COMPANY
A. History and Development of the Company
Our legal and commercial name is BioLineRx Ltd. We are a company
limited by shares organized under the laws of the State of Israel. Our principal executive offices are located at 2 HaMa’ayan Street,
Modi’in 7177871, Israel, and our telephone number is +972 (8) 642-9100.
Following the entry into the collaboration with Hemispherian, we
currently own 40% of Tetragon, the newly created company formed to develop GLIX1, with the remaining 60% owned by Hemispherian. Tetragon
is considered our partially owned subsidiary.
Our wholly owned subsidiary, BioLineRx USA, Inc., was incorporated
in Delaware on January 4, 2008, and is currently inactive.
We were founded in 2003 by leading institutions in the Israeli
life sciences industry. We completed our initial public offering in Israel in February 2007 and our ordinary shares are traded on the
TASE under the symbol “BLRX.” In July 2011, we listed our ADSs on Nasdaq and they are traded under the symbol “BLRX.”
In March 2017, we acquired Agalimmune a private U.K.-based company
and in June 2025, we sold Agalimmune, to a third party for future potential royalty consideration.
Our capital expenditures for each of the years ended December 31,
2024 and 2025 were immaterial and were $0.3 million for the year ended December 31, 2023. Our current capital expenditures involve acquisitions
of laboratory equipment, computers and communications equipment.
The SEC maintains an Internet site that contains reports, proxy
and information statements, and other information regarding issuers like BioLineRx that file electronically with the SEC. The address
of that site is www.sec.gov. We maintain a corporate
website at www.biolinerx.com. Information contained
on or accessible through our website is not a part of this Annual Report on Form 20-F, and the inclusion of our website address herein
is an inactive textual reference only.
35
We use our website (http://www.biolinerx.com)
as a channel of distribution of Company information. The information we post through this channel may be deemed material. Accordingly,
investors should monitor our website, in addition to following our press releases, SEC filings and public conference calls and webcasts.
The contents of our website are not, however, a part of this Annual Report on Form 20-F.
B. Business Overview
General
We are a biopharmaceutical company pursuing life-changing therapies
in oncology and rare diseases. Our first approved product, APHEXDA® (motixafortide), a novel peptide for the treatment of stem-cell
mobilization and solid tumors, with an indication in the United States for stem cell mobilization for autologous transplantation
in multiple myeloma, is being developed and commercialized by Ayrmid Pharma Ltd. (globally, excluding Asia) and Gloria, (in Asia). We
are also advancing the development of motixafortide for patients with pancreatic cancer and other solid tumors outside of Asia.
In October 2023, we out-licensed the rights to motixafortide for
all indications in substantially all of Asia to Gloria, and in November 2024, we out-licensed the global rights (other than in Asia) to
motixafortide for all indications, other than solid tumors, to Ayrmid. As a result of the November 2024 transaction, we shut down our
independent commercialization activities in the United States and refocused our operations on development activities in Israel in the
fields of oncology (including solid tumors) and rare diseases, at a significantly reduced annual cash burn rate.
We have retained the rights to develop motixafortide across all
solid tumor indications, in all territories other than Asia, including in PDAC, for which an investigator-initiated Phase 2b trial, sponsored
by Columbia University, and supported equally by us and Regeneron, is ongoing at a relatively minimal cost to us. We expect this program
to continue to advance without any significant expense to us.
In September 2025, we entered into a collaboration transaction
with Hemispherian a Norwegian biotech company focused on small molecule cancer therapeutics, for the development, clinical evaluation
and commercialization of GLIX1, Hemispherian’s lead drug candidate, a first-in-class, oral, small molecule targeting DNA damage
response in glioblastoma, or GBM, and other cancers. Under the terms of the Collaboration Agreement, development of GLIX1 is being carried
out by Tetragon.
A key pillar of our growth strategy is to in-license additional
assets in the fields of oncology and rare diseases – areas where significant unmet medical needs remain and where innovative therapies
can have a transformative impact on patient lives. We are committed to identifying and advancing therapeutic candidates that demonstrate
clear differentiation from currently available treatments, offering the potential for superior efficacy, improved safety, and novel mechanisms
of action. We have generated our pipeline through a systematic process of asset identification, rigorous scientific and clinical validation,
and disciplined in-licensing. We believe this methodical approach allows us to select candidates with a high probability of both therapeutic
and commercial success. Drawing on our substantial experience in asset scouting and evaluation and executing transactions structured with
back-ended, success-based consideration, we are seeking to secure assets with modest upfront payments, while aligning incentives with
our partners and maintaining a focus on cost-effective clinical development programs. With our deep expertise, strategic focus, and prudent
financial management, we believe we are uniquely positioned to bring forward novel therapies that can redefine standards of care and deliver
significant value to patients, healthcare providers, and stakeholders.
Our longer-term vision is to develop innovative assets with significant
potential value whose development costs have been offset by the royalties and milestones from our existing motixafortide partnerships.
We aim to continue pursuing new partnerships on these programs to create additional value for our shareholders.
36
Our Product Pipeline
The table below summarizes key information about our products and
our clinical programs:
GLIX1
In September 2025, we entered into a collaboration transaction
with Hemispherian for the development, clinical evaluation and commercialization of GLIX1, a first-in-class, oral, small molecule targeting
DNA damage response in glioblastoma and other solid tumors. GLIX1, Hemispherian’s lead drug candidate, is initially being developed
as a potential treatment for newly diagnosed and recurrent GBM.
GBM is the most common and aggressive form of primary brain cancer.
The current standard of care (SoC) treatment was established in 2005, with only limited further advancements since. Treatment includes
surgical resection, followed by radiotherapy, and concomitant and adjuvant chemotherapy (Temozolomide), yet most patients will succumb
to their disease within less than 18 months (median OS of 12-18 months). GBM occurs at all ages, but peaks in the fifth and sixth decades
of life, with an increasing incidence in light of the aging global population. The current standard of care (SoC) for newly diagnosed
GBM, established in 2005, consists of surgical resection followed by radiotherapy and treatment with temozolomide (TMZ). While the addition
of TMZ to radiotherapy has demonstrated a marginal improvement in overall survival—14.6 months with TMZ compared to 12.1 months
without—this benefit is primarily observed in patients whose tumors have a methylated MGMT promoter, a subgroup that comprises only
approximately 30% of GBM patients. There is currently no established standard of care for patients with recurrent GBM, further highlighting
the urgent need for new therapeutic options in this patient population. New and better treatments are desperately needed aiming at improving
survival, maintaining quality of life and delaying tumor progression and symptoms.
The annual incidence of GBM is expected to be approximately 18,500
patients in the U.S. and approximately 13,400 across the EU5 (France, Germany, Italy, Spain and the United Kingdom) by 2030. Based
on our estimates, we believe the total addressable market for newly diagnosed and recurrent GBM in the U.S., Germany, UK, France, Italy
and Spain will reach approximately $3.7 billion by 2030.
37
GLIX1 is a first-in-class therapeutic agent with a novel mechanism
of action that targets DNA damage repair by restoring Ten-Eleven Translocation 2 (TET2) activity, making it applicable to a broad range
of cancers. DNA methylation and demethylation are essential processes for normal cellular function. TET2 is a key enzyme responsible
for initiating the DNA demethylation cycle, which results in the formation of single-stranded DNA breaks that are well tolerated in healthy
cells. In cancer cells, however, hypermethylation in certain regions is a common feature, and TET2 activity is frequently inhibited by
oncometabolites, leading to increased DNA methylation in close genomic proximity. Restoration of TET2 activity in these cancer cells generates
numerous single-stranded DNA breaks at heavily methylated regions, which are subsequently converted into double-stranded DNA breaks. This
overwhelms the DNA repair capacity of the cancer cells, ultimately resulting in cell death. This mechanism underpins the therapeutic rationale
for targeting TET2 activity in cancers characterized by reduced TET2 activity.
Preclinical studies of GLIX1 have demonstrated its ability to restore
TET2 activity in cancer cells, resulting in increased levels of 5-hydroxymethylcytosine (5hmC) and the induction of double-stranded DNA
breaks, ultimately leading to cancer cell death. In tumor tissue, GLIX1 treatment was associated with a significant increase in 5hmC levels
compared to controls (p<0.001), confirming the compound’s on-target activity. Immunohistochemical analyses further showed that
restoration of 5hmC in cancer cells led to the accumulation of DNA damage markers and apoptosis. GLIX1 exhibited high potency, as reflected
by low IC50 values, across a variety of cancer cell lines. Importantly, GLIX1 demonstrated strong synergy with PARP inhibitors (PARPi),
sensitizing homologous recombination (HR)-proficient cancer cells to PARPi therapy. This finding suggests that GLIX1 may substantially
expand the population of patients who could benefit from PARP inhibitor-based regimens, beyond the small subset of HR-deficient cancers
currently addressed by these agents.
GBM was selected as the initial clinical indication for GLIX1 based
on several lines of evidence. GBM and other high-grade gliomas are characterized by significantly reduced 5hmC levels and increased DNA
methylation compared to healthy brain tissue. GLIX1 demonstrated efficacy in orthotopic GBM xenograft models, with treated animals showing
marked tumor reduction compared to controls. Additionally, GLIX1 was effective in cell lines resistant to TMZ, the current standard of
care, addressing a critical unmet need as more than half of GBM patients are TMZ-resistant due to unmethylated MGMT promoter status. Pharmacokinetic
studies in healthy mice showed that GLIX1 achieves good blood-brain barrier penetration following oral administration, with favorable
brain and plasma exposure profiles. Collectively, we believe these results support the advancement of GLIX1 into clinical development
for GBM and potentially other cancers with reduced TET2 activity or high HR proficiency. GBM has been selected as the initial target indication,
with data from this setting expected to support further development of GLIX1 in central nervous system malignancies as well as additional
cancer types.
An IND application was cleared by the FDA in August 2025, and a
Phase 1/2 study is expected to initiate in Q1 2026. GLIX1 has also been granted Orphan Drug Designation by both the FDA and the European
Medicines Agency, or EMA, underscoring the substantial unmet need in this indication. Further development in other solid tumors is being
planned.
The open-label dose escalation Phase 1 part of the trial is expected to recruit up to
30 patients with recurrent and progressive GBM and other high-grade gliomas. The objective of this part is to establish a maximum tolerated
dose (MTD) and/or a recommended dose based on safety, PK/PD and preliminary efficacy. Data from the Phase 1 part of the trial is
anticipated in H1 2027. The Phase 2a expansion part of the trial is planned to include various population cohorts including GBM (newly
diagnosed and/or recurrent), as well as additional cancers with/without SOC (e.g., PARP inhibitors). These cohorts are planned to provide
preliminary efficacy, PD assessments and dose optimization to provide the basis for a rapid and effective advanced clinical development
program. Data from the Phase 2 part of the trial is planned in H1 2028.
Motixafortide
Motixafortide is a novel, short peptide that functions as a high-affinity
antagonist for CXCR4, for the treatment of stem cell mobilization and solid tumors. CXCR4 is expressed by normal hematopoietic cells and
overexpressed in various human cancers where its expression correlates with disease severity. CXCR4 is a chemokine receptor that mediates
the homing and retention of hematopoietic stem cells, or HSCs, in the bone marrow, and also mediates tumor progression, angiogenesis (growth
of new blood vessels in the tumor), metastasis (spread of tumor to other organs) and survival. Before “motixafortide” was
approved by the World Health Organization, or WHO, in 2019 as an International Nonproprietary Name, this therapeutic candidate was known
as “BL-8040.” In October 2021, we received WHO approval of the United States Adopted Name, or USAN, “motixafortide.”
