous decrease of CA19-9, a clinically validated PDAC biomarker, was observed in the experimental arm reaching a
median percentage reduction from baseline of approximately 80% vs. an increase of 40% in the control arm.
Subgroup
analysis of patients with a range of pretreatment serum CEACAM1 between 6,000 pg/mL and 15,000 pg/mL, resulted in statistically significant
results as follows:
Metric CM24 + Nivolumab + Nal/IRI/5FU/LV Arm (n = 4) Nal/IRI/5FU/LV Arm (n = 7)
Hazard ratio for OS 0.21 (95% CI: 0.04-1.06)
Median OS 9 months 3.9 months
Hazard ratio for PFS < 0.1 (95% CI: 0-inf)
Median PFS 4.7 months 1.8 months
ORR 50% 0%
DCR 100% 43%
An
additional subgroup analysis of patients, which comprised 80% of the patients in the study cohort, with a range of pretreatment serum
CEACAM1 between 6,000 pg/mL and 15,000 pg/mL together with patients with pretreatment serum MPO levels of 200 ng/mL to 600 ng/mL, resulted
in statistically significant results as follows:
Metric CM24 + Nivolumab + Nal/IRI/5FU/LV Arm (n = 13) Nal/IRI/5FU/LV Arm (n = 11)
Hazard ratio for OS 0.39 (95% CI: 0.16-0.98)
Median OS 7.90 months 5.50 months
Hazard ratio for PFS 0.28 (95% CI: 0.11-0.73)
Median PFS 4.1 months 1.9 months
ORR 31% 0%
DCR 69% 36%
Additional
biomarkers analysis based on the patient pretreatment biopsies, demonstrated significant OS and PFS benefit (HR 0.1, P=0.013 and HR 0.19,
P=0.033, respectively) in patients with both high tumor CEACAM1 ( >100) and low Combined Positive Score (CPS≤1) (a measure of PD-L1
positive tumor cells) supporting the CM24/nivolumab combined treatment and its mechanistic rationale, and may open a new opportunity
for patients who are not eligible for anti-PD1 therapy in various indications.
The
CM24+nivolumab+Nal/IRI/5FU/LV regimen was well tolerated, with the most frequent treatment emergent Grade 3 or higher adverse events
being diarrhea (4 patients in the experimental arm vs. 1 patient in the control arm), fatigue (2 patients in the experimental arm vs.
no patients in the control) and neutropenia (2 patients in the experimental arm vs. no patients in the control). Accordingly, no meaningful
difference in safety and tolerability were observed between the experimental arm and standard-of-care arm.
63
Based
on the emerging role of NETs in cancer and the positive findings of our study in this selected population overlapping with CEACAM1 expression,
we are planning a 3-arm Phase 2b study comparing either CM24 plus a PD-1 inhibitor or CM24 monotherapy to standard of care chemotherapy
in multiple tumor types selected based on their NET and CEACAM1 expressions. This design will also investigate the contribution of parts
in regard to the need for PD1 blockade on top of CM24. We plan to target patients with higher serum levels of CEACAM1 and MPO, as they
are potentially more likely to benefit from CM24 treatment. We plan to initiate this study upon partnering or obtaining sufficient investment
to perform this study.
Competitive
Oncology Drugs in Development that Target CEACAM1
The
competitive landscape for CEACAM1-targeting monoclonal antibodies (mAbs) in oncology is still in early development, with most competing
programs remaining in the preclinical phase. Companies such as Ymmunobio (Switzerland), Agenus/Diatheria (Italy), and Neologics Bioscience
(China) are developing anti-CEACAM1 mAbs, but, to the best of our knowledge, none have progressed beyond preclinical studies
NT219
NT219
is a small molecule that presents what we believe is a new concept in cancer therapy by inhibiting two oncology-related pathways, namely
the IRS 1 and IRS 2 and STAT3. NT219 technology has been tested in a number of PDX models where biopsies from patients are implanted
into mice and used to test various cancer drugs. In such models, NT219, alone and in combination with several approved oncology drugs,
displayed potent anti-tumor effects and increased survival in experimental animals harboring various cancers by preventing the tumors
from developing resistance to approved cytotoxic, immune-oncologic, and targeted drug treatments, and by re-sensitizing tumors to the
approved drugs even after resistance has been acquired.
Background
on Cancer Drug Resistance
The
following are high-level summaries of the therapeutic areas we are currently investigating for NT219:
Solid
malignancies (e.g., head and neck, pancreatic, colon and non-small cell lung cancer). According to the Journal of Oncology Practice,
in 2020 roughly one in every 19 people worldwide would either be diagnosed with a solid tumor or be a cancer survivor. According to the
American Cancer Society, lung, pancreatic, and colon malignancies have high mortality rates and poor five-year survival prognosis. Novel,
emerging therapeutic approaches for targeting solid tumors are being developed and tested.
Tumor
Resistance to Cancer Therapies. Resistance to chemotherapy and to targeted therapies is a major problem facing oncology. The mechanisms
of resistance to ‘classical’ cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific
target proteins share many features, such as alterations in the drug target, activation of pro-survival pathways and ineffective induction
of cell death.
Evidence
suggests that among other mechanisms of resistance, inhibition of central oncological target kinases such as EGFR, MEK and mutated-BRAF
could trigger feedback activation of STAT3 and IRS-to-PI3K/AKT, major survival pathways that bypass (prevent) the anti-cancer effects
of various drugs.
Tumor
Resistance to Immunotherapy. While the advent of immune checkpoint blockade (ICB) has dramatically improved the prognosis of many
immune-infiltrated cancers, for others, unfortunately, these benefits have yet to be realized. The main challenge in this field is to
identify combination therapies that can convert immunosuppressive TME to immunoreactive and combat evolved resistance.
IRS.
Insulin Receptor Substrate (IRS) is a junction protein that mediates various mitogenic and anti-apoptotic signals mainly from Insulin-like
Growth Factor-1 Receptor (IGF1R) and Insulin Receptor (IR), but also from other oncogenes such as v-Src and ALK-fusion proteins. IRS
expression is often up-regulated in human tumors, such as prostate, pancreatic, liver, renal and ovarian cancer. Resistance to several
anti-cancer therapies (e.g., inhibitors of EGFR, MEK, mutated-BRAF, mTOR, as well as cytotoxic chemotherapy) may be mediated by IRS up-regulation,
as demonstrated in peer reviewed research articles published in scientific journals.
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STAT3.
STAT3 plays crucial roles in several cellular processes such as cell proliferation and survival and has been found to be aberrantly
activated in many cancer types (such as NSCLC, head and neck cancer, pancreatic cancer and many others). Much research has explored the
leading mechanisms for regulating the STAT3 pathway and its role in promoting tumorigenesis. Evidence suggests that feedback activation
of STAT3 plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies (such
as inhibitors of EGFR, MEK, ALK, as well as 5FU, oxaliplatin and irinotecan).
Mechanism
of Action
NT219
is a first in class small molecule and the only therapeutic candidate to the best of our knowledge that acts as a dual inhibitor of IRS1/2
and STAT3, both of which play major roles in oncogenesis and cancer drug resistance. While most targeted anti-cancer drugs inhibit the
“ON” signal, NT219 activates the “OFF” switch, leading to serine phosphorylation and degradation of IRS-1/2,
reducing STAT3 phosphorylation, and extensively blocking major oncogenic pathways.
IRS
down-regulation can be mediated by several oncogenic pathways (EGFR, MAPK, mTOR, etc.). Blockade of these pathways by various drugs,
could inhibit serine phosphorylation of IRS, leading to the activation of IRS to AKT survival bypass. Therefore, degradation of IRS1/2
by NT219 could potentially prevent resistance and prolong the tumor’s response to various targeted drugs, as depicted below:
There
have been reports in peer reviewed academic literature describing the involvement of Insulin-like Growth Factor-1 Receptor (IGF1R) up-regulation
in drug-resistance. In these cases, blockage of IGF1R direct substrates, IRS1/2, by NT219 could potentially overcome drug resistance.
The
same principle is true for STAT3. Feedback activation of STAT3 is a common resistance mechanism to many targeted cancer therapies (such
as the inhibitors of EGFR, MEK, BRAF) and cytotoxic chemotherapies. Combining these cancer therapies with NT219, which disrupt this feedback
mechanism, could potentially enhance cell death and delay resistance, suggesting a co-treatment strategy that may be broadly effective
in oncogene-addicted tumors.
Degradation
of IRS proteins and blockage of STAT3 by NT219 could potentially prevent resistance to multiple anti-cancer drugs, extend the duration
of effective drug treatment, and restore drug sensitivity in resistant tumors.
NT219
has high affinity and selective binding to its target proteins. NT219 binds covalently to IRS 1/2 and with low nano-molar affinity to
the STAT3. Data from preclinical work showed that a short exposure of cancerous cells to NT219 was sufficient to trigger irreversible
shutdown of these pathways, resulting in a long-term anti-cancer effect.
65
In
April 2021, we reported additional preclinical data supporting the mechanism of action of NT219, that was presented in a poster entitled
“Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2,” at the American Association of Cancer
Research (AACR) 2021 Annual Meeting. CRC represents the fourth most frequent cause of brain metastasis, which is the most common brain
tumor. The preclinical data updates and expands on the results previously reported by the Company in collaboration with Dr. Ido Wolf,
Head of the Oncology Division at Tel Aviv Sourasky Medical Center. The study included an analysis of more than 16,000 human CRC local
and metastasis samples and revealed an increased amplification of IRS2 in brain metastases. In an in vitro system mimicking the brain
microenvironment, IRS2-overexpressed CRC cells showed prolonged survival. Importantly, transcriptomic analysis demonstrated significant
enrichment of the oxidative phosphorylation (OXPHOS) pathway by IRS2. CRC cells expressing IRS2 showed increased mitochondrial activity
and glycolysis-independent viability. Inhibition of IRS2 using NT219 dose- dependently inhibited IRS2-expressing cells viability and
OXPHOS genes expression. The Wnt/β-catenin pathway was among the most significantly enriched pathways in the brain metastasis, as
IRS2-expressing cells showed increased transcriptional activity of the β-catenin. In addition, NT219 decreased the transcriptional
activity of β-catenin in IRS2- expressing CRC cells to a greater extent than AKT and PI3K inhibitors, and most significantly suggested
relevance of IRS2 in activating β- catenin. It was further shown that 5-FU, a chemotherapy approved for treating CRC, elevated β-catenin
expression, and that NT219 diminished both 5FU-induced and the basal level of the β-catenin expression. Utilizing an intracranial
animal model, it was also demonstrated that while 5-FU alone had no significant effect, the combination of 5-FU and NT219 significantly
inhibited the formation of brain metastasis and extended survival rates of the study mice.