The FDA-approved trade or brand name of motixafortide is APHEXDA.
38
Inhibition of CXCR4 by motixafortide leads to the mobilization
of HSCs from the bone marrow to the peripheral blood, enabling their collection for subsequent autologous or allogeneic transplantation
in cancer and other patients requiring the mobilization of HSCs. Clinical data has demonstrated the ability of motixafortide to mobilize
higher numbers of long-term engrafting HSCs (CD34+CD38-CD45RA-CD90+CD49f+) as compared to G-CSF.
Motixafortide also mobilizes cancer cells from the bone marrow,
detaching them from their survival signals and sensitizing them to chemotherapy. In addition, motixafortide has demonstrated a direct
anti-cancer effect by inducing apoptosis (cell death) and inhibiting proliferation in various cancer cell models (multiple myeloma, non-Hodgkin’s
lymphoma, leukemia, non-small-cell lung carcinoma, neuroblastoma and melanoma).
In the field of immuno-oncology, motixafortide mediates infiltration
of effector T-cells while reducing immune suppressor cells (Tregs and MDSCs) in the tumor microenvironment, or TME.
The following is a summary of our motixafortide principal development activities.
Stem cell mobilization
Multiple Myeloma
In September 2023, the FDA approved motixafortide in combination
with G-CSF to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients
with multiple myeloma. In March 2025, marketing authorization with the FDA was transferred to Ayrmid.
In November 2023, we initiated pivotal bridging study preparation
activities with Gloria, our Asia partner, to support potential approval and commercialization of motixafortide in stem-cell mobilization
in China. In February 2024, an IND was filed with the Center for Drug Evaluation of the National Medical Products Administration, which
was approved in May 2024. The study in China was originally planned to commence in the first half of 2025 and was initiated in November
2025, with data approximately 18 months later.
Sickle Cell Disease
In March 2023, we entered into a clinical collaboration with Washington
University School of Medicine in St. Louis to advance a Phase 1 clinical trial in which motixafortide would be evaluated as a monotherapy
and in combination with natalizumab (VLA-4 inhibitor), as novel regimens to mobilize CD34+ hematopoietic stem cells (HSC) for gene therapies
in Sickle Cell Disease. The proof-of-concept investigator-initiated study planned to enroll ten adults with a diagnosis of SCD that were
receiving automated red blood cell exchanges via apheresis. The trial’s primary objective was to assess the safety and tolerability
of motixafortide alone and in combination with natalizumab in SCD patients, defined by dose-limiting toxicities. Secondary objectives
included determining the number of CD34+ hematopoietic stem and progenitor cells (HSPCs) mobilized via leukapheresis; and determining
the pharmacokinetics of CD34+ HSPCs mobilization to peripheral blood in response to motixafortide alone and motixafortide plus natalizumab
in SCD patients. The study began in 2023 and was completed during 2025. Following the out-licensing of motixafortide to Ayrmid, the study
was continued under the Ayrmid License Agreement. Final results from the study were presented in a poster presentation at the 67th American
Society of Hematology (ASH) Annual Meeting in December 2025. A summary of the published abstract is set forth below.
Ten subjects were enrolled (median age 29.5 yrs, 50% male, 90%
SS). Motixafortide alone and in combination with natalizumab were safe and well tolerated. Common adverse events were transient and included
Grade 1-2 injection site and systemic reactions (pruritic – 90%; tingling/pain – 80%; urticaria – 40%). No Grade 4 adverse
events, dose limiting toxicities or complicated vaso-occlusive crises were observed.
39
Motixafortide alone, and in combination with natalizumab, resulted
in robust CD34+ HSC mobilization to the peripheral blood, or PB. Motixafortide alone mobilized a median of 189 CD34+ cells/μl (range
77-690) to the PB at 10-14 hours post motixafortide administration, with a median 4.22x106 CD34+
cells/kg as part of a single blood volume collection, projecting the collection of 16.9x106 HSCs
in a normal, single-day four-blood-volume apheresis collection session. Motixafortide in combination with natalizumab mobilized a median
of 312 CD34+ cells/μl (range 117-447) at 14 hours post motixafortide administration, with median 4.89x106 CD34+
cells/kg collected as part of a single blood volume collection, projecting the collection of 19.6x106 CD34+
HSCs in a single-day four-blood -volume apheresis collection session. In two subjects with prior plerixafor mobilization, motixafortide
alone, and in combination with natalizumab led to 2.7-2.8 fold higher PB CD34+ cells/μl and 2.8-3.2 fold higher CD34+ cells/kg, respectively.
Moreover, while all SCD subjects mobilized well, two phenotypic SCD subgroups were identified with distinct mobilization kinetics, “super”
(n=4) and “standard” (n=6) mobilizers. Motixafortide mobilized significantly higher CD34+ HSCs in super vs standard mobilizers
(median 481 vs 132 CD34+ cells/μl) (p<0.0001), while with motixafortide in combination with natalizumab the difference in super
vs standard was not significant (p=0.1156).
In conclusion, this first-in-human trial demonstrated the potential
of motixafortide alone, and in combination with natalizumab, as novel G-CSF-free regimens to safely optimize HSC mobilization in SCD (median
CD34+ cells/μl: plerixafor=73, motixafortide=189, motixafortide+natalizumab=312).
In May 2024, we announced that we entered into a multi-center Phase
1 clinical trial sponsored by St. Jude Children’s Research Hospital, Inc. to evaluate motixafortide for the mobilization of CD34+
hematopoietic stem cells (HSCs) used in the development of gene therapies for patients with SCD. Investigators in the trial from
St. Jude Children’s Research Hospital, Inc. and two other clinical sites have extensive SCD gene therapy clinical development experience
and are recognized leaders in the field. Following the out-licensing of motixafortide to Ayrmid, the study is being continued under the
Ayrmid License Agreement. The first patient in the study was dosed in February 2025 and data is expected in 2026.
Pancreatic Cancer
In January 2016, we entered into a clinical collaboration with
MSD (a tradename of Merck & Co., Inc., Kenilworth, New Jersey) in the field of cancer immunotherapy. Based on this collaboration,
in September 2016 we initiated a Phase 2a study, known as the COMBAT/KEYNOTE-202 study, focusing on evaluating the mechanism of action
and safety of motixafortide in combination with KEYTRUDA® (pembrolizumab),
MSD’s anti-PD-1 therapy, in 37 patients with metastatic PDAC. The study was an open-label, multicenter, single-arm trial designed
to evaluate the mechanism of action, safety and tolerability, and clinical response of the combination of these therapies. The mechanistic
evaluation consisted of multiple pharmacodynamic parameters, including the ability to improve infiltration of T-cells into the tumor and
their reactivity. Top-line results showed that the dual combination demonstrated encouraging disease control and overall survival in patients
with metastatic pancreatic cancer. In addition, assessment of patient biopsies supported motixafortide’s ability to induce infiltration
of tumor-reactive T-cells into the tumor, while reducing the number of immune regulatory cells.
In July 2018, we announced the expansion of the COMBAT/KEYNOTE-202
study under the collaboration to include a triple combination arm investigating the safety, tolerability and efficacy of motixafortide,
KEYTRUDA® and chemotherapy. We initiated this
arm of the trial in December 2018. In February 2020, we completed the recruiting of a total of 43 patients for the study and in December
2020, we announced the final results of the study. The results of the study showed substantial improvement as compared to comparable historical
results of other pancreatic cancer studies across all study endpoints. Of the 38 evaluable patients, median overall survival was 6.5 months,
median progression free survival was 4.0 months, confirmed overall response rate was 13.2%, overall response rate was 21.2% and disease
control rate was 63.2%. The combination was generally well tolerated, with a safety profile consistent with the individual safety profile
of each component alone; adverse event and severe adverse event profiles were as expected with chemotherapy-based treatment regimens.
In October 2020, we announced that motixafortide will be tested
in combination with the anti-PD-1 cemiplimab (LIBTAYO®)
and standard-of-care chemotherapy (gemcitabine and nab-paclitaxel) in first-line PDAC. This investigator-initiated Phase 2, single-arm
study (CheMo4METPANC), led by Columbia University and supported equally by BioLineRx and Regeneron, initially enrolled 11 PDAC patients
in a pilot phase. In September 2023, we reported preliminary data from the pilot phase of the study. As of July 2023, of those 11 patients,
seven patients (64%) experienced a partial response (PR), of which six (55%) are now confirmed PRs, with one patient experiencing resolution
of the hepatic (liver) metastatic lesion. Three patients (27%) experienced stable disease, resulting in a disease control rate of
91%. These findings compare favorably to historic partial response and disease control rates of 23% and 48%, respectively, reported
with the chemotherapy combination of gemcitabine and nab-paclitaxel. In May 2025, we reported updated results from the pilot phase, indicating
that four of 11 patients remained progression free after more than one year. Two patients underwent definitive treatment for mPDAC –
one had complete resolution of all radiologically detected liver lesions and underwent definitive radiation to the primary pancreatic
tumor, and one had a sustained partial response and underwent pancreaticoduodenectomy with pathology demonstrating a complete response.
An analysis of pre- and on-treatment biopsies and peripheral blood mononuclear cells (PBMCs) also revealed that CD8+ T-cell tumor infiltration
increased across all eleven patients treated with the motixafortide combination.
40
Based on the preliminary data from the pilot phase, the planned
single-arm study was amended to a significantly larger, randomized multi-center study, with a new planned total of 108 patients. The amended
Phase 2b study is evaluating the combination of motixafortide, PD-1 inhibitor cemiplimab, and standard of care chemotherapies gemcitabine
and nab-paclitaxel, versus gemcitabine and nab-paclitaxel alone. The trial's primary endpoint is progression free survival, and a pre-specified
interim futility analysis will be conducted when 40% of progression free survival events are observed, which is planned for 2026. Secondary
objectives include safety, response rate, disease control rate, duration of clinical benefit and overall survival. In February 2024, the
first patient was dosed, with full enrollment planned in 2027.
We have also been advancing plans in collaboration with Gloria,
our Asia partner, for a Phase 2b randomized study assessing motixafortide in combination with the PD-1 inhibitor zimberelimab and standard-of-care
chemotherapy as first-line treatment in patients with metastatic pancreatic cancer. IND submission and protocol finalization was planned
for the first half of 2025. However, Gloria is not currently advancing this study according to schedule and it is unclear when such study
will be initiated, if at all. There can be no assurance that Gloria will meet its obligations under the Gloria License Agreement.
Other Studies
In addition to the above, from time to time a number of Company-sponsored
and investigator-initiated studies may be conducted in a variety of indications, to support the interest of the scientific and medical
communities in exploring additional uses for motixafortide. These studies serve to potentially further elucidate the mechanism of action
for motixafortide, generate data about motixafortide’s potential use in other indications, and inform the life-cycle management
process of motixafortide. The results of studies such as these are presented from time to time at relevant professional conferences.
Orphan Drug Designations
Motixafortide has been granted three Orphan Drug Designations by
the FDA: for use to mobilize HSCs from the bone marrow to peripheral blood for collection in autologous or allogeneic transplantation
(granted in July 2012); for the treatment of AML (granted in September 2013); and for the treatment of pancreatic cancer (granted in February
2019). Orphan Drug Designation is granted to therapeutics intended to treat rare diseases or conditions that affect not more than 200,000
people in the United States (or diseases or conditions that affect more than 200,000 people but where there is no reasonable expectation
that the product development cost will be recovered from product sales in the United States). If an Orphan Drug-Designated product subsequently
receives FDA approval for the disease or condition for which it was designated, the product is entitled to a seven-year marketing exclusivity
period, which means that the FDA may not approve any other applications to market the same drug for the same indication, except in very
limited circumstances (such as a showing of clinical superiority to the product with orphan exclusivity by means of greater effectiveness,
greater safety or providing a major contribution to patient care or in instances of drug supply issues), for seven years. In addition,
Orphan Drug Designation enables sponsors to apply for certain federal grants and tax credits for clinical trials and provides an exemption
from the Prescription Drug User Fee so long, as the sponsor’s annual revenue is below $50,000,000.