In
October 2021, an article was published in Nature Cancer demonstrating mechanisms behind cancer cell persistence frequency and potential
of NT219 to reduce therapeutic resistance. The article titled, “IRS1 phosphorylation underlies the non-stochastic probability of
cancer cells to persist during EGFR inhibition therapy”. The lead author of the publication is Ravid Straussman, M.D., Ph.D., Department
of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. The article demonstrated mechanistic evidence of cancer cells’
inherited therapeutic resistance, termed chance to persist (CTP). It was shown in preclinical models, that the CTP EGFR inhibition is
modulated by serine/threonine phosphorylation of the IRS1. Specifically, it has been shown that higher phosphorylation of IRS1 multiple
serine/threonine sites, which blocks IRS1 activity, results in increased susceptibility to EGFR inhibitors. A combination of NT219, which
triggers serine phosphorylation and subsequent degradation of IRS1 and EGFR inhibitors, resulted in a synergistic effect, leading to
tumor regression and delayed recurrence upon treatment withdrawal.
Preclinical
results
In
preclinical studies, NT219, in combination with several approved cancer drugs, displayed potent anti-tumor effects and increased survival
in various cancers by preventing the tumors from developing drug resistance and restoring sensitivity to the drugs after resistance is
acquired. NT219 has shown efficacy in various PDX models originated from head and neck, cancer, non-small cell lung cancer (NSCLC), sarcoma,
melanoma, pancreatic, and colon cancers.
Efficacy
of NT219 was demonstrated in combination with three major classes of oncology drugs:
1) Antibodies such as the EGFR antibody (Erbitux) and the immuno-oncology anti-PD1 antibody (Opdivo™, Keytruda);
2) Kinase Inhibitors such as blockers of EGFR (Tagrisso, Tarceva), MEK (Mekinist), Mutated BRAF (Zelboraf), and mTOR (Afinitor); and
3) Chemotherapy agents such as gemcitabine (Gemzar), 5FU, and Oxaliplatin.
In
2021, we expanded an existing research agreement, led by Menashe Bar-Eli, Ph.D., Professor, Department of Cancer Biology, at The University
of Texas MD Anderson Cancer Center, to evaluate the potential efficacy of the combination of NT219 and immuno-oncology drugs, such as
anti-CTLA4 or anti-PD1/PDL1 antibodies.
66
In April 2023, we reported
preclinical results of this research and supportive mechanism of action data, that was presented in a poster entitled “NT219 induces
tumor PD-L1 expression and potentiates anti-PD-1 efficacy” at the American Association of Cancer Research (AACR) 2023 Annual Meeting.
The findings showed that NT219 sensitizes resistant melanoma tumors to αPD-1 and prolongs mouse survival, providing a rationale
for combining anti-PD-1 therapy with NT219 as a potential strategy to overcome resistance to immune checkpoint blockade (ICB) therapy.
Immune profiling of the ICB-resistant
tumors following treatment of the mice with the combination of NT219 with α-PD-1 or α-CTLA4 demonstrates reprograming of
the TME and reveals enhanced infiltration and activation of cytotoxic T cells and NK cells, paralleled with a decrease in T regulatory
cells, M2 macrophages and monocytic and MDSCs, suggesting the potential of this combinations to restore the efficacy of anti-PD-1 and
anti-CTLA4 therapies by converting immunosuppressive TME to immunoreactive.
In April 2024, we reported
preclinical data, showing the potential of NT219 to effectively suppress cancer stem cells, a critical cell population for tumor propagation,
characterized by self-renewal and multipotency, and known to promote resistance and tumor recurrence, in a poster presentation entitled
“NT219, a dual inhibitor of IRS1/2 and STAT3, suppresses cancer stem cell mediated resistance to KRASG12C and KRASG12D inhibitors
in solid tumor” at the American Association of Cancer Research (AACR) 2024 Annual Meeting. In addition, the data demonstrated the
synergistic effect of NT219 and mKRAS inhibitors, suggesting a novel mechanism to combat resistance to both KRASG12C and KRASG12D inhibitors
in lung cancer and pancreatic cancers, respectively, both aggressive diseases with unmet medical need.
Clinical Development
The NT219 clinical development
strategy will align with preclinical findings, focusing on STAT3 and IRS/AKT pathway inhibition as key resistance mechanisms. Initial
tumor targets will reflect MEK/ERK pathway involvement, particularly those with erb-b pathway dependence or driver mutations.
Additionally, evidence of NT219’s single-agent activity in preclinical studies will be considered in the clinical plan.
The primary endpoint of the
NT219 first-in-human study was to evaluate the drug’s safety both as a monotherapy and in combination with the antibody cetuximab.
Initial evidence supporting NT219’s efficacy was assessed as a secondary endpoint.
The first in human Phase
1 study of NT219 evaluated single agent NT219 at a dose escalation, in patients with advanced cancer diseases. Patients for this component
of the trial (deemed Part A) were evaluated for safety as the primary endpoint, and efficacy as a secondary endpoint. The escalation
took the form of a 3+3 standard design, together with a “backfill” groups enrolling of up to 3 additional patients at doses
which had already been deemed safe. Patients were administered NT219 weekly until disease progression or study withdrawal for any other
cause.
Part B of the Phase 1 clinical
trial of NT219 was a dose escalation study of NT219, beginning with 6mg/kg, in combination with the standard dose of cetuximab (ERBITUX®),
in patients with recurrent and/or metastatic SCCHN and colorectal adenocarcinoma (CRC). In this arm, patients with advanced cancer, who
were eligible for cetuximab therapy (e.g., SCCHN and CRC), received a combination of the drugs, with NT219 being administered first,
followed by cetuximab, in a similar course of weekly administrations. The combination was evaluated in a similar 3+3 design and backfill
groups as described for single agent part of the study.
These two parts of the study
provided information regarding the safety of NT219 as a single agent and in combination with cetuximab, including the determination of
the RP2D, as well as preliminary efficacy signal of NT219 as a single agent and in combination with cetuximab.
In the dose escalation part
of the study of NT219 as a single agent, 20 patients were evaluable of which 2 patients demonstrated partial response (1 confirmed, 1
nonconfirmed) and 5 patients demonstrated stable disease. In the dose escalation study of NT219 in combination with cetuximab, anti-tumor
activity was observed in previously treated HPV negative 2L/3L R/M SCCHN patients. 18 SCCHN patients were enrolled in the combination
arm; 16 patients were evaluable for efficacy, 8 of which were at the highest dose levels of 50+100 mg/kg. Out of these 8 patients, 2
patients demonstrated confirmed partial response and 3 patients demonstrated stable disease, representing a 25% objective response rate
(ORR) and 62.5% disease control rate (DCR). Median follow-up across all dose levels is 9.4 months (95% CI: 3.4-10.0, 8 out of 15
patients remaining in follow up). Safety profile was well tolerated and manageable including at the recommended dose level of 100mg/kg.
Most common treatment emergent AEs were infusion related reactions and nausea and no treatment-related Grade 4/5 AEs were observed. Pharmacokinetic
analysis demonstrated dose dependent increase.
67
Biomarker analysis of biopsies
collected from SCCHN patients before treatment with NT219 (50mg/kg) and cetuximab, demonstrated enhanced activation of IGF1R and STAT3
in responders (PR) as compared to non-responding patients (progressed disease), suggesting these NT219’s targets as potential biomarkers
for NT219+cetuximab therapy. We believe these initial results should be further explored in a higher number of patients.
The recommended Phase 2 dose
for NT219 in combination with cetuximab for the treatment of R/M SCCHN patients based on the Phase 1/2 dose escalation study was determined
to be 100mg/kg.
In February 2025, we entered
into a research agreement with the University of Colorado for an investigator-initiated Phase 2 study evaluating NT219 in patients with
recurrent and/or metastatic squamous cell carcinoma of the head and neck, which was initiated in June 2025.
Competitive Oncology Drugs in Development
that Target IRS1/2 or STAT3
We are not familiar with
other therapeutic candidates acting as dual inhibitor of both IRS1/2 and STAT3. Similarly, we are not aware of any other inhibitor of
IRS1/2 in active development. However, there are some clinical-stage STAT3 inhibitors, such as danvatirsen, an antisense nucleotide developed
by AstraZeneca for pancreatic, NSCLC and mismatch repair deficient colorectal cancers. Although they are not direct competitors of NT219,
inhibitors of Insulin Like Growth Factor 1 Receptor (IGF1R) acting upstream of IRS1/2, such as dalotuzumab, developed by Merck &
Co for pancreatic cancer, or ganitumab, developed by Amgen in Ewing Sarcoma, are also closely monitored.
Intellectual Property
Patents, trademarks and licenses and market
exclusivity
Our policy is to seek to
protect our proprietary position by, among other methods, filing U.S. and foreign patent applications related to our proprietary technology,
inventions and improvements that are important to the development of our business. We also rely on our trade secrets, know-how and continuing
technological innovation to develop and maintain our proprietary position. We vigorously defend our intellectual property to preserve
our rights and gain the benefit of our technological investments. Our business is not dependent, however, upon any single patent, trademark
or contract. See “Item 3. Key Information – D. Risk Factors – Risks Related to Intellectual Property”.
CAPTN-3 Tri-specific
Platform
● Patent Family 1 relates to conditionally activated tri-specific antibodies that engage T cells, NK cells, and tumor cells, including the antibody clone identified as IM1240, compositions thereof, and methods of use thereof for treating cancer in a subject in need. The tri-specific antibodies further include a cleavable capping technology for regulating the binding/activation of T cells to within a TME and for extending the half-life of the antibodies. National Phase applications have been entered and are pending in Australia, Brazil, Canada, China, Europe, Israel, India, Japan, the Republic of Korea, Mexico, and the United States. The expected term of any granted national phase application is May 4, 2041, not including patent term extension.
68
● Patent Family 2 relates to conditionally activated tri-specific antibodies that engage T cells, and tumor cells using two arms targeting tumor antigens. A patent has been granted in China. National Phase applications have been entered and are pending in China (as a divisional), Europe, Hong Kong, and the United States. The expected term of any granted national phase application is March 26, 2044, not including patent term extension.
● In addition, we own two additional patent families related to conditionally activated tri-specific antibodies that engage T cells, NK cells and tumor cells and cover different TAAs with their respective CDRs and compositions thereof, and methods of use thereof for treating cancer as well as GvHD, viral or bacterial infections. National phase applications for a patent family related to anti 5T4 antibodies have been entered in Australia, Brazil, Canada, China, Eurasia (allowed), Europe, Israel, India, Japan, the Republic of Korea, Mexico, and the United States. A U.S. provisional patent application related to conditionally activated tri-specific antibodies targeting trophoblast cell surface antigen 2 (TROP2) has also been filed in 2025.
CM24
FameWave’s patent and
patent application portfolio, covering the entire CEACAM1 antibody termed CM24 and other antibodies and uses thereof, includes six patent
families, covering anti CEACAM1 antibodies and their uses in the treatment of cancer and other diseases.
● Patent Family 1 relates to anti-human CEACAM1 antibodies, hybridoma cells producing these antibodies and methods of using the antibodies. United States patents as well as European counterparts were granted, as well as patents in Brazil, Canada, China, Israel, Japan, Korea and Russia, all of which have a maximum term of April 29, 2030. The European patents were validated in France; Germany; Ireland; Italy; The Netherlands; Poland; Spain; Switzerland; and United Kingdom.
● Patent Family 2 relates to antibodies (in particular chimeric antibodies) as well as molecules having at least the antigen-binding portion of an antibody against the human protein CEACAM1. Two United States patents as well as two European counterparts were granted. The European patents are validated in Germany, France, Spain, Italy, United Kingdom, Ireland, The Netherlands, Poland and Switzerland. Patents were also granted in Brazil, Canada, China, India, Israel, Japan, Korea and Russia. The patents of this family have a maximum term of October 10, 2032, except for the U.S. patents that has a maximum term of May 22, 2030.
● Patent Family 3 relates to compositions comprising anti-human CEACAM1 antibodies, compositions comprising antibodies capable of inhibiting or blocking the interaction between PD-1 and its ligands, and methods for their combined use in treating cancer. Patents have been granted in the United States, Europe (2 patents), Brazil, Canada, China, India, Japan, Korea, Mexico and Russia. The European patents were validated in United Kingdom, Ireland, The Netherlands, Germany, Spain, Italy, France, Switzerland and Poland. These patents have a maximum term of November 25, 2034.
● Patent Family 4 relates to humanized antibodies, including CM24, capable of specific binding to human CEACAM1 molecules containing human-to-murine back-mutations in non-CDR variable regions, and their encoding polynucleotide sequences. Patents have been granted in the United States (2 patents), Europe, Brazil, Canada, China, Eurasia (validated in Russia), India, Israel, Japan Korea and Mexico (2 patents) with a maximum term of April 27, 2035. The European patent was validated in United Kingdom, Ireland, The Netherlands, Germany, Spain, Italy, France, Switzerland and Poland. A continuation-in-part application is pending in the United States.
● Patent Family 5 relates to use of CM24 in inhibition of NET-mediated activities and in prevention and treatment of pathologies associated with these activities. An international (PCT) application was filed on November 9, 2023, claiming priority from U.S. provisional applications filed on November 10, 2022, and September 21, 2023. National phase applications were filed and are pending in the US, Israel, Japan, Mexico, Korea, India, Europe, Russia, China, Canada, and Brazil.
69
License Agreement with Tel HaShomer
On April 16, 2012, cCAM entered
into a license agreement with THM and Ramot at Tel Aviv University Ltd. (“Ramot”), which was effective as of May 25, 2010,
pursuant to which THM and Ramot granted cCAM a worldwide, royalty-bearing, exclusive license to develop, manufacture, produce, market
and sell any biopharmaceutical product and/or diagnostic product using patents and inventions owned by THM and Ramot in connection with
uses of the glycoprotein CEACAM1 (the “THM License Agreement”). The THM License Agreement was subsequently amended in 2013
and in 2015.
In conjunction with the closing
of the reversion agreement amongst MSD, cCAM and FameWave, the parties executed an Assignment and Assumption Agreement by and between
FameWave and cCAM (an MSD subsidiary), according to which cCAM assigned to FameWave all its rights, title and interest in, to and under
the License Agreement, which Assignment and Assumption Agreement was countersigned by each of Ramot and THM, as a condition for closing
of such reversion agreement (defined as the transfer of those certain assets from cCAM and MSD to FameWave).
Under the terms of the THM
License Agreement, THM and Ramot retain ownership of the licensed information (defined as the patents and inventions licensed under the
License Agreement). However, FameWave will own all rights to any data and information created and/or generated by cCAM and subsequently
by FameWave, whether or not its development is based on the licensed information, including any proprietary intellectual or industrial
property rights. FameWave and THM and/or Ramot will jointly own all rights to any data and information mutually created and/or generated
by FameWave together with THS/Ramot/Sheba employees or agents, or TAU’s students, employees or agents.
FameWave has the right to
grant sub-licenses to third parties in accordance with the terms set forth in the THM License Agreement. THM and Ramot retain the right
to use the licensed information solely for academic and/or scholarly purposes, provided that such use does not harm and/or expose FameWave’s
confidential information.
In consideration for the
license grant, FameWave agreed to pay to THM an annual license fee, royalties based on a percentage of “Net Sales”, a percentage
of the sales-based sublicense fees, and a percentage of the sublicense fees. Additionally, FameWave has undertaken to pay certain milestone
payments and a percentage of all consideration received by FameWave or its shareholders as a result of or in connection with an exit
event (as defined). Finally, THM also received an assignable warrant to purchase, upon the closing of an IPO of FameWave, ordinary shares
of FameWave, at a price equal to a certain percentage of the forecast initial market value of FameWave for each share as was determined,
prior to the IPO, for the purpose of the IPO.
FameWave agreed to bear sole
responsibility and payment obligations for any damage caused by or on behalf of FameWave or any sublicensee as a result of or in connection
with the THM License Agreement and/or the exercise of the license. FameWave is also required to indemnify THM, Sheba, TAU and Ramot,
and their respective employees, agents and representatives, from and against any and all loss, liability, claims, damages and expenses
(including legal costs and attorneys’ fees) of whatever kind or nature by a third-party that arise out of and/or result from the
THM License Agreement and/or the exercise of the license, or to the extent that they are based on a claim that the licensed information,
the products or other material produced by FameWave infringes any third-party’s intellectual property rights including copyright,
trade secret, patent, or trademark.
Pursuant to the THM License
Agreement, FameWave undertook to develop, manufacture, sell and market products pursuant to the milestones and time schedule attached
to the THM License Agreement. FameWave is required to bear all costs and fees incurred prior to and during the term of the THM License
Agreement, in connection with the preparation, filing, maintenance, prosecution and the like of any patents deemed necessary to protect
the licensed information, and in case of third-party infringement, FameWave is obligated, at its expense, to institute, prosecute and
control any action or proceeding with respect to such infringement.
THM is entitled to appoint
an observer to FameWave’s board of directors who has all the rights of any other director of FameWave save for the right to vote.
To date, THM has not acted on this right.
FameWave has agreed to purchase
and maintain, at its own expense, insurance which covers its liability pursuant to the THM License Agreement, in its name and naming
the indemnified parties as additional insured parties.
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The term of the THM License
Agreement continues on a product-by-product and country-by-country basis, until the later of (i) the date of expiry of the last of the
licensed patents in such country; or (ii) the expiry of a period of 15 years from the first commercial sale in such country.
THM and Ramot may terminate
the THM License Agreement and/or the license if (i) the first commercial sale of the product has not been made within two years from
FDA or CE marketing approval; (ii) FameWave breaches any of its obligations under the THM License Agreement and such breach is not cured
within 60-90 days, depending on the materiality of the breach; (iii) FameWave becomes insolvent, or petitions are filed against it under
insolvency laws; (iv) FameWave has ceased to carry on business as an ongoing concern; or (v) FameWave has challenged, challenges, or
causes any third-party to challenge, the intellectual property rights or other rights or THM or Ramot to the licensed information anywhere
in the world.
Upon termination of the THM
License Agreement, other than due to expiration of the THM License Agreement, all rights granted to FameWace revert to THM and Ramot
and FameWave will not be entitled to make any further use in the licensed information. The THM License Agreement is governed by the laws
of the State of Israel.
NT219
TyrNovo’s patent and
patent application portfolio, covering NT219 and other compounds, includes six patent families, covering compounds that modulate protein
kinase signaling and their use in treatment of protein kinase related disorders, including cancer and neurodegenerative disorders.
● Patent Family 1 relates to compounds modulating the insulin-like growth factor receptor signaling and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer. This family includes a U.S. patent which is due to expire on April 2, 2028.