In January 2020, the EMA granted an Orphan Drug Designation to
motixafortide for the treatment of pancreatic cancer. In addition, in December 2023, the EMA granted Orphan Drug Designation to motixafortide
for treatment of patients undergoing hematopoietic stem cell transplantation. The EMA grants orphan medicinal product designation to investigational
drugs intended to treat, prevent or diagnose a life-threatening or chronically debilitating disease affecting fewer than five in 10,000
people in the EU and for which no satisfactory treatment is available or, if such treatment exists, the medicine must be of significant
benefit to those affected by the condition. Orphan medicinal product designation provides regulatory and financial incentives for companies
to develop and market therapies, including ten years of market exclusivity, protocol assistance, fee reductions and EU-funded research.
41
BL-5010
Our commercialized, legacy therapeutic product, BL-5010, is a customized,
proprietary pen-like applicator containing a novel, acidic, aqueous solution for the non-surgical removal of skin lesions. It offers an
alternative to painful, invasive and expensive removal treatments including cryotherapy, laser treatment and surgery. Since the treatment
is non-invasive, it poses minimal infection risk and eliminates the need for anesthesia, antiseptic precautions and bandaging. The pre-filled
device controls and standardizes the volume of solution applied to a lesion, ensuring accurate administration directly on the lesion and
preventing both accidental exposure of the healthy surrounding tissue and unintentional dripping. It has an ergonomic design, making it
easy to handle, and has been designed with a childproof cap. BL-5010 is applied topically on a skin lesion in a treatment lasting a few
minutes with the pen-like applicator and causes the lesion to gradually dry out and fall off within one to four weeks.
In December 2014, we entered into an exclusive out-licensing arrangement
with Perrigo Company plc, or Perrigo, for the rights to BL-5010 for over-the-counter, or OTC, indications in Europe, Australia and additional
selected countries. In March 2016, Perrigo received CE Mark approval for BL-5010 as a novel OTC treatment for the non-surgical removal
of warts. The commercial launch of products for treatment of this first OTC indication (warts/verrucas) commenced in Europe in the second
quarter of 2016. Since then, Perrigo has invested in improving the product and during 2019 launched an improved version of the product
in several European countries. In March 2020, we agreed that Perrigo could relinquish its license rights for certain countries that had
been included in its territory according to the original license agreement, and was also no longer obligated to develop, obtain regulatory
approval for, and commercialize products for a second OTC indication. In turn, in March 2020, we agreed with our licensor of the rights
to BL-5010, Innovative Pharmaceutical Concepts (IPC) Inc., or IPC, to return to IPC those license rights no longer out-licensed to Perrigo
as a result of the agreement described in the preceding sentence, in consideration of the payment to us of royalties or fees on sublicense
receipts.
Expanding our Product Portfolio
Following entry into the Gloria License Agreement and the Ayrmid
License Agreement as well as the shutdown of our U.S. commercial operations, we have refocused our operations on development activities
in Israel in the fields of oncology and rare diseases, at a significantly reduced annual cash burn rate.
We are continuing to advance the development of motixafortide for
patients with pancreatic cancer and other solid tumors.
In addition, as part of our future growth strategy, we intend to
pursue additional in-licensing opportunities as well as other strategic transactions such as co-development agreements, acquisitions,
and technology partnerships, to expand and diversify our product pipeline. We will specifically target innovative therapeutic candidates
that complement our existing portfolio and align with our core expertise in oncology and rare disease. Through these strategic in-licensing
efforts, we aim to enhance shareholder value while advancing our mission of bringing novel therapies to patients in need.
Out-Licensing Agreements
Out Licensing of Motixafortide in All Territories Except Asia
On November 20, 2024, we entered into a license agreement, or the
Ayrmid License Agreement with Ayrmid pursuant to which we granted to Ayrmid an exclusive, transferable, royalty-bearing, sublicensable
license with respect to the intellectual property rights and know-how associated with motixafortide, in order to commercialize motixafortide
across all indications, except solid tumor indications, in all territories other than Asia, or collectively, the Ayrmid Territory.
42
Pursuant to the terms of the Ayrmid License Agreement, Ayrmid
paid a non-refundable $10 million upfront payment and we are entitled to up to $87 million of certain commercial and sales milestones
based on defined sales targets of motixafortide in the Ayrmid Territory. Additionally, we are eligible to receive tiered double-digit
royalties (ranging from 18-23%) on aggregate net sales of motixafortide on a country-by-country basis until the longer of (i) fifteen
years from the date of the first sale of motixafortide by Ayrmid in such country, (ii) the last to expire of any licensed patents with
respect to motixafortide in such country, (iii) the expiration of regulatory exclusivity in such country and (iv) the expiration of motixafortide’s
orphan drug status, if any, in such country, it being noted that such royalties may be subject to reduction in certain specific circumstances.
In connection with the Ayrmid License Agreement, we and Ayrmid
also entered into a manufacturing and supply agreement, or the Supply Agreement, according to which we will supply motixafortide to Ayrmid
during the term of the Ayrmid License Agreement, on a cost-plus basis, for both commercial and development supply. Furthermore, the Supply
Agreement provides Ayrmid with “step-in rights” with respect to the manufacture and supply of motixafortide upon the occurrence
of certain trigger events. In addition, we and Ayrmid entered into a transition services agreement pursuant to which we agreed to provide
Ayrmid with certain services related to the development and commercialization of motixafortide within the Ayrmid Territory during a defined
transition period, on a cost basis.
The Ayrmid License Agreement will continue on a country-by-country
basis in the Ayrmid Territory until the expiration of the royalty term or earlier termination thereof. The Ayrmid License Agreement may
also be terminated by either party in the case of a material breach or bankruptcy. Further, if our license agreement with Biokine Therapeutics
Ltd., or the Upstream License, is terminated in whole or in part, the Ayrmid License Agreement will immediately terminate. In such event,
Ayrmid will have the right to enter into a direct license agreement with the licensor of such Upstream License on substantially similar
terms.
Following the Ayrmid License Agreement, we shut down our commercial
operations in the United States and undertook certain cost-cutting and workforce reduction measures. As a result, we have significantly
reduced our expenditures and as of the date of this Annual Report on Form 20-F have 24 full-time employees and 4 part-time employees.
Out Licensing of Motixafortide in Asia
On August 27, 2023, we entered into the Gloria License Agreement,
with Hong Seng Technology Limited, or HST, and Gloria, and/or with HST, the Gloria Licensee, pursuant to which we granted HST an exclusive,
royalty-bearing, sublicensable license with respect to the intellectual property rights and know-how associated with motixafortide in
order to develop and commercialize motixafortide in Asia (other than Israel and certain other countries), or the Gloria Territory, and
to engage and authorize Gloria to perform services under the Gloria License Agreement in the Territory.
Pursuant to the terms of the Gloria License Agreement, the Gloria
Licensee made a $15 million upfront payment in October 2023, upon the closing of the transaction. We are entitled to up to $49 million
based on the achievement of certain development and regulatory milestones in China and Japan, and up to $197 million in sales milestones
based on defined sales targets of motixafortide in the Gloria Territory. Additionally, we are eligible to receive tiered, double-digit
royalties (ranging from 10-20%), on aggregate net sales of motixafortide in the Gloria Territory payable on a country-by-country basis
until the longer of (i) fifteen years from the date of the first sale of motixafortide by Licensee, (ii) the last to expire valid claim
of any licensed patents with respect to motixafortide in such country and (iii) the expiration of motixafortide’s orphan drug status
in such country. The royalties payable by Gloria Licensee to us are to be reduced by 50% following the end of the initial royalty term
and are also to be reduced upon the occurrence of certain events, including, on a country-by-country basis, the entry of a generic product
in such country.
43
The Gloria License Agreement includes various development obligations
for the Gloria Licensee pursuant to an agreed-upon development plan, including the execution of a registrational study in stem-cell mobilization
and the execution of a randomized Phase 2b study in first-line pancreatic adenocarcinoma.
Out-Licensing Agreement with Perrigo
See “—Our Product Portfolio— BL-5010.
Collaboration Agreement with Hemispherian
On September 29, 2025, we entered into a collaboration with Hemispherian
for the development, clinical evaluation and commercialization of GLIX1, a first-in-class, oral, small molecule targeting DNA damage response
in glioblastoma and other solid tumors. As part of the collaboration, (i) we and Hemispherian entered into a Collaboration and Shareholders
Agreement, or the Collaboration Agreement, which governs the ownership, governance, funding, administration, and related operational and
commercial terms of Tetragon Biosciences, Ltd, a newly-created company owned by us and Hemispherian, or Tetragon, and (ii) Hemispherian
and Tetragon entered into an Asset Transfer Agreement (the “ATA”), pursuant to which Hemispherian transferred to Tetragon
certain intellectual property, regulatory filings, know-how, and related assets primarily in respect of GLIX1, Hemispherian’s lead
compound, or the Transferred Assets. The transactions closed on the same day.
Pursuant to the Collaboration Agreement, Hemispherian will initially
hold 60% of the issued share capital of Tetragon, and we will hold the remaining 40%. As consideration for Hemispherian’s contribution
of the Transferred Assets, we agreed to invest $5 million in Tetragon, or the Threshold Amount, within 36 months as of the date of the
Collaboration Agreement, in tranches according to a development plan, which period may be extended by an additional six months upon the
occurrence of certain events as specified in the Collaboration Agreement, or the Threshold Term. If we do not invest the full Threshold
Amount by the end of the Threshold Term, Hemispherian will have the right to repurchase, for nominal consideration, a pro rata portion
of the Company’s shares in Tetragon corresponding to the unfunded portion of the Threshold Amount.
Following the investment of the Threshold Amount, we may make additional
investments in Tetragon. For each incremental $1 million invested by us beyond the Threshold Amount, we will be entitled to an additional
1% equity interest, up to an aggregate maximum ownership of 70%. Following the attainment of a 50% stake by us in Tetragon, Hemispherian
will have the right to co-invest alongside us on the same terms in order to maintain a 50% ownership stake in Tetragon.
Furthermore, under the terms of the Collaboration Agreement, we
will be responsible for managing and implementing Tetragon’s activities and overseeing Tetragon’s operations, budget, and
expenses. Following the closing, Tetragon will pay Hemispherian a monthly advisory fee of $80,000 for a period of 24 months or until the
termination of Tetragon, whichever occurs first.
The Collaboration Agreement provides for the establishment of a
board of directors of Tetragon as well as a steering committee with joint representation from both us and Hemispherian. We hold the deciding
vote in the event of any deadlock on either of such corporate bodies. In addition, the Collaboration Agreement includes restrictions on
the transfer of shares of Tetragon by us and Hemispherian, requiring the consent of the other party, subject to certain exceptions, including
transfers to permitted transferees or transfers in connection with a merger or acquisition transaction. The Collaboration Agreement further
provides a bring-along right, which may be exercised by a simple majority of the shareholders and the board of directors, subject to the
consent rights described above.
Tetragon has a first look right, as well as a right of first refusal,
on other assets in Hemispherian’s pipeline for defined periods specified in the ATA.