● Patent Family 2 also relates to compounds modulating the insulin-like growth factor receptor signaling and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer, and specifically discloses and claims NT219. Patents were granted in Europe and Israel, and have a maximum term of June 7, 2029, and in the United States, with a maximum term of April 2, 2028. A reissue application of the U.S. patent has been filed. The European patent was validated in France, Germany, Italy, The Netherlands, Spain, Switzerland, and the United Kingdom.
● Patent Family 3 relates to compounds having a benzo[e][1,3]thiazin-7-one core and methods of using these compounds as chemotherapeutic agents for the treatment of protein kinase related disorders, in particular cancer. Patents were granted in Europe and the United States, with a maximum term of December 27, 2031, and April 9, 2032, respectively. The European patent was validated in France, Germany, Italy, Spain, and the United Kingdom.
● Patent Family 4 relates to combinations of the compounds disclosed in Patent Families 1-3, acting as dual modulators of IRS and STAT3, with various targeted drug classes (inhibitors of EGFR, mTOR; MEK or mutated B-Raf), as well as chemotherapeutic agents (Gemcitabine, 5-FU, Irinotecan and Oxaliplatin), and use of such combinations for the treatment of cancer. Patents were granted in Australia, Brazil, Canada, China, Europe, Japan and Israel, and have a maximum term of February 4, 2036, and in the United States, with a maximum term of August 12, 2036. A patent application is pending in the United States. The first European patent was validated in Switzerland, Germany, Spain, France, Great Britain, Ireland, Italy and The Netherlands. The second European patent is being validated in Switzerland, Spain, Great Britain, Ireland and through the Unitary Patent system.
● Patent Family 5 relates to specific combinations of the compounds disclosed in Patent Families 1-3, with various antibodies against PD-1 protein and/or anti-programmed cell death protein 1 ligand (PD-L1). Patents were granted in Japan, Israel, Mexico and Russia and have a maximum term of November 16, 2037. Patent applications are pending in Brazil, Canada, China, Europe and the United States.
● Patent Family 6 relates to NT219 trans isomer, a method to prevent its conversion from the trans active form to a less active form (cis) and a method of maintaining the active form during manufacturing, storage and handling until administered to the patient. A Chinese patent was granted and has a maximum term of February 17, 2042. Patent applications are pending in Brazil, Canada, China, Europe, India, Israel, Japan, Korea, Mexico, and the United States.
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Exclusive License Agreement with Yissum
In August 2013, TyrNovo entered
into a license agreement with Yissum, which was subsequently amended in April 2014 and March 2017, pursuant to which Yissum has granted
TyrNovo an exclusive license (with the right to sublicense) for the development, use, manufacturing and commercialization of products
using certain patents and know-how owned by Yissum and patent applications filed by Yissum in connection with unique inhibitors of the
IGF-1R Pathway (the “Yissum License Agreement”).
Under the terms of the Yissum
License Agreement, Yissum shall retain the ownership of the Licensed Technology (as such term is defined therein). All rights in the
results of the activities carried out by TyrNovo or third parties in the development of these products (and certain results obtained
under material transfer agreements signed by TyrNovo and Yissum (the “TyrNovo MTAs”)) shall be solely owned by TyrNovo (unless
an employee of the Hebrew University of Jerusalem or each of its branches is an inventor of any of the patents claiming such results,
in which case they shall be owned jointly by Yissum and TyrNovo). TyrNovo has the right to grant sub-licenses to third parties in accordance
with the terms set forth in the Yissum License Agreement.
TyrNovo has agreed to pay
Yissum a percentage of “net sales” as royalties and to pay Yissum a percentage of the income that it receives from granting
sub-licenses to third parties. Additionally, in the event of an M&A prior to an IPO, TyrNovo will be required to pay Yissum a percentage
of the proceeds received under such M&A. In the event of an IPO, then prior to the closing of such IPO, TyrNovo shall issue to Yissum
such number of ordinary shares equal to a certain percentage of all TyrNovo shares. According to the settlement agreement with BIRAD
and an amendment to the Yissum license agreement, BIRAD is entitled to receive a portion of Yissum’s royalties on net sales.
TyrNovo is required to indemnify
Yissum, the Hebrew University of Jerusalem, their directors, employees, executive officers, consultants or representatives and any other
persons acting on their behalf under the license against any liability, including product liability, damages, losses, expenses, fees
and reasonable legal expenses arising out of TyrNovo’s actions or omissions or which derive from its use, development, manufacture,
marketing, sale or sublicensing of any licensed product, licensed technology, and certain information obtained under the TyrNovo MTAs,
or exercise of the Yissum License Agreement, and the TyrNovo MTAs.
TyrNovo has agreed to maintain,
and to add Yissum as an additional insured party with respect to, clinical trials, comprehensive general liability and product liability
insurance as well as an insurance policy with respect to the foregoing indemnification prior to the time when it commences clinical trials
and concludes its first commercial sale.
The term of the Yissum License
Agreement shall expire upon the later of (i) the date of expiration in such country of the last to expire licensed patent included in
the licensed technology; or (ii) the end of a period of 15 years from the first commercial sale in such country, while the license granted
under the Yissum License Agreement will terminate upon the later of (unless the license has been earlier terminated or expired) (i) the
date of expiration in such country of the last to expire licensed patent included in the licensed technology; (ii) the date of expiration
of any exclusivity on the product granted by a regulatory or government body in such country; or (iii) the end of a period of 15 years
from the first commercial sale in such country.
TyrNovo has the right to
terminate the Yissum License Agreement upon a prior written notice. Either party has the right to terminate the Yissum License Agreement
if the other party is in material breach and has not cured such material breach within a certain number of days as of the receipt of
a written notice notifying it of such breach. Additionally, Yissum has the right to terminate the Yissum License Agreement immediately
in the event that TyrNovo does not comply with its obligation (following a certain amount of months cure period) to use commercially
reasonable efforts to develop and commercialize the products; if an attachment is made over the majority of TyrNovo’s assets or
if execution proceedings are taken against TyrNovo and are not set aside within a certain amount of days; or if TyrNovo challenges in
any forum the validity of one or more of the licensed patents. Upon termination of the Yissum License Agreement, TyrNovo shall assign
to Yissum all the results obtained during the development of the product. If Yissum licenses to third parties such results, then TyrNovo
shall be entitled to a percentage of the net proceeds actually received by Yissum from such third parties, up to an amount covering TyrNovo’s
expenses incurred during the development of such assigned results.
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Market exclusivity
In the branded pharmaceutical
industry, a significant part of a branded drug’s commercial value is usually realized during the period in which the product has
market exclusivity. In the U.S. and some other countries, when market exclusivity expires and generic versions of a product are approved
and marketed, there can often be substantial and rapid declines in the branded product’s sales. The rate of this decline varies
by country and by therapeutic category, and by the number of generic competitors entering the market, among other factors; however, following
patent expiration, branded products may continue to have market viability based upon the goodwill associated with the product name, which
may benefit from trademark protection.
A pharmaceutical brand product’s
market exclusivity is generally determined by two forms of intellectual property: patent rights held by the brand company and regulatory
forms of exclusivity to which the NDA-holder is entitled.
Patents are an important
factor in determining market exclusivity for many branded pharmaceuticals. Patents generally provide the patent holder with the right
to exclude others from making, using, offering for sale, selling, or importing an invention related to the medicine. Patents may cover,
among other things, the active ingredient(s), various uses of a drug product, pharmaceutical formulations, drug delivery mechanisms and
processes for (or intermediates useful in) the manufacture of products, and polymorphs. Protection for individual products extends for
varying periods in accordance with the expiration dates of patents in the various countries. The protection afforded, which may also
vary from country to country, depends upon the type of patent, its scope of coverage and the availability of meaningful legal remedies
in the country.
Market exclusivity is also
sometimes influenced by regulatory exclusivity rights. Many developed countries provide certain non-patent incentives for the development
of medicines. For example, the U.S., the European Union and Japan each provide for a minimum period of time after the approval of a new
drug during which the regulatory agency may not rely upon the data of the original applicant to approve a competitor’s generic
copy. Regulatory exclusivity rights are also available in certain markets as incentives for research on new indications, on orphan drugs
and on medicines useful in treating pediatric patients. Regulatory exclusivity rights are independent of any patent rights and can be
particularly important when a drug lacks broad patent protection. Most regulatory forms of exclusivity, however, do not prevent a competitor
from gaining regulatory approval prior to the expiration of regulatory data exclusivity on the basis of the competitor’s own safety
and efficacy data on its drug, even when that drug contains the same active ingredient or is otherwise identical to that marketed by
the original applicant.
It is not possible to predict
the length of market exclusivity for any of our branded products with certainty because of the complex interaction between patent and
regulatory forms of exclusivity, and inherent uncertainties concerning patent litigation. There can be no assurance that a particular
product will enjoy market exclusivity for the full period of time currently estimated or that the actual period of exclusivity will correspond
to our estimates.
Government Regulations and Funding
Pharmaceutical companies
are subject to extensive regulation by foreign, federal, state and local agencies, such as the FDA in the U.S., the Ministry of Health
in Israel, or the various European and other regulatory authorities. The manufacture, distribution, marketing and sale of pharmaceutical
products are subject to government regulation in the U.S. and various foreign countries. Additionally, in the U.S., we must follow the
rules and regulations established by the FDA requiring the presentation of data indicating that our products are safe and efficacious
and are manufactured in accordance with cGMP guidelines. If we do not comply with applicable requirements, we may be fined, the government
may refuse to approve our marketing applications or allow us to manufacture or market our products, our products may be subject to detention
and/or seizure, shipments of our products could be refused entry into the United States, and we may be criminally prosecuted. We and
our manufacturers and CROs may also be subject to regulations under other foreign, federal, state and local laws, including, but not
limited to, the U.S. Occupational Safety and Health Act, the Resource Conservation and Recovery Act, the Clean Air Act and import, export
and customs regulations as well as the laws and regulations of other countries. As a result, pharmaceutical companies must ensure their
compliance with the Foreign Corrupt Practices Act.