The ATA and the Collaboration Agreement contain customary representations
and warranties, indemnification and other provisions customary for transactions of this nature. In addition, we have provided an indemnification
to Hemispherian in an amount of up to 50% of Hemispherian’s potential tax liability in Israel arising from the unlikely event of
the payment of future dividend distributions by Tetragon to its shareholders, net of amounts recoverable under any double tax treaties
available to Hemispherian.
44
The Collaboration Agreement and the ATA include termination events,
including failure to fund the Threshold Amount within the Threshold Term, or prolonged inability of Tetragon to operate due to insufficient
financial resources.
In-Licensing Agreements
We have in-licensed and intend to continue to in-license development,
production and marketing rights from selected research and academic institutions in order to capitalize on the capabilities and technology
developed by these entities. We also seek to obtain technologies that complement and expand our existing technology base by entering into
license agreements with pharmaceutical and biotechnology companies. When entering into in-license agreements, we generally seek to obtain
unrestricted sublicense rights consistent with our primarily partner-driven strategy. We are generally obligated under these agreements
to diligently pursue product development, make development milestone payments, pay royalties on any product sales and make payments upon
the grant of sublicense rights. We generally insist on the right to terminate any in-license for convenience upon prior written notice
to the licensor.
The scope of payments we are required to make under our in-licensing
agreements is comprised of various components that are paid commensurate with the progressive development and commercialization of our
drug products.
Our in-licensing agreements generally provide for the following
types of payments:
• Revenue sharing payments. These are payments to be made to licensors with respect to revenue we receive from sub-licensing to third parties for further development and commercialization of our drug products. These payments are generally fixed at a percentage of the total revenues we earn from these sublicenses.
• Milestone payments. These payments are generally linked to the successful achievement of milestones in the development and approval of drugs, such Phases 1, 2 and 3 of clinical trials and approvals of NDAs, and achievement of sales milestones.
• Royalty payments. To the extent we elect to complete the development, licensing and marketing of a therapeutic candidate, we are generally required to pay our licensors royalties on the sales of the end drug product. These royalty payments are generally based on the net revenue from these sales. In certain instances, the rate of the royalty payments decreases upon the expiration of the drug’s underlying patent and its transition into a generic drug.
• Additional payments. In addition to the above payments, certain of our in-license agreements provide for a one-time or periodic payment that is not linked to milestones. Periodic payments may be paid until the commercialization of the product, either by direct sales or sublicenses to third parties. Other agreements provide for the continuation of these payments even following the commercialization of the licensed drug product.
The following are descriptions of our in-licensing agreements associated
with our therapeutic candidates. In addition to the in-licensing agreements discussed herein, we have entered into other in-licensing
arrangements in connection with our therapeutic candidates in clinical, advanced preclinical and feasibility stages.
Motixafortide
In September 2012, we in-licensed the rights to motixafortide under
a license agreement with Biokine. Pursuant to the agreement, Biokine granted us an exclusive, worldwide, sublicensable license to develop,
manufacture, market and sell certain technology relating to a short peptide that functions as a high-affinity antagonist for CXCR4 and
the uses thereof.
45
There were no upfront payments due under the agreement. We are
obligated to pay a monthly development fee of $27,500 for certain development services that Biokine has committed to provide to us under
the agreement. The payment of this monthly fee is required to continue until March 2029.
We are responsible for paying all development costs incurred by
the parties in carrying out the development plan.
The agreement also grants us the right to grant sublicenses for
the licensed technology. In the case of a sublicense, we were initially required to pay Biokine a payment of 40% of the amounts we receive
as consideration in connection with a sublicense, including royalties, license fees, milestone payments, license maintenance fees and
equity, or the Sublicense Receipts. In October 2018, the agreement was amended to reduce the payments associated with sublicensing to
20% of Sublicense Receipts, in return for the payment by us of $10 million in cash plus $5 million in our restricted ADSs. Biokine is
also eligible to receive up to a total of $2.5 million in future milestone payments. In the case of self-commercialization, we are obligated
to make royalty payments of 10% of net sales, subject to certain limitations.
Before we in-licensed motixafortide, Biokine had received funding
for the project from the IIA, and as a condition to IIA giving its consent to our in-licensing of motixafortide, we were required to agree
to abide by any obligations resulting from such funding. However, we have the right to offset the full amount of any royalty payments
payable to the IIA from any payments otherwise due to Biokine as sublicensing royalties as described above.
We are obligated under the agreement with Biokine to make commercially
reasonable, good faith efforts to sublicense or commercialize motixafortide for fair consideration.
We have the first right to prepare, file, prosecute and maintain
any patent applications and patents, in respect of the licensed technology and any part thereof, at our expense, provided that we are
required to consult with Biokine regarding patent prosecution and patent maintenance. In addition, we have the right to take action in
the prosecution, prevention, or termination of any patent infringement of the licensed technology. We are responsible for all the expenses
of any patent infringement suit that we bring, including any expenses incurred by Biokine in connection with such suits, with such expenses
reimbursable from any sums recovered in such suit or in the settlement thereof for. After such reimbursement, if any funds remain, both
we and Biokine are each entitled to a certain percentage of any remaining sums.
The agreement will remain in effect until the expiration of all
of our royalty and sublicense revenue obligations to Biokine, determined on a product-by-product and country-by-country basis. We may
terminate the agreement for any reason on 90 days’ prior written notice to Biokine. Either party may terminate the agreement for
a material breach by the other party if the breaching party is unable to cure the breach within 30 days after receiving written notice
of the breach from the non-breaching party. With respect to any termination for a material breach, if the breach is not susceptible to
cure within the stated period and the breaching party uses diligent, good faith efforts to cure such breach, the stated period will be
extended by an additional 30 days. In addition, either party may terminate the agreement upon the occurrence of certain bankruptcy events.
Termination of the agreement will result in a loss of all of our
rights to the drug and the licensed technology, which will revert to Biokine. In addition, any sublicense of ours will terminate provided
that, upon such termination and at the request of the sublicensee, Biokine will be required to enter into a separate license agreement
with the sublicensee on substantially the same terms as those contained in the applicable sublicense agreement.
BL-5010
In November 2007, we in-licensed the rights to develop and commercialize
BL-5010 under a license agreement with IPC. Under the agreement, IPC granted us an exclusive, worldwide, sublicensable license to develop,
manufacture, market and sell certain technology relating to an acid-based formulation for the non-surgical removal of skin lesions and
the uses thereof. We are obligated to use commercially reasonable efforts to develop the licensed technology in accordance with a specified
development plan, including meeting certain specified diligence goals. We are required to make low, single-digit royalty payments on the
net sales of the licensed technology if we manufacture and sell it on our own, subject to certain limitations. Our royalty payment obligations
are payable on a product-by-product and country-by-country basis, until the last to expire of any patent included within the licensed
technology in such country. We also have the right to grant sublicenses for the licensed technology and are required to pay IPC a payment,
within our standard range of sublicense receipt consideration, based on the revenues we receive as consideration in connection with any
sublicensing, development, manufacture, marketing, distribution or sale of the licensed technology.
46
The license agreement remains in effect until the expiration of
all of our license, royalty and sublicense revenue obligations to IPC, determined on a product-by-product and country-by-country basis,
unless we terminate the license agreement earlier. We may terminate the license agreement for any reason on 30 days’ prior written
notice. Either party may terminate the agreement for material breach if the breach is not cured within 30 days after written notice from
the non-breaching party. If the breach is not susceptible to cure within the stated period and the breaching party uses diligent, good
faith efforts to cure such breach, the stated period will be extended by an additional 30 days. In addition, either party may terminate
the agreement upon the occurrence of certain bankruptcy events.
Termination of the agreement will result in a loss of all of our
rights to the licensed technology, which would revert to IPC. In addition, any sublicense of the licensed technology will terminate provided
that, upon termination, at the request of the sublicensee, IPC is required to enter into a license agreement with the sublicensee on substantially
the same terms as those contained in the sublicense agreement.
Intellectual Property
Our success depends in part on our ability to obtain and maintain
proprietary protection for our therapeutic candidates, technology and know-how, to operate without infringing the proprietary rights of
others and to prevent others from infringing our proprietary rights. 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 trade secrets, know-how and continuing technological innovation, as well
as on regulatory exclusivity, such as Orphan Drug designation or new chemical entity, or NCE, protection to develop and maintain our proprietary
position.
Patents
As of March 8, 2026, we owned or exclusively licensed for use within
our field of business 21 patent families that collectively contain 141 granted patents, 3 allowed patent applications and 97 pending patent
applications relating to the three candidates listed below. We are also pursuing patent protection for other drug candidates in our pipeline.
Patents related to our therapeutic candidates may provide future competitive advantages by providing exclusivity related to the composition
of matter, formulation, and method of administration of the applicable compounds and could materially improve the value of our therapeutic
candidates. The patent positions for our three therapeutic candidates are described below and include both issued patents and pending
patent applications we own or exclusively license. We vigorously defend our intellectual property to preserve our rights and gain the
benefit of our investment.
• The motixafortide drug product composition of matter and methods of manufacturing thereof are covered by a granted U.S. patent and patent applications pending in the USA (two applications received notice of allowance). Israel, Europe, Japan, Canada, Australia, China, India, Mexico, Brazil, Hong-Kong and Korea. The patents, if granted, will expire in December 2041, not including any applicable patent term extension, which may add an additional term of up to five years for the U.S. patents. We also have an exclusive license to a patent family that covers motixafortide combined with a PD1 antagonist for the treatment of cancer. Patents of this family have been granted in the U.S., Israel, Australia, China, India, Mexico and Hong Kong; and member patent applications are pending in Australia, Hong Kong, Europe, China, Canada, India, Israel and Brazil. The granted U.S. patent and patents to issue in the future based on pending patent applications in this family will expire in 2036, not including any applicable patent term extension. In addition, we have an exclusive license to nineteen other patent families pending or granted worldwide directed to methods of synthesis of motixafortide and methods of use of motixafortide either alone or in combination with other drugs for the treatment of certain types of cancer and other indications. Furthermore, we have Orphan Drug status for AML, pancreatic cancer and stem cell mobilization, as well as data exclusivity protection afforded to motixafortide as an NCE.
47
• With respect to BL-5010, we have an exclusive license to a patent family directed to a novel applicator uniquely configured for applying the BL-5010 composition to targeted skin tissue safely and effectively. Patents in this family have been granted in the U.S., Europe, Israel, Japan, China, Australia and New Zealand. The patents will expire in 2033-2034.
• With respect to GLIX1 Tetragon owns the following: (i) the use of GLIX1 for treating cancer of the central nervous system, e.g., glioblastoma, is covered by patents granted in the United States, Europe, China, Japan and eight other countries. The term of these patents will expire in 2040; (ii) the use of GLIX1 for treating cancer, in which cytidine deaminase (CDA) is not over-expressed, is covered by patents granted in Europe and Japan. A member patent application has been allowed in the United States, while other member applications are pending in China and other countries. The term of the patents, if granted, will expire in 2040; (iii) the use of GLIX1 for treating chronic myelogenous leukemia (CML) is covered by member applications pending in Europe and Korea. The term of the patents, if granted, will expire in 2040; and (iv) the use of GLIX1 in combination with a PARP inhibitor, for treating HR-proficient cancers is covered by patent applications pending in the United States, Europe, Japan, China, Canada, Australia, Mexico, Brazil, Korea and Israel. The term of the patents, if granted, will expire in 2044.
The patent positions of companies like ours are generally uncertain
and involve complex legal and factual questions. Our ability to maintain and solidify our proprietary position for our technology will
depend on our success in obtaining effective claims and enforcing those claims once granted. We do not know whether any of our patent
applications or those patent applications that we license will result in the issuance of any patents. Our issued patents and those that
may issue in the future, or those licensed to us, may be challenged, narrowed, circumvented or found to be invalid or unenforceable, which
could limit our ability to stop competitors from marketing related products or the length of term of patent protection that we may have
for our products. Neither we nor our licensors can be certain that we were the first to invent the inventions claimed in our owned or
licensed patents or patent applications. In addition, our competitors may independently develop similar technologies or duplicate any
technology developed by us, and the rights granted under any issued patents may not provide us with any meaningful competitive advantages
against these competitors. Furthermore, because of the extensive time required for development, testing and regulatory review of a potential
product, it is possible that, before any of our products can be commercialized, any related patent may expire or remain in force for only
a short period following commercialization, thereby reducing any advantage of the patent.
Trade Secrets
We may rely, in some circumstances, on trade secrets to protect
our technology. However, trade secrets can be difficult to protect. We seek to protect our proprietary technology and processes, in part,
by confidentiality agreements and assignment of invention agreements with our employees, consultants, scientific advisors and contractors.
We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises
and physical and electronic security of our information technology systems. While we have confidence in these individuals, organizations
and systems, such agreements or security measures may be breached, and we may not have adequate remedies for any breach. In addition,
our trade secrets may otherwise become known or be independently discovered by competitors.
Trademarks
We also rely on protection available under trademark laws. As of
March 8, 2026, we have registered textual trademarks for “APHEXDA” in Israel, Australia, Brazil, Canada, China, EU, UK, Japan,
Republic of Korea and the USA, as well as registered logo marks for “APHEXDA” in Israel, Australia, Brazil, China, EU, UK,
Japan, Republic of Korea and the USA. We also have the same pending logo trademark in Canada. We further have registered textual trademarks
for “BioLineRx” in the USA and registered logo marks for “BioLineRx” in Israel and the USA, and a pending national
application for the textual trademark “BioLineRx” in the USA (subject to approval of a transformation request). We also claim
common law protections for other marks we use in our business. Competitors and other companies could adopt similar marks or try to prevent
us from using our marks, consequently impeding our ability to build brand identity and possibly leading to customer confusion.
48
Manufacturing
With respect to GLIX1, we rely on contract manufacturers for clinical
and pre-clinical development. For motixafortide, we also rely on contract manufacturers for clinical development and fulfillment of our
obligations under the Ayrmid License Agreement and Gloria License Agreement. We are currently in the process of transferring responsibility
for manufacturing of motixafortide to Ayrmid. In addition, under the Gloria License Agreement, the Gloria Licensee may in the future serve
as an additional source for the manufacture of motixafortide. Nevertheless, we will still retain the right to manufacture motixafortide
in the future for our own clinical development and future commercialization in the indications and territories where we have retained
rights. Given the long lead times and cost of establishing additional manufacturing sites, we expect that the manufacture of GLIX1 and
motixafortide will occur at single contract manufacturers for the foreseeable future. Our manufacturing partners have a limited number
of facilities in which our therapeutic candidates can be produced.
Our laboratories are located in our headquarters in Modi’in,
Israel, and are in part compliant with FDA regulations setting forth current good laboratory practices, or GLP. While our bioanalytical
laboratory complies with these regulations, the chemistry and formulation laboratories, as well as the analytical laboratories, are limited
in manufacturing scale and resources and therefore are intended to support our projects for research and development activities only.
These laboratories are not compliant with current good manufacturing practices, or cGMP. Hence, we cannot independently manufacture drug
substances or drug products for our current clinical trials or for commercial distribution.
Our current and any future third-party manufacturers, their facilities
and all lots of drug substance and drug products used in our clinical trials and commercial sales are required to be in compliance with
cGMP. The cGMP regulations include requirements relating to organization of personnel, buildings and facilities, equipment, control of
components and drug product containers and closures, production and process controls, packaging and labeling controls, holding and distribution,
laboratory controls, records and reports, and returned or salvaged products. The manufacturing facilities for our products must meet cGMP
requirements and FDA satisfaction before any product is approved and we can manufacture commercial products. Our current and any future
third-party manufacturers are also subject to periodic inspections of facilities by the FDA and other authorities, including procedures
and operations used in the testing and manufacture of our products to assess our compliance with applicable regulations.
Failure to comply with statutory and regulatory requirements subjects
a manufacturer to possible legal or regulatory action, including refusal to approve pending applications, license suspension or revocation,
withdrawal of an approval, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, cyber letters,
modification of promotional materials or labeling, product recalls, product seizures or detentions, refusal to allow imports or exports,
total or partial suspension of production or distribution, debarment, injunctions, fines, consent decrees, additional reporting requirements
and oversight if we become subject to a corporate integrity agreement or similar agreements to resolve allegations of non-compliance with
these laws, refusals of government contracts and new orders under existing contracts, exclusion from participation in federal and state
healthcare programs, restitution, disgorgement or civil or criminal penalties, including fines and individual imprisonments.
49
Contract Research Organizations
We outsource certain preclinical and clinical development activities
to CROs, which meet FDA or European Medicines Agency regulatory standards. We create and implement the drug development plans and, during
the preclinical and clinical phases of development, manage the CROs according to the specific requirements of the therapeutic candidate
under development.
Competition
The life science industry is intensely competitive. We face potential
competition from both large and small pharmaceutical and biotechnology companies, academic institutions, governmental and public and private
research institutions. Many of these organizations have substantially greater financial, technical, manufacturing and marketing resources
than we do. In certain cases, our competitors may also be able to use alternative technologies that do not infringe upon our patents to
formulate the active materials in our therapeutic candidates. They may, therefore, bring to market products that are able to compete with
our candidates, or other products that we may develop in the future.
Any therapeutic candidates that we successfully develop and commercialize
will compete with existing therapies and new therapies that may become available in the future. The key competitive factors affecting
the success of each therapeutic candidate, if approved, is likely to be their safety, efficacy, convenience, price, the level of proprietary
and generic competition, and the availability of coverage and reimbursement from government and other third‑party payors. Our competitors
may also obtain FDA or other regulatory approval for their therapeutic candidates more rapidly than we may be able to do so for any existing
or new product candidates of ours, which could result in their establishing a strong market position before we are able to enter the market.
GLIX1
Glioblastoma
In the field of glioblastoma (GBM), therapeutic candidates compete
indirectly with a small number of established modalities. In newly diagnosed GBM, the backbone therapeutic regimen remains temozolomide
chemotherapy. In addition, Novocure’s Tumor Treating Fields (TTFields) device, Optune®, is FDA-approved for maintenance in
combination with temozolomide. Oncologists have limited options for recurrent GBM. Bevacizumab (Avastin® and biosimilars) is FDA-approved
for adult patients with GBM that has progressed following prior therapy. Local therapy with the GLIADEL® wafer (carmustine implant)
is also indicated as an adjunct to surgery for recurrent GBM.
Blood-brain barrier constraints, profound heterogeneity, and an
immunosuppressive microenvironment have historically limited the impact of systemic immunotherapies, with mutational biomarkers such as
MSI-H being rare in GBM. Multiple agents are being evaluated, some in late-stage or pivotal development, including radiotherapeutics Reyobiq
by Plus Therapeutics and TLX-101 by Telix, cancer vaccines TVI-Brain-1 by TVAX Biomedical and IGV-001 by Imvax and GSK’s PARP inhibitor
niraparib. In addition, multiple agents are being evaluated within the GBM AGILE adaptive platform trial, such as AstraZeneca’s
ATM inhibitor AZD-1390, Vigeo Therapeutics’ thrombospondin agonist VT-1021, Biohaven’s troriluzole, and Polaris’ arginine-deprivation
therapy pegargiminase.
GBM has shown a high attrition rate, with multiple failures across
mechanisms to improve survival endpoints. Examples include VAL-083 by Kintara Therapeutics and regorafenib by Bayer), which were evaluated
in the GBM AGILE trial, underscoring the persistent difficulty of converting early signals into registrational success.
TET2 landscape
The competitive landscape of TET2 agonists is sparse. Most notably,
GLIX1 competes mechanistically with ONR-001 by Oniria Therapeutics, a preclinical allosteric TET2 activator developed against treatment-resistant
colorectal cancer, melanoma and other hematologic and solid tumors. In addition, Vitamin C (ascorbic acid) is a co-factor of TET enzymes
and can enhance TET2-dependent activity. In the clinic, high-dose Vitamin C is explored in multiple cancer indications, largely by academic
investigators. Industry-sponsored clinical developments in oncology include General Oncology that combine low-dose Vitamin C with other
therapies in advanced BRCA or PALB2-mutated metastatic cancer pancreatic and breast cancer. In addition, Vitamin C treatment is tested
clinically in cancer-associated and other diseases. For instance, late-stage fixed-dose combinations that include Vitamin C are developed
by Quercis Pharma, testing isoquercetin-based Kinisoquin in preventing cancer-associated thrombosis, and Renovion, testing ARINA-1 to
prevent bronchiolitis obliterans syndrome.
50
Motixafortide
Stem cell mobilization
Motixafortide competes directly with Mozobil® (plerixafor),
which is marketed by Sanofi Genzyme as a stem cell mobilizer for autologous stem cell transplantation. During the third quarter of 2023,
Mozobil’s last-to-expire U.S. listed patent expired. As a result, several companies have launched generic formulations of plerixafor
at prices substantially lower than Mozobil, including Dr. Reddy’s Laboratories Ltd., Teva Pharmaceuticals USA, Inc., MSN Laboratories
Private Ltd., Eugia Pharma Specialities Ltd., Amneal EU Ltd., Gland Pharma Ltd., Hetero Labs Ltd and Meitheal Pharmaceuticals, Inc.
The competitive development pipeline in stem cell mobilization
is currently limited, but we are aware of Exicure’s burixafor in combination with propranolol and G-CSF, which is under clinical
investigation for stem cell mobilization in multiple myeloma and may compete with motixafortide in the future.
CXCR4 landscape
A new CXCR4 inhibitor, XOLREMDI®, was approved by the FDA
in 2024 for WHIM syndrome and has recently entered late-stage clinical trials for chronic neutropenia. We are also aware of other CXCR4
inhibitors in various stages of development, including burixafor being developed by Exicure for stem cell mobilization in multiple myeloma
and PTX-9908 being developed by TCM Biotech in hepatocellular carcinoma. Other approaches include radiotherapeutics targeting CXCR4-expressing
cells for various cancer indications, including those being developed by PentixaPharm.
Pancreatic cancer
Immuno-oncology is an area of significant interest in the pharmaceutical
market, particularly immuno-oncology combination therapies. Thousands of immuno-oncology combination treatments are currently being tested
in clinical trials that aim to transform scientific innovation into practice-changing cancer drugs.
In the field of pancreatic ductal adenocarcinoma (PDAC), motixafortide
competes indirectly with the few currently approved treatments for PDAC. Motixafortide is believed to modulate the effector/suppressor
cell ratio toward a proinflammatory profile, which may act synergistically with checkpoint inhibitor agents to enhance the anti-tumor
activity of infiltrated T cells. In the first-line setting, gemcitabine in combination with Abraxane® or the FOLFIRINOX regimen are
the current standards of care. In February 2024, Ipsen’s Onivyde® obtained approval in first-line metastatic PDAC as part of
the NALIRIFOX regimen based on the Phase III NAPOLI-3 trial.
Oncologists have limited options among existing therapies for second-line
metastatic patients. Onivyde® is FDA-approved in combination with 5-FU and leucovorin for patients previously treated with gemcitabine-based
therapy. LYNPARZA® is approved for maintenance treatment of germline BRCA-mutated metastatic pancreatic cancer (approximately 7%
of all cases). Recently, BIZENGRI® gained accelerated approval as a second-line treatment for patients with NRG1 fusions (less than
1% of all cases).