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These regulatory requirements
impact our operations and differ from one country to another, so that securing the applicable regulatory approvals of one country does
not necessarily imply the approval of another country. The approval procedures involve high costs and are manpower intensive, usually
extend over many years and require highly skilled and professional resources.
U.S. Food and Drug Administration Approval
Process
The steps usually required
to be taken before a new drug may be marketed in the U.S. generally include:
● completion of preclinical laboratory and animal testing;
● completion of required chemistry, manufacturing and controls testing;
● the submission to the FDA of an IND application, which must be evaluated and found acceptable by the FDA before human clinical trials may commence;
● performance of (or reference to) adequate human clinical trials and studies to establish the safety, pharmacokinetics and efficacy of the proposed drug for its intended use;
● submission and approval of an NDA or BLA; and
● agreement with FDA of the language on the package insert.
Clinical studies are conducted
under protocols detailing, among other things, the objectives of the study, what types of patients may enter the study, schedules of
tests and procedures, drugs, dosages, and length of study, as well as the parameters to be used in monitoring safety, and the efficacy
criteria to be evaluated. A protocol for each clinical study and any subsequent protocol amendments must be submitted to the FDA as part
of the IND review process.
In all the countries that
are signatories of the Helsinki Declaration (including Israel), the prerequisite for conducting clinical trials (on human subjects) is
securing the preliminary approval of the competent authorities of that country to conduct medical experiments on human subjects in compliance
with the other principles established by the Helsinki Declaration.
The clinical testing of a
drug product candidate generally is conducted in three sequential phases prior to approval, but the phases may overlap or be combined.
A fourth, or post approval, phase may include additional clinical studies. The phases are generally as follows:
● Phase I. The Phase I clinical trial is generally conducted on 15-40 patients with advanced metastatic cancers for drugs intended for oncology indications or healthy volunteers for all other indications. Phase I clinical trials typically involve administering escalating doses of the therapeutic candidate in the participants to assess safety, dosage tolerance, determine the maximal tolerated dose (MTD and potentially also the recommended Phase 2 dose (RP2D) and for small non-biological compounds also, absorption, metabolism, distribution and excretion. ;
● Phase II. The Phase II clinical trial involves administering the therapeutic candidate to a small population of sick patients to identify possible adverse events, or safety risks, and preliminary indicia of efficacy for the targeted disease or medical condition;
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● Phase III. The Phase III clinical trial usually comprises multi-center, double-blind controlled trials in hundreds or even thousands of subjects at various sites to assess as fully as possible both the safety and the effectiveness of a drug. Specifically, the Phase III clinical trial is intended to make a comparison between the therapeutic candidate and the standard therapy and/or placebo. These trials are intended to establish the overall benefit/risk profile of the product and to provide an adequate basis for product labeling; In certain circumstances, particularly in oncology indications involving serious or life-threatening diseases or limited treatment options, clinical trials may be conducted as single-arm, open-label studies without a control group. In such cases, regulatory authorities may evaluate the results using alternative endpoints or comparisons to “real world data”; and
● Phase IV. In some cases, the FDA may condition approval of an NDA/BLA for a product candidate on the sponsor’s agreement to conduct additional clinical trials after approval. In other cases, a sponsor may voluntarily conduct additional clinical trials after approval to gain more information about the drug. Such post-approval studies are typically referred to as Phase IV clinical trials.
All clinical trials used
as support for an IND or application for marketing approval must be conducted in accordance with the FDA’s good clinical practices,
or GCP, requirements, including clinical trials conducted outside of the United States. If a clinical trial conducted outside of the
United States is not conducted in accordance with the FDA’s GCP requirements, the FDA may not accept the study as support for an
IND or application for marketing approval. The FDA may order the temporary or permanent discontinuation of a clinical study at any time
or impose other sanctions if it believes that the clinical study is not being conducted in accordance with FDA requirements or that the
participants are being exposed to an unacceptable health risk. An institutional review board, or IRB, generally must approve the clinical
trial design and patient informed consent at study sites that the IRB oversees and also may halt a study, either temporarily or permanently,
for failure to comply with the IRB’s requirements, or may impose other conditions. Additionally, some clinical studies, mostly
in certain types of Phase III clinical trial studies where it is required under the applicable clinical trial protocol, are overseen
by an independent group of qualified experts organized by the clinical study sponsor, known as a data safety monitoring board or committee.
This group recommends whether or not a trial may move forward at designated check points based on access to certain data from the study.
The clinical study sponsor may also suspend or terminate a clinical trial based on evolving business objectives and/or competitive climate.
As a therapeutic candidate
matures through the clinical testing phases, manufacturing processes are further defined, refined, controlled, and eventually validated
around the time that the Phase III clinical trial is completed. The level of control and validation required by the FDA increases as
clinical studies progress. We and the third-party manufacturers on which we rely for the manufacture of our therapeutic candidates and
their respective components (including the APIs) are subject to requirements that drugs be manufactured, packaged and labeled in conformity
with cGMP and other FDA requirements specific to investigational drug candidates. To comply with cGMP requirements and other requirements,
manufacturers must continue to spend time, money and effort to meet requirements relating to personnel, facilities, equipment, production
and process, labeling and packaging, quality control, recordkeeping and other requirements.
Assuming completion of all
required testing in accordance with all applicable regulatory requirements, detailed information on the product candidate is submitted
to the FDA in the form of an NDA/BLA, requesting approval to market the product for one or more indications, together with payment of
a user fee, unless waived. An NDA/BLA includes all relevant data available from pertinent nonclinical and clinical studies, including
negative or ambiguous results as well as positive findings, together with detailed information on the chemistry, manufacture, controls
and proposed labeling, among other things. To support marketing approval, the data submitted must be sufficient in quality and quantity
to establish the safety and efficacy of the product candidate for its intended use to the satisfaction of the FDA.
If an NDA/BLA submission
is accepted for filing, the FDA begins an in-depth review of the NDA. Under the Prescription Drug User Fee Act, or PDUFA, the FDA’s
goal is to complete its initial review and respond to the applicant within ten months of submission, unless the application relates to
an unmet medical need, or is for a serious or life-threatening indication, in which case the goal may be within six months of NDA submission.
However, PDUFA goal dates are not legal mandates, and the FDA response often occurs several months beyond the original PDUFA goal date.
Further, the review process and the target response date under PDUFA may be extended if the FDA requests or the NDA/BLA sponsor otherwise
provides additional information or clarification regarding information already provided in the NDA/BLA. The NDA/BLA review process can,
accordingly, be very lengthy. During its review of an NDA/BLA, the FDA may refer the application to an advisory committee for review,
evaluation and recommendation as to whether the application should be approved. The FDA is not bound by the recommendation of an advisory
committee, but it typically follows such recommendations. Data from clinical studies are not always conclusive and the FDA and/or any
advisory committee it appoints may interpret data differently than the applicant.
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After the FDA evaluates the
NDA/BLA and performs a pre-approval inspection, or “PAI”, on manufacturing facilities where the drug product and/or its API
will be produced. The FDA may also conduct Bioresearch Monitoring, or “BIMO”, at clinical and potentially key laboratories
that participated in the Phase III trial. The FDA will either approve commercial marketing of the therapeutic candidate with prescribing
information for specific indications or issue a complete response letter indicating that the application is not ready for approval and
stating the conditions that must be met in order to secure approval of the NDA. If the complete response letter requires additional data
and the applicant subsequently submits that data, the FDA nevertheless may ultimately decide that the NDA/BLA does not satisfy its criteria
for approval. The FDA could also approve the NDA/BLA with a Risk Evaluation and Mitigation Strategies, or REMS, plan to mitigate risks,
which could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution
methods, patient registries and other risk minimization tools. The FDA also may condition approval on, among other things, changes to
proposed labeling, development of adequate controls and specifications, or a commitment to conduct post-marketing testing. Such post-marketing
testing may include Phase IV clinical trials and surveillance to further assess and monitor the product’s safety and efficacy after
approval. Regulatory approval of drug product candidates for serious or life-threatening indications may require that participants in
clinical studies be followed for long periods to determine the overall survival, or OS, benefit of the drug product candidate.
If the FDA approves one of
our therapeutic candidates, we will be required to comply with a number of post-approval regulatory requirements. We would be required
to report, among other things, adverse reactions and production problems to the FDA, provide updated safety and efficacy information
and comply with requirements concerning advertising and promotional labeling for any of our therapeutic candidates. Also, quality control
and manufacturing procedures must conform to cGMP for approved drug products after our NDA/BLA is approved, if at all, and the FDA periodically
inspects manufacturing facilities to assess compliance with cGMP, which imposes extensive procedural, substantive and recordkeeping requirements.
If we seek to make certain changes to an approved product, such as certain manufacturing changes, we may be required to submit a supplemental
application to the FDA and, depending on the nature of the change, obtain FDA review and approval before the change can be implemented.
For example, if we change the manufacturer of a product or our API, the FDA may require stability or other data from the new manufacturer,
and such data will take time and are costly to generate, and the delay associated with generating these data may cause interruptions
in our ability to meet commercial demand, if any. While physicians may use products for indications that have not been approved by the
FDA, we may not label or promote the product for an indication that has not been approved. Securing FDA approval for new indications
is similar to the process for approval of the original indication and requires, among other things, submitting data from adequate studies
that demonstrate the product’s safety and efficacy in the new indication. Even if such studies are conducted, the FDA may not approve
any change in a timely fashion, or at all.
Section 505(b)(1) New Drug Applications
A Section 505(b)(1) NDA or
BLA, known as the “full NDA or BLA,” is an application that contains full reports of investigations of safety and efficacy
performed by the drug sponsor. CM24, IM1240 and NT219 are not a combination therapeutic candidate or a therapeutic candidate that is
comprised of an API that has already undergone some or all necessary human clinical trials in another therapeutic candidate. Therefore,
if CM24, IM1240 or NT219 are approved for human clinical trials by the FDA or any foreign regulatory agency and show adequate safety
and efficacy data in human clinical trials, we anticipate that CM24, IM1240 and NT219 will require a 505(b)(1) BLA or NDA.
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Special Protocol Assessment
The special protocol assessment,
or SPA, process is designed to facilitate the FDA’s review and approval of drugs by allowing the FDA to evaluate the proposed design
and size of Phase III clinical trials that are intended to form the primary basis for determining a drug product’s efficacy. Upon
specific request by a clinical trial sponsor, the FDA will evaluate the protocol and respond to a sponsor’s questions regarding,
among other things, primary efficacy endpoints, trial design and data analysis plans, within 45 days of receipt of the request.
The FDA ultimately assesses
whether the protocol design and planned analysis of the trial are acceptable to support regulatory approval of the therapeutic candidate
with respect to effectiveness of the indication studied. All agreements and disagreements between the FDA and the sponsor regarding an
SPA must be clearly documented in an SPA letter or the minutes of a meeting between the sponsor and the FDA.
Even if the FDA agrees to
the design, execution and analyses proposed in protocols reviewed under the SPA process, the FDA may revoke or alter its agreement, such
as under the following circumstances:
● public health concerns emerge that were unrecognized at the time of the protocol assessment, or the director of the review division determines that a substantial scientific issue essential to determining safety or efficacy has been identified after testing has begun;
● a sponsor fails to follow a protocol that was agreed upon with the FDA; or
● the relevant data, assumptions or information provided by the sponsor in a request for SPA change, are found to be false statements or misstatements, or are found to omit relevant facts.
In addition, a documented
SPA may be modified, and such modification will be deemed binding on the FDA review division, except under the circumstances described
above, if the FDA and the sponsor agree in writing to modify the protocol and such modification is intended to improve the study.
European Regulatory Authorities
In order to perform trials
in Europe or market or sell our therapeutic candidates in Europe, we must comply with EU Clinical Trial Regulation (CTR) 536/2014, which
stipulates that sponsors seeking approval to conduct a clinical trial in one or more European countries must submit a single online application
via the Clinical Trials Information System (CTIS). This streamlined process enhances efficiency by enabling simultaneous evaluation by
multiple European regulatory authorities and ethics committees, facilitating faster approval and coordination of multinational trials.
Regarding marketing approval
for new drugs, the centralized procedure, managed by the European Medicines Agency (EMA), allows for a single application for marketing
authorization valid across all EU Member States. The European Commission is the authorizing body for all centrally authorized products
and makes a legally binding decision based on EMA’s recommendation. Once granted by the European Commission, the centralized marketing
authorization is valid in all EU Member States as well as in the European Economic Area (EEA) countries: Iceland, Liechtenstein, and
Norway. Our therapeutic candidates, such as CM24, NT219 or IM1240, may be approved through the centralized process.
The Israeli Ministry of Health
Our operations may be subject
to permits from the Israeli Ministry of Health as follows:
First, pertaining to the
import of drugs and/or raw materials, we are required to apply to the Israeli Ministry of Health (“IMOH”) for approval from
its medical devices and accessories unit (AMAR).
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Second, pertaining to research
and development, when we conduct trials in humans in Israel, the trials will be subject to the approval of the local (medical center)
as well as the higher (IMOH) Helsinki Committee, which acts by force of the Public Health Regulations (Trials in Human Beings), 1980
(Trials in Human Subjects Regulations), as amended, and according to the guidelines of the Helsinki Declaration, or any other approval
required by the Ministry of Health. According to the Trials in Human Beings Regulations, the Helsinki Committee must approve every experimental
process that involves human beings. The Helsinki Committee is an institutional committee that acts in the medical institution in Israel
where the trial is performed and is the party that approves and supervises the entire trial process. In practice, the physician, who
is the principal investigator in the trial, submits an application that includes, among other documents, the investigator brochure, clinical
trial protocol and the informed consent form, on behalf of the requesting party. This committee may request changes and/or additional
documents. Applications that are approved by the Helsinki Committee are forwarded to the “high committee” at the IMOH, which
reviews all documents. The IMOH may request additional changes or documents (such as an Investigational Medicinal Product Document, or,
for short, IMPD, which includes details regarding the manufacturing testing and quality of the drug to be tested) as part of its approval
process. The IMOH sends its decision to the medical institute. According to the procedure for medical trials in human beings of the IMOH,
the Helsinki Committee will not approve performance of a medical trial unless it is absolutely convinced that the following conditions,
among others, are fulfilled: (a) the expected benefits for the participant in the medical trial and to the requesting party justify the
risk and the inconvenience involved in the medical trial to its participant; (b) the available medical and scientific information justifies
the performance of the requested medical trial; (c) the medical trial is planned in a scientific manner that enables a solution to the
tested question and is described in a clear, detailed and precise manner in the protocol of the medical trial, conforming with the Helsinki
principles Declaration; (d) the risk to the participant in the medical trial is as minimal as possible; (e) optimal monitoring and follow-up
of the participant in the medical trial; (f) the initiator, the Principal Investigator and the medical institute are capable and undertake
to allocate the resources required for adequate execution of the medical trial, including qualified personnel and required equipment;
(g) the Principal Investigator and the sub-investigator(s) have the appropriate training in the conduct of clinical trials and have necessary
professional experience in conducting such clinical trials; the investigators will follow GCP guidelines, the IMOH and local SOPs; and
(h) the nature of the commercial agreement with the Principal Investigator and the medical institute does not impair the adequate performance
of the medical trial. The IMOH also licenses and regulates the marketing of pharmaceuticals in Israel, requiring the relevant pharmaceutical
to meet internationally recognized cGMP standards.
Pervasive and continuing regulation in
the U.S.
After a drug is approved
for marketing and enters the marketplace, numerous regulatory requirements continue to apply. These include, but are not limited to:
● cGMP regulations require manufacturers, including third-party manufacturers, to follow stringent requirements for the methods, facilities and controls used in manufacturing, processing and packing of a drug product;
● labeling, promotion, and advertising regulations and the FDA prohibitions against the promotion of drugs for unapproved uses (known as off-label uses), as well as requirements to provide adequate information on both risks and benefits during promotion of the drug;
● approval of product modifications or use of a drug for an indication other than approved in an NDA and/or BLA;
● adverse drug experience regulations, which require us to report information on adverse events within the FDA’s specified timeframe;
● post-market testing and surveillance requirements, including Phase IV trials, when necessary for public health protection, or to provide additional safety and effectiveness data for the drug;
● additional FDA reviews and approvals after the initial approval, particularly for any modification in conditions of use, active ingredient(s), route of administration, dosage form, strength or bioavailability, which may require submission accompanied by additional clinical data (which may require additional clinical studies) necessary to demonstrate the safety and effectiveness of the product with the proposed changes; and
● the FDA’s recall authority, whereby it can ask, or under certain conditions order, drug manufacturers to recall from the market a product that is in violation of governing laws and regulation.
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Other U.S. Healthcare Laws and Compliance
Requirements
For products distributed
in the United States, we are also subject to additional healthcare regulation and enforcement by the federal government and the states
in which we conduct our business. Potentially applicable federal and state healthcare laws and regulations that may affect our business
include, but are not limited to, the following:
● The federal Anti-Kickback Statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving, or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order, or recommendation of, any good or service, for which payment may be made under federal healthcare programs such as Medicare and Medicaid;
● The federal Anti-Inducement Law (also known as the Civil Monetary Penalties Law), which prohibits a person from offering or transferring remuneration to a Medicare or State healthcare program beneficiary that the person knows or should know is likely to influence the beneficiary’s selection of a particular provider, practitioner or supplier of any item or service for which payment may be made, in whole or in part, by Medicare or a State healthcare program;
● The Ethics in Patient Referrals Act, commonly referred to as the Stark Law, and its corresponding regulations, prohibit physicians from referring patients for designated health services (including outpatient prescription drugs) reimbursed under the Medicare program to entities with which the physicians or their immediate family members have a financial relationship, subject to narrow regulatory exceptions, and prohibits those entities from submitting claims to Medicare for payment of items or services provided to a referred beneficiary;
● The federal False Claims Act imposes criminal and civil penalties, as well as permitting civil whistleblower or qui tam actions, against individuals or entities for knowingly presenting, or causing to be presented, to the federal government claims for payment that are false or fraudulent or making a false statement to avoid, decrease, or conceal an obligation to pay money to the federal government;
● The so-called federal “Sunshine Act” requires certain pharmaceutical and medical device companies to monitor and report certain payments and other transfers of value to physicians (as defined by such law), certain other healthcare providers, and teaching hospitals as well as ownership and investment interests held by physicians and their immediate family members to CMS for disclosure to the public;
● The Health Insurance Portability and Accountability Act of 1996, imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program and also prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with the delivery of or payment for healthcare benefits, items, or services. This statute also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information on certain covered entities (including healthcare providers, health plans, and healthcare clearinghouses), and their business associates that provide services to or on behalf of the covered entity that involve the use or disclosure of individually identifiable health information; and
● Analogous state laws and regulations, such as state anti-kickback and false claims laws that may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payers, including private insurers, and some state laws that require pharmaceutical companies to report or disclose pricing or other financial information and to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government.
The scope and enforcement
of federal and state healthcare laws and regulations are broad and often uncertain and subject to change. Compliance efforts may involve
substantial costs and resources and federal or state regulatory authorities may review and challenge our prior, current, and/or future
activities under these laws. Any action against us for an alleged or suspected violation, regardless of the outcome or success of our
defense against such actions, could have a material adverse effect on our reputation, business, results of operations, and financial
condition, causing us to incur significant legal expenses and divert our management’s attention from the operation of our business.