51
Multiple targeted, biomarker-specific treatments have been approved
across solid tumors. These include Merck’s KEYTRUDA® for MSI-H/dMMR cancers (approximately 1% of all pancreatic cancer cases)
and ENHERTU® for HER2-positive solid tumors (approximately 2-6% of PDAC) following prior systemic treatment.
We are aware of late clinical-stage development in metastatic PDAC
by other companies, including daraxonrasib, a RAS inhibitor by Revolution Medicines, and quemliclustat from Arcus Biosciences. In China,
several advanced antibody modalities have entered late-stage development, including assets targeting Claudin 18.2-positive tumors and
PD-1-directed bispecifics.
In recent years, there have been multiple clinical failures of
compounds for advanced PDAC, most notably FibroGen’s pamrevlumab, Erytech’s eryaspase, and Astellas’ zolbetuximab. Despite
a busy early-stage clinical pipeline, there are only a few Phase III and approved assets, demonstrating a high attrition rate in PDAC.
BL-5010
BL-5010 competes with a variety of approved destructive and non-destructive
treatments for skin lesions. Both Endwarts® (Meda
Health) and Eskata® (Aclaris therapeutics) are
medical device-based treatments marketed for removal of warts.
Government Regulation
We operate in a highly controlled regulatory environment. Stringent
regulations establish requirements relating to analytical, toxicological and clinical standards and protocols in respect of the testing
of pharmaceuticals and medical devices. Regulations also cover research, development, manufacturing and reporting procedures, both pre-
and post-approval. In many markets, especially in Europe, marketing and pricing strategies are subject to national legislation or administrative
practices that include requirements to demonstrate not only the quality, safety and efficacy of a new product, but also its cost-effectiveness
relating to other treatment options. Failure to comply with regulations can result in stringent sanctions, including product recalls,
withdrawal of approvals, seizure of products and criminal prosecution.
Before obtaining regulatory approvals for the commercial sale of
our therapeutic candidates, we or our licensees must demonstrate through preclinical studies and clinical trials that our therapeutic
candidates are safe and effective. Historically, the results from nonclinical studies and early clinical trials often have not accurately
predicted results of later clinical trials. In addition, a number of pharmaceutical products have shown promising results in early clinical
trials but subsequently failed to establish sufficient safety and efficacy results to obtain necessary regulatory approvals. We have incurred
and will continue to incur substantial expense for, and devote a significant amount of time to, preclinical studies and clinical trials.
Many factors can delay the commencement and rate of completion of clinical trials, including the inability to recruit patients at the
expected rate, the inability to follow patients adequately after treatment, the failure to manufacture sufficient quantities of materials
used for clinical trials, and the emergence of unforeseen safety issues and governmental and regulatory delays. If a therapeutic candidate
fails to demonstrate safety and efficacy in clinical trials, this failure may delay development of other therapeutic candidates and hinder
our ability to conduct related preclinical studies and clinical trials. Additionally, as a result of these failures, we may also be unable
to find additional licensees or obtain additional financing.
Governmental authorities in all major markets require that a new
pharmaceutical product or medical device be approved or exempted from approval before it is marketed, and have established high standards
for technical appraisal, which can result in an expensive and lengthy approval process. The time to obtain approval varies by country.
In the past, it generally took from six months to four years from the application date, depending upon the quality of the results produced,
the degree of control exercised by the regulatory authority, the efficiency of the review procedure and the nature of the product. Some
products are never approved. In recent years, there has been a trend towards shorter regulatory review times in the United States as well
as certain European countries, despite increased regulation and higher quality, safety and efficacy standards.
52
Historically, different requirements by different countries’
regulatory authorities have influenced the submission of applications. However, a trend toward harmonization of drug and medical device
approval standards, starting in individual countries in Europe and then in the EU as a whole, in Japan, the United Kingdom and in the
United States under the aegis of what is now known as the International Council on Harmonisation, or ICH (created as the International
Conference on Harmonisation in 1990), is gradually narrowing these differences. In many cases, compliance with ICH standards can help
avoid duplication of non-clinical and clinical trials and enable companies to use the same basis for submissions to each of the respective
regulatory authorities. The adoption of the Common Technical Document format by the ICH has greatly facilitated use of a single regulatory
submission for seeking approval in the ICH regions and many other countries worldwide.
Summaries of the United States, EU, United Kingdom and Israeli regulatory processes
follow below.
United States
In the United States, drugs are subject to rigorous regulation
by the FDA. The U.S. Federal Food, Drug and Cosmetic Act, or FDCA, and other federal and state statutes and regulations govern, among
other things, the research, development, testing, manufacture, storage, record-keeping, packaging, labeling, adverse event reporting,
advertising, promotion, marketing, distribution and import and export of pharmaceutical products. Failure to comply with the applicable
U.S. requirements may subject us to stringent administrative or judicial sanctions, such as agency refusal to approve pending applications,
warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions or criminal
prosecution.
Unless a drug is exempt from the NDA process or the Biologics License
Application, or BLA, process or subject to another regulatory procedure, the steps required before a drug may be marketed in the United
States include:
• completion of preclinical laboratory tests, animal studies and formulation development;
• submission to the FDA of an Investigational New Drug, or IND, application to conduct human clinical testing;
• completion of adequate and well controlled clinical trials to determine the safety and efficacy of the drug for each indication as well as to establish the exposure levels;
• submission to the FDA of an application for marketing approval;
• satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is manufactured; and
• FDA review and approval of the drug and drug labeling for marketing.
Preclinical studies include laboratory evaluation of product chemistry,
toxicity, formulation and stability, as well as animal studies. For preclinical studies conducted in the United States, and certain studies
carried out outside the United States, we submit the results of the nonclinical studies, together with manufacturing information and analytical
results, to the FDA as part of an IND, which must become effective before we may commence human clinical trials.
Clinical Trials (INDs)
Clinical trials involve the administration of the investigational
drug to people under the supervision of qualified investigators in accordance with the principles of good clinical practice, or GCP. We
conduct clinical trials under protocols detailing the trial objectives, the parameters to be used in monitoring safety, and the effectiveness
criteria to be evaluated. We must submit each U.S. study protocol to the FDA as part of an IND. An IND will automatically become effective
30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions about issues such as the conduct of the
trials as outlined in the IND. In such a case, the IND sponsor and the FDA must resolve any outstanding FDA concerns or questions before
clinical trials can proceed. Submission of an IND does not always result in the FDA allowing clinical trials to commence and the FDA may
halt a clinical trial if unexpected safety issues surface or the study is not being conducted in compliance with applicable requirements.
53
The FDA may refuse to accept an IND for review if applicable regulatory
requirements are not met. Moreover, the FDA may delay or prevent the start of clinical trials if the manufacturing of the study drug fails
to meet cGMP requirements or the clinical trials are not adequately designed. Such government regulation may delay or prevent the study
and marketing of potential products for a considerable time period and may impose costly procedures upon a manufacturer’s activities.
In addition, the FDA may, at any time, impose a clinical hold on ongoing clinical trials. If the FDA imposes a clinical hold, clinical
trials cannot continue without FDA authorization and then only under terms authorized by the FDA.
Success in early-stage clinical trials does not assure success
in later-stage clinical trials. Results obtained from clinical activities are not always conclusive and may be susceptible to varying
interpretations that could delay, limit or prevent regulatory approval. Even if a therapeutic candidate receives regulatory approval,
later discovery of previously unknown problems with a product may result in restrictions on the product or even withdrawal of marketing
approval for the product.
Foreign clinical trials may or may not be conducted under an IND.
However, their safety assessments should be submitted annually.
We conduct clinical trials typically in three sequential phases
(1-3), but the phases may overlap or be combined. An institutional review board, or IRB, must review and approve each trial before it
can begin. Phase 1 includes the initial administration of a tested drug to a small number of humans. These trials are closely monitored
and may be conducted in patients but are usually conducted in healthy volunteer subjects. These trials are designed to determine the metabolic
and pharmacologic actions of the drug in humans and the side effects associated with increasing doses as well as, if possible, to gain
early evidence of effectiveness. Phase 2 usually involves trials in a limited patient population to evaluate dosage tolerance and appropriate
dosage, identify possible adverse effects and safety risks and preliminarily evaluate the efficacy of the drug for specific indications.
Phase 3 trials are large trials used to further evaluate clinical efficacy and test further for safety by using the drug in its final
form in an expanded patient population. There can be no assurance that we or our licensees will successfully complete Phase 1, Phase 2
or Phase 3 testing with respect to any therapeutic candidate within any specified period of time, if at all. Furthermore, clinical trials
may be suspended at any time on various grounds, including a finding that the subjects or patients are being exposed to an unacceptable
health risk. We and our licensees perform some of our nonclinical and clinical testing outside of the United States. The acceptability
of the results of our preclinical and clinical testing by the FDA will be dependent upon adherence to applicable U.S. and foreign standards
and requirements, including GLP, GCP and the Declaration of Helsinki for protection of human subjects.
Marketing Applications (NDAs and BLAs)
After successful completion of the required clinical testing, an
NDA, or in the case of certain biological products, a BLA, is prepared and submitted to the FDA. FDA approval of the NDA or BLA is required
before product marketing may begin in the United States. The NDA/BLA must include the preclinical and clinical testing results and a compilation
of detailed information relating to the product’s pharmacology, toxicology, chemistry, manufacture and manufacturing controls. The
cost of preparing and submitting an NDA may be substantial. Under U.S. federal law, the submission of NDAs is generally subject to substantial
application user fees, and the manufacturer and/or sponsor under an NDA approved by the FDA is also subject to annual product and establishment
user fees. These fees are typically increased annually.
54
The FDA has 60 days from its receipt of an NDA/BLA to determine
whether the application will be accepted for filing based on the FDA threshold determination that the application is sufficiently complete
to permit substantive review. Once the submission is accepted for filing, the FDA begins an in-depth review of the submitted application.
Under U.S. federal law, the FDA has agreed to certain performance goals in the review of NDAs/BLAs. Most such applications for non-priority
drug products are to be reviewed within 10 months following acceptance of the application for filing. The review process may be significantly
extended by FDA requests for additional information or clarification or if the applicant submits a major amendment during the review.
The FDA may also refer applications to an advisory committee, typically a panel that includes clinicians and other experts, for review,
evaluation and a recommendation as to whether the application should be approved. This often, but not exclusively, occurs for novel drug
products or drug products that present difficult questions of safety or efficacy. The FDA is not bound by the recommendation of an advisory
committee.
Before approving an application, the FDA typically will inspect
the facility or facilities where the product is manufactured. The FDA will not approve the application unless the FDA determines that
the product is manufactured in substantial compliance with cGMP. If the FDA determines that the NDA or BLA is supported by adequate data
and information, the FDA may issue an approval letter. During review, the FDA may request additional information via an information request,
or IR letter, or state deficiencies via a deficiency letter, or DR letter. Upon compliance with the conditions stated, the FDA will typically
issue an approval letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific
indications. As a condition of approval, the FDA may require additional trials or post-approval testing and surveillance to monitor the
drug’s safety or efficacy, the adoption of risk evaluation and mitigation strategies, and may impose other conditions, including
labeling and marketing restrictions on the use of the drug, which can materially affect its potential market and profitability. Once granted,
product approvals may be withdrawn if compliance with regulatory standards for manufacturing and quality control are not maintained or
if additional safety problems are identified following initial marketing.
If the FDA’s evaluation of the NDA or BLA submission or manufacturing
processes and facilities is not favorable, the FDA may refuse to approve the NDA or BLA and may issue a complete response letter. The
complete response letter, or CRL, indicates that the review cycle for an application is complete and that the application is not ready
for approval. The complete response letter will describe specific deficiencies and, when possible, will outline recommended actions the
applicant might take in order to place the application in condition for approval. Following receipt of a CRL, the company may submit additional
information and start a new review cycle, withdraw the application or request a hearing. Failure to take any of the above actions may
result in the FDA considering the application withdrawn following one year from issuance of the CRL. In such cases, the FDA will notify
the company and the company will have 30 days to respond and request an extension of time in which to resubmit the application. The FDA
may grant reasonable requests for extension. If the company does not respond within 30 days of the FDA’s notification, the application
will be considered withdrawn. Even with submission of additional information for a new review cycle, the FDA ultimately may decide that
the application does not satisfy the regulatory criteria for approval.
The Pediatric Research Equity Act, or PREA, requires NDAs and BLAs
(or supplements) for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration to contain
results assessing the safety and efficacy for the claimed indication in all relevant pediatric subpopulations. Data to support dosing
and administration also must be provided for each pediatric subpopulation for which the drug is safe and effective. The FDA may grant
deferrals for the submission of results or full or partial waivers from the PREA requirements (for example, if the product is ready for
approval in adults before pediatric studies are complete, if additional safety data is needed, among others). In addition, under the Best
Pharmaceuticals for Children Act, or BPCA, the FDA may issue a written request to the company to conduct clinical trials in the pediatric
population that are related to the moiety and expand on the claimed indication. The studies are voluntary but may award the company with
6 months of marketing exclusivity if conducted according to good scientific principles and address the written request. Finally, a sponsor
can request that a product that must be studied under PREA to be studied also under the BPCA to allow the sponsor to be eligible for six-months
of pediatric exclusivity. The pediatric studies requested under BPCA are usually more extensive and would generally also fulfill the PREA
requirement; however, even if the sponsor does not complete the studies outlined in the BPCA written request, it is still required to
complete any studies required under PREA.
55
Post-Marketing Requirements
Once an NDA or BLA is approved, the drug sponsor will be subject
to certain post-approval requirements, including requirements for adverse event reporting, submission of periodic reports, manufacturing,
labeling, packaging, advertising, promotion, distribution, record-keeping and other requirements. For example, the approval may be subject
to limitations on the uses for which the product may be marketed or conditions of approval, or contain requirements for costly post-marketing
testing and surveillance to monitor the safety or efficacy of the product or require the adoption of risk evaluation and mitigation strategies.
In addition, the FDA requires the reporting of any adverse effects observed after the approval or marketing of a therapeutic candidate
and such events could result in limitations on the use of such approved product or its withdrawal from the marketplace. Also, some types
of changes to the approved product, such as manufacturing changes and labeling claims, are subject to further FDA review and approval.
Additionally, the FDA strictly regulates the promotional claims that may be made about prescription drug products. In particular, the
FDA requires substantiation of any claims of superiority of one product over another including, in many cases, requirements that such
claims be proven by adequate and well controlled head-to-head clinical trials. To the extent that market acceptance of our therapeutic
candidates may depend on their superiority over existing products, any restriction on our ability to advertise or otherwise promote claims
of superiority, or any requirements to conduct additional expensive clinical trials to provide proof of such claims, could negatively
affect the sales of our therapeutic candidates and our costs.
Orphan Drug Designation
The Orphan Drug Act, or ODA, provides for granting special status
to a drug or biological product to treat a rare disease or condition (i.e., a disease or condition that affects fewer than 200,000 individuals
in the United States), or a disease or condition that affects more than 200,000 individuals in the United States but where there is no
reasonable expectation that the product development cost will be recovered from product sales in the United States, upon request of a
sponsor. This status is referred to as orphan designation (or sometimes “orphan status”). For a therapeutic candidate to qualify
for orphan designation, both the candidate and the disease or condition must meet certain criteria specified in the ODA’s implementing
regulations (set forth at 21 CFR Part 316). Orphan designation qualifies the sponsor of the candidate for various development incentives
of the ODA, including tax credits for qualified clinical testing, waiver of NDA/BLA user fees and eligibility for seven-year marketing
exclusivity, referred to as orphan exclusivity upon marketing approval. The granting of an orphan designation request does not alter the
standard regulatory requirements and process for obtaining marketing approval. Safety and effectiveness of a candidate must still be established
through adequate and well-controlled studies.
Expedited Programs for Serious Conditions
The FDA has put in place four programs intended to facilitate and
expedite development and review of a new drug intended to address an unmet medical need in the treatment of a serious or life-threatening
condition: fast track designation, breakthrough therapy designation, accelerated approval and priority review designation. Each program
offers the sponsor a defined set of opportunities such as expedited development and review, intensive FDA guidance during development,
marketing approval based on an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict
the drug’s clinical benefit, and a shorter time for review of marketing application. Fast Track and Breakthrough Therapy designations
may be requested during development, while Accelerated Approval and Priority Review relate to the marketing approval stage.
56
European
Union/European Economic Area
Clinical Trials
Within the European Union (EU) and the European Economic Area (EEA),
which is composed of the 27 member states of the EU plus Norway, Iceland and Liechtenstein, the authorization of clinical trials occurs
at member state level. The European Medicines Agency, or EMA, plays a key role in ensuring that GCP standards are applied across the European
Economic Area, or EEA, in cooperation with the member states. It also manages a database of clinical trials carried out in the EU.
Clinical trials in the EU are regulated under Regulation (EU) 536/2014
(CTR), as amended on April 5, 2022. As opposed to the previous Directive 2001/20/EC (CTD), which as an EU directive was not directly applicable
in the member states, the CTR (as an EU regulation) has immediate effect for the whole EU and did not have to be transposed into national
law. While national laws implementing the CTD varied to a great extent, the CTR provides for a significant further harmonization of the
law governing clinical trials in the EU. After significant delay, the CTR became applicable on January 31, 2022. The CTR now harmonizes
the assessment and supervision processes for clinical trials throughout the EU via the Clinical Trials Information System (CTIS), which
includes a centralized EU portal and database for clinical trials. From 31 January 2023 onwards, clinical trial sponsors need to apply
to start a clinical trial via CTIS. Additionally, CTIS is used to coordinate the assessment between Member States, handle regulatory queries,
and communicate the respective national decisions to the sponsor. Therefor CTIS ensures the harmonized and transparent approval system
envisaged by the CTR. In accordance with the CTR, the Data submitted, will be published in the EU database. From 31 January 2025, any
trials previously approved under the CTD that continue to run after such date will need to comply with CTR and their sponsors must have
recorded the required information on such trials in CTIS. The CTR provides inter alia:
• Consistent rules for conducting clinical trials throughout the EU;
• Making information on the authorization, conduct and results of each clinical trial carried out in the EU publicly available;
• Harmonized electronic submission and assessment process for clinical trials conducted in multiple member states;
• Improved collaboration, information sharing and decision-making between and within member states;
• Increased transparency of information on clinical trials; and
• Higher standards of safety for all participants in EU clinical trials, also ensured through compliance with Good Clinical Practice (GCP).
The authorization of a clinical trial (Phase 1-3) in an EU member
state requires the submission of a clinical trial application (CTA) via the EU Portal, CTIS. The application will be reviewed by the competent
authorities of the member states where the trial is supposed to take place. The application and approval process is conducted by the member
states under the cooperation system set forth in the CTR. Particularities under member states’ national law still apply to some
extent. In general, the CTA should include, among other documents, the study protocol, results of the nonclinical studies and manufacturing
information and analytical results. A detailed list is listed in Annex I of the CTR. Also, the sponsor has to suggest one of the concerned
member states as reporting member state. The concerned member state may, within three days of submission of the application, raise objections
to the proposal or declare their willingness to act as the reporting member state. The reporting member state is designated no later than
six days after submission. The reporting member state validates the application within ten days and requests additional documentation
if it is incomplete. The sponsor has ten days (max.) to supply the requested documents. The reporting Member State decides on the completeness
of the application within five days. Once validation has been successful, the evaluation phase begins. The CTR aims at speeding up the
validation and review of clinical trial applications and therefore provides strict deadlines.
57
Marketing Authorization Procedures
A medicinal product may only be placed on the market in the EEA
if it has obtained a marketing authorization according to the applicable EU and/or member state law. A marketing authorization may either
be granted in a national procedure, or in a coordinated procedure of several member states pursuant to Directive 2001/83/EC, as amended
on January 1, 2025, or under the centralized EU procedure in accordance with Regulation (EC) No. 726/2004, as amended on January 28, 2022.
Depending on the nature of the medicinal product, several different legal frameworks of the EU and the member states may be relevant for
the market clearance.
Centralized Procedure (CP)
The Centralized Procedure according to Regulation 726/2004/EC (as
amended on January 28, 2022) allows a marketing authorization holder to market the medicine and make it available to patients and healthcare
professionals throughout the entire EEA on the basis of a single marketing authorization, granted by the European Commission based on
the opinion of the Committee for Medicinal Products for Human Use (CHMP), which is responsible for the scientific assessment, acting in
its capacity as the European Licensing Authority on the advice of the EMA. The EMA is the administrative body responsible for coordinating
the existing scientific resources available in the member states for evaluation, supervision and pharmacovigilance of medicinal products.
The marketing authorization needs to be renewed after 5 years, after which it is often valid indefinitely. Therefor a re-evaluation of
the risk-benefit balance is necessary for the renewal. A renewal application must be submitted to the Agency at the latest 9 months
before the expiry date of the MA. The MA validity period is calculated from the date of notification of the Commission Decision.
Certain medicinal products (e.g., products derived from biotechnology,
advanced-therapy medicinal products, orphan medicinal products and medicinal products for human use, which contain an active substance
authorized in the European Union after May 20, 2004 and which are intended for the treatment of AIDS, cancer, neurodegenerative disorders,
diabetes, auto-immune diseases and other immune dysfunctions or viral diseases) must be authorized centrally. The centralized authorization
procedure is optional for other medicinal products if they contain a new active substance which on May 20, 2002 was not authorized in
the European Union, or if the applicant shows that the medicinal product concerned constitutes a significant therapeutic, scientific or
technical innovation or that the granting of authorization is in the interest of patients in the European Union. For each application
submitted to the EMA for scientific assessment, the EMA is required to ensure that the opinion of the Committee for Medicinal Products
for Human Use, or CHMP, is given within 210 days after receipt of a valid application or within 150 days by means of an accelerated procedure
(excluding clock stops); the review period can be extended. If the opinion is positive, the EMA is required to send the opinion to the
European Commission, which is responsible for preparing the decision granting a marketing authorization. If the initial opinion of the
CHMP is negative, the applicant is afforded an opportunity to seek a re-examination of the opinion. The CHMP is required to re-examine
its opinion within 60 days following receipt of the request by the applicant. A refusal of a centralized marketing authorization constitutes
a prohibition on placing the given medicinal product on the market in the EU. The European Commission is further empowered to suspend,
revoke, or withdraw an authorization where safety concerns arise or where regulatory requirements have been breached. Any post‑authorization
changes must be implemented in compliance with the procedural requirements laid down in Commission Regulation (EC) No 1234/2008.