If our operations or business arrangements are found to be in violation of any such requirements, we may be subject to penalties, including
civil or criminal penalties, monetary damages, the curtailment or restructuring of our operations, or exclusion from participation in
government contracting, healthcare reimbursement or other government programs, including Medicare and Medicaid, any of which could adversely
affect our financial results.
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Reimbursement in the United States
Sales of our oncology therapeutic
candidates, if approved, in the United States may depend, in significant part, on the extent to which the approved products will be covered
and reimbursed by third-party payers, such as government health programs, commercial insurance and managed healthcare organizations.
Patients who are prescribed treatments for their conditions and providers prescribing treatments generally rely on third-party payers
to reimburse all or part of the associated healthcare costs. Patients and providers are unlikely to use our products unless coverage
is provided and reimbursement is adequate to cover a significant portion of the cost of therapies in which our products are used. There
is significant uncertainty related to third-party payer coverage and reimbursement of newly approved products. In the United States,
no uniform policy of coverage and reimbursement for products exists among third-party payers. Therefore, coverage and reimbursement for
products can differ significantly from payer to payer. Decisions regarding the extent of coverage and amount of reimbursement to be provided
for each of our product candidates will be made on a plan-by-plan basis. One payer’s determination to provide coverage for a product
does not assure that other payers will also provide coverage, and adequate reimbursement, for the product. Additionally, the coverage
determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for
the use of our approved product and therapeutic candidates to each payer separately, with no assurance that coverage and adequate reimbursement
will be obtained.
The third-party payers are
increasingly challenging the prices charged for medical products and services. Additionally, the containment of healthcare costs has
become a priority of federal and state governments, and the prices of drugs have been a focus in this effort. The United States government
and state legislatures have shown significant interest in implementing cost-containment programs, including price controls, restrictions
on reimbursement, discount and rebate requirements, and requirements for substitution of generic products. Adoption of price controls
and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could
further limit our net revenue and results. If these third-party payers do not consider our drug products to be cost-effective compared
to other available therapies, they may not cover our therapeutic candidates, if approved, as a benefit under their plans or, if they
do, the level of payment may not be sufficient to allow us to sell our drug products on a profitable basis.
The Medicare Prescription
Drug Improvement and Modernization Act of 2003 (the MMA) imposed new requirements for the distribution and pricing of prescription drugs
for Medicare beneficiaries and included a major expansion of the prescription drug benefit under Medicare Part D. Under Part D, Medicare
beneficiaries may enroll in prescription drug plans offered by private entities which will provide coverage of outpatient prescription
drugs. Part D plans include both stand-alone prescription drug benefit plans and prescription drug coverage as a supplement to Medicare
Advantage plans. Unlike Medicare Parts A and B, Part D coverage is not standardized. Part D prescription drug plan sponsors are not required
to pay for all covered Part D drugs, and each drug plan can develop its own drug formulary that identifies which drugs it will cover
and at what tier or level. However, Part D prescription drug formularies must include drugs within each therapeutic category and class
of covered Part D drugs, though not necessarily all the drugs in each category or class. Any formulary used by a Part D prescription
drug plan must be developed and reviewed by a pharmacy and therapeutic committee. Government reimbursement for some of the costs of prescription
drugs may increase demand for our therapeutic candidates, if approved, if they are covered by a Part D prescription drug plan. However,
any negotiated prices for our therapeutic candidates, if approved, covered by a Part D prescription drug plan will likely be lower than
the prices we might otherwise obtain. Moreover, while the MMA applies only to drug benefits for Medicare beneficiaries, private payers
often follow Medicare coverage policy and payment limitations in setting their own payment rates. Any reduction in payment that results
from the MMA may result in a similar reduction in payments from non-governmental payers.
Legislative and Regulatory Reform of the
United States Healthcare System
In the United States, there
have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other
things, impact our business and any of our therapeutic candidates or any other therapeutic candidate that we may develop or acquire in
the future. We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, could have a
material adverse effect on our reputation, business, financial condition, or operations.
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On March 23, 2010, President
Obama signed the “Patient Protection and Affordable Care Act” (P.L. 111-148) (the “ACA”) and on March 30,
2010, he signed the “Health Care and Education Reconciliation Act” (P.L. 111-152), collectively commonly referred to as the
“Healthcare Reform Law.” The Healthcare Reform Law included a number of new rules regarding health insurance, the provision
of healthcare, conditions to reimbursement for healthcare services provided to Medicare and Medicaid patients, and other healthcare policy
reforms. Through the law-making process, substantial changes have been and continue to be made to the current system for paying for healthcare
in the U.S., including changes made to extend medical benefits to certain Americans who lacked insurance coverage and to contain or reduce
healthcare costs (such as by reducing or conditioning reimbursement amounts for healthcare services and drugs, and imposing additional
taxes, fees, and rebate obligations on pharmaceutical and medical device companies). This legislation was one of the most comprehensive
and significant reforms ever experienced by the U.S. in the healthcare industry and has significantly changed the way healthcare is financed
by both governmental and private insurers. This legislation has impacted the scope of healthcare insurance and incentives for consumers
and insurance companies, among others. Additionally, the Healthcare Reform Law’s provisions were designed to encourage providers
to find cost savings in their clinical operations. Pharmaceuticals represent a significant portion of the cost of providing care. This
environment has caused changes in the purchasing habits of consumers and providers and resulted in specific attention to the pricing
negotiation, product selection and utilization review surrounding pharmaceuticals. This attention may result in products we may commercialize
or promote in the future and our therapeutic candidates, being chosen less frequently or the pricing being substantially lowered. At
this stage, it is difficult to estimate the full extent of the direct or indirect impact of the Healthcare Reform Law on us.
These structural changes
could entail further modifications to the existing system of private payers and government programs (such as Medicare, Medicaid, and
the Children’s Health Insurance Program), creation of government-sponsored healthcare insurance sources, or some combination of
both, as well as other changes. Restructuring the coverage of medical care in the U.S. could impact the reimbursement for prescribed
drugs and pharmaceuticals, including products we and our development or commercialization partners are currently developing or those
that we may commercialize or promote in the future. If reimbursement for any product we may commercialize is substantially reduced or
otherwise adversely affected in the future, or rebate obligations associated with them are substantially increased, it could have a material
adverse effect on our reputation, business, financial condition or results of operations.
Extending medical benefits
to those who currently lack coverage will likely result in substantial costs to the U.S. federal government, which may force significant
additional changes to the healthcare system in the U.S. Much of the funding for expanded healthcare coverage may be sought through cost
savings. While some of these savings may come from realizing greater efficiencies in delivering care, improving the effectiveness of
preventive care and enhancing the overall quality of care, much of the cost savings may come from reducing the cost of care and increased
enforcement activities. Cost of care could be reduced further by decreasing the level of reimbursement for medical services or products
(including any product we may commercialize or promote or those therapeutic candidates currently being developed by us), or by restricting
coverage (and, thereby, utilization) of medical services or products. In either case, a reduction in the utilization of, or reimbursement
for any product we may commercialize or promote or any therapeutic candidate for which we receive marketing approval in the future, could
have a material adverse effect on our reputation, business, financial condition or results of operations.
Several states and private
entities initially mounted legal challenges to the Healthcare Reform Law, in particular, the ACA, and they continue to litigate various
aspects of the legislation. On June 28, 2012, the U.S. Supreme Court generally upheld the provisions of the ACA at issue as constitutional.
However, the U.S. Supreme Court held that the legislation improperly required the states to expand their Medicaid programs to cover more
individuals. As a result, states have a choice as to whether they will expand the number of individuals covered by their respective state
Medicaid programs. Some states have not expanded their Medicaid programs and have chosen to develop other cost-saving and coverage measures
to provide care to currently uninsured individuals. Many of these efforts to date have included the institution of Medicaid-managed care
programs. The manner in which these cost-saving and coverage measures are implemented could have a material adverse effect on our reputation,
business, financial condition or results of operations.
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Further, the healthcare regulatory
environment has seen significant changes in recent years and is still in flux. Legislative initiatives to modify, limit, replace,
or repeal the ACA and judicial challenges have continued. We cannot predict the impact on our business of future legislative and
legal challenges to the ACA or other aspects of the Healthcare Reform Law or other changes to the current laws and regulations. The financial
impact of U.S. healthcare reform legislation over the next few years will depend on a number of factors, including the policies
reflected in implementing regulations and guidance and changes in sales volumes for therapeutics affected by the legislation. From time
to time, legislation is drafted, introduced and passed in the U.S. Congress that could significantly change the statutory provisions
governing coverage, reimbursement, and marketing of pharmaceutical products. In addition, third-party payer coverage and reimbursement
policies are often revised or interpreted in ways that may significantly affect our business and our products.
For example, during his first
term in office, President Trump supported the repeal of all or portions of the ACA. President Trump also issued an executive order in
which he stated that it is his administration’s policy to seek the prompt repeal of the ACA and in which he directed executive
departments and federal agencies to waive, defer, grant exemptions from, or delay the implementation of the provisions of the ACA to
the maximum extent permitted by law. Congress has enacted legislation that repeals certain portions of the ACA, including but not limited
to the Tax Cuts and Jobs Act, passed in December 2017, which included a provision that eliminates the penalty under the ACA’s
individual mandate, effective January 1, 2019, as well as the Bipartisan Budget Act of 2018, passed in February 2018, which,
among other things, repealed the Independent Payment Advisory Board (which was established by the ACA and was intended to reduce the
rate of growth in Medicare spending).
In December 2018, a
district court in Texas held that the individual mandate is unconstitutional and that the rest of the ACA is, therefore, invalid. On
appeal, the Fifth Circuit Court of Appeals affirmed the holding on the individual mandate but remanded the case back to the lower court
to reassess whether and how such holding affects the validity of the rest of the ACA. The Fifth Circuit’s decision on the individual
mandate was appealed to the U.S. Supreme Court. On June 17, 2021, the Supreme Court held that the plaintiffs (comprised of the state
of Texas, as well as numerous other states and certain individuals) did not have standing to challenge the constitutionality of the ACA’s
individual mandate and, accordingly, vacated the Fifth Circuit’s decision and instructed the district court to dismiss the case.
As a result, the ACA will remain in-effect in its current form for the foreseeable future; however, we cannot predict what additional
challenges may arise in the future, the outcome thereof, or the impact any such actions may have on our business.
Trump’s current administration
has also taken several measures focusing on healthcare and drug pricing and access in particular. For example, President Trump has signed
multiple executive orders addressing drug pricing including: on April 15, 2025, outlining several actions the Secretary of the Department
of HHS must take to optimize healthcare regulations that will provide access to prescription drugs at lower costs; on May 5, 2025, aiming
to promote domestic production of critical medicines; and on May 12, 2025, aiming to establish a most-favored-nation (“MFN”)
drug pricing policy that would tie U.S. drug prices to the prices paid for drugs in other countries. On November 6, 2025, CMS announced
a new voluntary payment initiative called the GENEROUS Model (GENErating cost Reductions for U.S. Medicaid Model) where drug manufacturers
may voluntarily offer supplemental rebates to participating state Medicaid programs that are intended to provide such Medicaid programs
with a MFN price for participating manufacturers’ products. On December 23, 2025, CMS published two proposed rules that would incorporate
MFN pricing principles into federal reimbursement for prescription drugs. The first proposal, the GLOBE Model (Global Benchmark for Efficient
Drug Pricing Model) for Medicare Part B, would require manufacturers of specified single source drugs and sole source biologics to pay
incremental rebates based on international benchmark prices, with participation triggered for products meeting CMS’s spending and
eligibility criteria. The second proposal, the GUARD Model (Guarding U.S. Medicare Against Rising Drug Costs) for Medicare Part D, would
similarly mandate manufacturer rebates for qualifying sole source drugs where the Medicare net price exceeds an MFN benchmark derived
from international reference pricing methodologies. On February 5, 2026, the Trump administration launched the TrumpRx platform designed
to allow consumers to purchase certain drugs at reduced prices as negotiated between the drug manufacturers and the Trump administration.
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On the legislative front,
the American Rescue Plan Act of 2021 was signed into law on March 11, 2021, which, in relevant part, eliminates the statutory Medicaid
drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source drugs and innovator multiple source
drugs, beginning January 1, 2024. And, in July 2021, the Biden administration released an executive order entitled, “Promoting
Competition in the American Economy,” with multiple provisions aimed at prescription drugs. In response, on September 9, 2021,
HHS released a “Comprehensive Plan for Addressing High Drug Prices” that outlines principles for drug pricing reform and
sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take
to advance these principles. And, on August 16, 2022, the Inflation Reduction Act of 2022 (“IRA”) was signed into law. Among
other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare, imposes rebates under Medicare
Part B and Medicare Part D to penalize price increases that outpace inflation, and replaces the Part D coverage gap discount program
with a new discounting program. The IRA also authorizes HHS to implement many of these provisions through guidance, as opposed to regulation,
for the initial years. On July 4, 2025, President Trump signed the One Big Beautiful Bill Act into law which, among other things, is
expected to reduce funding to federal healthcare programs, imposes additional requirements to be eligible for healthcare, and clarifies
exclusions for orphan drugs under IRA’s Drug Price Negotiation Program. On January 15, 2026, President Trump also called on Congress
to enact “The Great Healthcare Plan,” to, among other things, codify and expand MFN pricing, lower government subsidies to
private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase,
and enact restrictions on pharmacy benefit managers. These actions and policies may significantly reduce U.S. drug prices, potentially
impacting manufacturers’ global pricing strategies and profitability, while increasing their operational costs and compliance risks.
There is uncertainty as to
what healthcare programs and regulations may be implemented or changed at the federal and/or state level in the U.S. or the effect of
any future legislation or regulation on us. Furthermore, we cannot predict what actions the Trump administration may implement in connection
with initiatives to reform the United States’ healthcare system including the Healthcare Reform Law or IRA. However, it is possible
that such initiatives could have an adverse effect on our ability to obtain approval and/or successfully commercialize products in the
U.S. in the future, if applicable.
Grants from the Israel Innovation Authority
IIA.
Under the Innovation Law
and the IIA’s rules and guidelines, a qualifying research and development program may be eligible for grants of up to 50% of the
program’s approved research and development expenses. In general, the recipient of the grants is required to return the grants
by the payment of royalties on the revenues generated from the sale of IIA-funded products (and related services), generally at a rate
of 3% or 5% of revenues (which rates may be increased under certain circumstances, as described below) up to the aggregate amount of
the total grants received by the IIA (which may be increased under certain circumstances, as described below), plus annual interest (as
determined in the IIA’s rules and guidelines). Following the full payment of such royalties and interest, there is generally no
further liability for royalty payment. Nonetheless, the restrictions under the Innovation Law (as generally specified below) will continue
to apply even after repayment of the full amount of royalties payable pursuant to the grants.
The pertinent obligations
under the Innovation Law and IIA’s rules and guidelines are as follows:
● Local manufacturing obligation. The terms of the grants under the Innovation Law and the IIA’s rules and guidelines provide that a company that received IIA grants, or the Recipient Company, is prohibited from manufacturing products developed using these IIA grants outside of Israel (unless the IIA approved grant program includes a pre-determined portion of manufacturing that may be performed outside Israel) without receiving prior approval from the IIA (except for the transfer of less than 10% of the manufacturing capacity in the aggregate in excess of such pre-approved portion (if any), which requires only a notice). If the Recipient Company receives approval to manufacture products developed with IIA’s grants outside of Israel in excess of such pre-approved portion (if any), it will be required to pay increased royalties to the IIA, up to 300% of the grant amount plus accrued interest, depending on the manufacturing volume that is performed outside of Israel in excess of any pre-approved portion. The Recipient Company may also be subject to accelerated royalty repayment rates;
● Certain reporting obligations. A recipient of IIA grant is required to notify the IIA of certain events enumerated in the IIA’s rules and guidelines; and
● Know-how transfer limitation. Under the IIA’s rules and guidelines, the transfer of IIA funded know-how outside of Israel requires prior IIA approval and is generally subject to payment of a redemption fee to the IIA calculated according to formulas provided under the IIA’s rules and guidelines, up to 600% of the grants amount (less paid royalties, if any, and depreciation, but no less than the total grants received) plus accrued interest. Upon payment of such a fee, the know-how and the manufacturing rights of the products supported by such IIA funding cease to be subject to the Innovation Law and to the IIA’s rules and guidelines.
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Approval of the transfer
of IIA funded know-how to another Israeli company is also required and may be granted only if the recipient assumes all of our responsibilities
towards the IIA, including the restrictions on the transfer of know-how and manufacturing rights outside of Israel (although such transfer
will not be subject to the payment of a redemption fee, such transfer will include an obligation to pay royalties to the IIA from the
income of such sale transaction as part of the royalty payment obligation).
TyrNovo received the IIA’s
approval for the production of NT219’s API and final product by certain third-party manufacturers outside of Israel in consideration
for (among other things) the future payment of increased royalties as stipulated under the IIA’s rules and guidelines and described
above.
The IIA’s approval
is not required for the export of any products resulting from the IIA research or development grants.
As of December 31, 2025,
TyrNovo had received grants from the IIA in a total amount of approximately NIS 5.5 million (approximately $1.73 million), no royalties
had been paid in respect to the grants received by TyrNovo from the IIA. There is no guarantee that TyrNovo will receive any further grants from the IIA or that the grants will be in
the scope received in the past.
The restrictions under the
Innovation Law may impair our ability to enter into agreements to perform or outsource manufacturing outside of Israel, or otherwise
transfer or sell TyrNovo’s IIA funded know-how outside of Israel, without the approval of the IIA. Furthermore, in the event that
we undertake a transaction involving the transfer to a non-Israeli entity of TyrNovo know-how developed with IIA funding pursuant to
a merger or similar transaction, the consideration available to TyrNovo’s and/or our shareholders may be reduced by the amounts
it is required to pay to the IIA. Further, failure to comply with the requirements under the Innovation Law and the IIA’s rules
and guidelines may subject TyrNovo to financial sanctions, to mandatory repayment of grants received by it (together with interest and
penalties). In addition, the Government of Israel may, from time to time, audit sales of products which it claims incorporate technology
funded via IIA programs and this may lead to additional royalties being payable on additional products and may subject such products
to the restrictions and obligations specified hereunder.
C. Organizational Structure
Our corporate structure consists
of Purple Biotech Ltd., incorporated under the laws of the State of Israel, our wholly-owned subsidiaries, FameWave, incorporated under
the laws of the State of Israel, Kitov USA Inc. (currently inactive), incorporated under the laws of the state of Delaware, Purple Biotech
GmbH, incorporated under the laws of Switzerland (currently inactive and in the process of dissolution), and Immunorizon Ltd., incorporated
under the laws of the State of Israel, and our majority owned subsidiary TyrNovo, incorporated under the laws of the State of Israel,
of which we own approximately 98.47% of its shares.
D. Property, Plant and Equipment
All of our facilities are
leased, and we do not own any real property. The principal executive offices for Purple Biotech, TyrNovo, FameWave and Immunorizon are
in a commercial office building located in the Science Park in Rehovot, Israel. On July 27, 2025, we signed an amendment to our existing
lease agreement for this office
The agreement extends the
lease term by 12 months, running from January 1, 2026, through December 31, 2026. Additionally, we were granted an option to extend the
lease for another 48 months, potentially continuing the term until December 31, 2030. This option renews automatically unless we provide
written notice of our intent not to renew at least 150 days before the end of the 2026 extension.
We have no material tangible
fixed assets apart from the property described above. We believe our facilities are adequate and suitable for our current needs.
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