The EMA’s Committee for Advanced Therapies (CAT) is responsible
for assessing the quality, safety and efficacy of advanced therapy medicinal products (ATMP). ATMP include gene therapy medicinal products,
somatic cell therapy medicinal products and tissue engineered medicinal products. The main responsibility of the CAT is to prepare a draft
opinion on an application for marketing authorization for an ATMP candidate that is submitted to the EMA. The EMA’s Committee for
Medicinal Products for Human Use (CHMP) then provides a final opinion regarding the application for marketing authorization. The European
Commission grants or refuses marketing authorization after the CHMP has delivered its opinion. ATMP are further regulated under Regulation
(EC) No 1394/2007 on advanced therapy medicinal products, as amended on July 26, 2024 and Directive 2001/83/EC on medicinal products for
human use, as amended on January 1, 2025.
58
National Authorization Procedure
A National Authorization Procedure is used when applying for a
marketing authorization in one individual EEA state. The national procedure can only be used if the medicinal product does not already
have a marketing authorization in another EEA state. The national authorization has validity for five years. After this period the authorization
can be renewed for another five years.
Mutual Recognition Procedure (MRP)
The mutual recognition procedure (Art. 28 Directive 2004/27/EC)
can be used if a medicinal product already has a marketing authorization in one EEA member state, and the authorization holder would like
to extend the authorization to other member states. An application for mutual recognition may be addressed to one or more EEA countries.
The country in which the national marketing authorization has been granted acts as the “Reference Member State,” and the other
countries concerned (Concerned Member States) can, upon successful completion of the procedure, recognize the marketing authorization.
To this end, the marketing authorization holder shall request the Reference Member State either to prepare an assessment report on the
product or, if necessary, to update any existing assessment report. The assessment time is 180 days plus 30 days.
If the Member State concerned considers that the recognition of
an authorization would pose a risk to public health, it shall notify the other Member States so that, if necessary, with the involvement
of the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), measures can be taken to resolve the
conflict and enable the authorization to be recognized.
Decentralized Procedure (DCP)
The decentralized procedure (introduced by Directive 2004/27/EU)
is used in cases where the medicinal product has not received a marketing authorization in the EU at the time of application. It allows
the common assessment of an application submitted simultaneously to several member states. One of the member states will take the lead
in evaluating the application as Reference Member State to facilitate agreement with the Concerned Member States and the grant of a national
marketing authorization in all of these member states. To this end, the Reference Member State conducts a detailed review and prepares
a draft assessment report, a draft assessment report, a draft summary of product characteristics and a draft of the labelling and package
leaflet and shall send these documents to the Concerned Member States to provide comments. The assessment time is 210 days plus 30 days.
Upon successful completion of the authorization procedure, the medicinal product will receive uniform national approval in the member
states concerned.
Manufacturing Requirements
Any medicinal product placed on the market in the EEA must be manufactured
in accordance with the principles of good manufacturing practice as set out in Directive EC2017/1572 supplementing Directive 2001/83/EC
of the European Parliament and of the Council as regards the principles and guidelines of good manufacturing practice for medicinal products
for human use for human use and Volume 4 of the “Rules Governing Medicinal Products in the European Community”. Directive
2017/1572/EU has replaced Directive 2003/94/EC. Directive 2003/94/EC will still be applicable to clinical trials conducted in accordance
with the former regime under transitional provisions. Furthermore, distribution of medicinal products in the EU is subject to Directive
2001/83/EC and current guidance on good distribution practice, or GDP. Additionally, an official manufacturing license is required before
production can commence. Moreover, EU law requires the clinical results in support of clinical safety and efficacy to be based upon clinical
trials conducted in the EU in compliance with the requirements of the CTR and Directive 2005/28/EC, which implement good clinical practice
in the conduct of clinical trials on medicinal products for human use. Clinical trials conducted outside the EU and used to support applications
for marketing within the EU must have been conducted in a way consistent with the principles set out in the CTR or if conducted prior
to 31 January 2022, its predecessor Directive 2001/20/EC. The conduct of a clinical trial in the EU requires, pursuant to the CTR, authorization
by the relevant national competent authority where a trial takes place, and an ethics committee to have issued a favorable opinion in
relation to the arrangements for the trial. It also requires that the sponsor of the trial, or a person authorized to act on his behalf
in relation to the trial, be established in the EU. The GMP requirements also apply tp investigational medicinal products and must be
released by a qualified person.
59
Law Relating to Pediatric Research
Regulation (EC) 1901/2006 (as amended by Regulation (EC) 1902/2006
and Regulation (EU) 2019/5), or the Pediatric Regulation, was adopted on December 12, 2006. This Regulation governs the development of
medicinal products for human use in order to meet the specific therapeutic needs of the pediatric population (children aged 0 to 17 years).
It requires any application for marketing authorization made after July 26, 2008 in respect of a medicinal product not authorized in the
EU on January 26, 2007, the time the Regulation entered into force, to include studies in children conducted in accordance with a pediatric
investigation plan agreed to by the relevant European authorities. The approval authority may reject an application for approval or restrict
the approval if the paediatric investigation plan has not been complied with and no exemption applies. The results of the studies will
be published in the CTIS. This does not apply if the product is subject to an agreed waiver or deferral or if the product is excluded
from the scope of Regulation 1901/2006, which is the case for inter alia generics, homeopathic
and traditional (herbal) medicinal products. Waivers can be granted in certain circumstances where pediatric studies are not required
or desirable. Deferrals can be granted in certain circumstances where the initiation or completion of pediatric studies should be deferred
until appropriate studies in adults have been performed. Moreover, this regulation imposes the same obligation from January 26, 2009 on
an applicant seeking approval of a new indication, pharmaceutical form or route of administration for a product already authorized and
still protected by a supplementary protection certificate granted under Regulation (EC) no. 469/2009 or its precursor Regulation (EEC)
1768/92 by a patent that qualifies for the granting of such a supplementary protection certificate. The pediatric Regulation 1901/2006
also provides, subject to certain conditions, a reward for performing such pediatric studies, regardless of whether the pediatric results
provided resulted in the grant of a pediatric indication. This reward comes in the form of an extension of six months to the supplementary
protection certificate granted in respect of the product, unless the product is subject to Orphan Drug designation, in which case the
10-year market exclusivity period for such orphan products is extended to 12 years. If any of the non-centralized procedures for marketing
authorization have been used, the six-month extension of the supplementary protection certificate is only granted if the medicinal product
is authorized in all member states. Where the product is no longer covered by a patent or supplementary protection certificate, the applicant
may make a separate application for a Pediatric Use Marketing Authorization, or PUMA, which, on approval, will provide eight years’
protection for data and 10 years’ marketing protection for the pediatric results.
Post-authorization Obligations
An authorization to market a medicinal product in the EU carries
with it an obligation to comply with many post-authorization regulations relating to the marketing and other activities of authorization
holders. These may include requirements relating to provision of a risk management plan and provision of annual periodic safety update
reports, carrying out of post-authorization efficacy studies and/or post-authorization safety studies, maintenance of a pharmacovigilance
system master file, adverse event reporting, signal detection and management and other pharmacovigilance activities conducted under an
established quality system, advertising, packaging and labelling, patient package leaflets, and distribution. These obligations also include
reporting side effects via EudraVigilance. The regulations frequently operate within a criminal law framework, and failure to comply with
the requirements may not only affect the authorization, but also can lead to financial and other sanctions levied on the company in question
and responsible officers. As an example, the mandatory designation of a Qualified Person for Pharmacovigilance (QPPV) constitutes a requirement
whose breach can be subject to sanctions, EU pharmacovigilance legislation has been significantly modified by the Pharmacovigilance Directive,
Directive 2010/84/EU (as amended on January 20, 2011) which amended the legal framework of pharmacovigilance for medicines marketed within
the EU provided in Regulation (EC) No 726/2004 with respect to EU authorized medicinal products and in Directive 2001/83/EC with respect
to nationally authorized medicinal products (including those authorized through the mutual recognition and decentralized systems). Furthermore,
EU good pharmacovigilance practice (GVP) rules apply. With the amended pharmacovigilance requirements, the financial and organizational
burden on market authorization holders increased significantly, such as the obligation to maintain a pharmacovigilance system master file
that applies to all holders of marketing authorizations granted in accordance with Directive 2001/83/EC (as amended on January 1, 2025)
or Regulation (EC) No 726/2004 (as amended on January 28, 2022). Marketing authorization holders must furthermore collect data on adverse
events associated with use of the authorized product outside the scope of the authorization. Pharmacovigilance for biological products
and medicines with a new active substance is strengthened by subjecting their authorization to additional monitoring activities. The EMA
specifies the medicinal products concerned in the “List of Medicinal Products under Additional Monitoring”, which must be
regularly updated and reviewed. This ensures that safety‑relevant information is collected more quickly and that risks can be identified
and managed at an early stage.
60
Another relevant aspect in the EU regulatory framework is the “sunset
clause”: a provision leading to the cessation of the validity of any marketing authorization if it is not followed by marketing
within three years or, if marketing is interrupted for a period of three consecutive years.
Data Privacy in the EU
The EU has a strict regime on data privacy under the General Regulation
on Data Protection, Regulation 2016/679 (GDPR), as amended on May 4, 2016, that has become applicable on May 25, 2018. The GDPR as an
EU regulation does not have to be implemented into member states’ national law but applies directly in all member states. It applies
to companies with an establishment in the European Economic Area (EEA) that includes the 27 member states of the EU and Norway, Iceland
and Liechtenstein. Furthermore, the GDPR applies to companies not located in the EEA but processing personal data of individuals located
in the EEA (e.g., through online business). The GDPR implements stringent operational requirements for controllers of personal data, including,
for example, obligations to justify the collection, use and other processing of personal data (e.g., based on the individual’s consent),
to notify the individuals concerned about data processing activities, to protect all processed personal data through appropriate technical
and organizational measures, and to implement a data protection compliance management. Furthermore, the GDPR defines high data security
and compliance standards for the transfer of personal data to third countries, including the U.S. In addition, the GDPR requires companies
to carry out a data protection impact assessment, appoint a data protection officer, report data breaches to the supervisory authority,
and notify the individuals affected. Where personal data is processed by third‑party companies, these processors must be contractually
obligated to comply with the provisions of the GDPR. Data subjects also have the right to request the deletion of their data or the restriction
of processing, which has implications for data retention and overall compliance.
The operational requirements under the GDPR are even stricter in
case of sensitive personal data, such as health or genetic data, that typically have to be stored in a pseudonymized (i.e., key-coded)
manner. The GDPR provides that EU member states may in certain areas deviate from GDPR standards which results in varying laws and regulations
at member states level. The applicable data protection laws in the EEA may limit our ability to share and otherwise process personal data.
If our business falls below the GDPR standards, we may be subject to severe administrative fines up to 20,000,000 or up to 4 % of the
total worldwide annual turnover of our preceding financial year, if greater, and other administrative penalties including criminal liability,
which may be onerous and adversely affect our business, financial condition, results of operations and prospects. Failure to comply with
the GDPR and related laws may also give risk to increased risk of private actions, including a new form of class action that is available
under the GDPR.
61
Israel
Israel Ministry of the Environment - Toxin Permit
In accordance with the Israeli Dangerous Substances Law - 1993,
the Israeli Ministry of the Environment is required to grant a permit in order to use toxic materials. Because we utilize toxic materials
in the course of operation of our laboratories, we were required to apply for a permit to use these materials. Our current toxin permit
will remain in effect until August 2031.
Clinical Testing in Israel
In order to conduct clinical testing on humans in Israel, special
authorization must first be obtained from the ethics committee and the head of the medical center in which the clinical studies are planned
to be conducted, as required under the Guidelines for Clinical Trials in Human Subjects implemented pursuant to the Israeli Public Health
Regulations (Clinical Trials in Human Subjects), as amended from time to time, and other applicable legislation. These regulations require
authorization by the institutional ethics committee and the head of the medical center. Israeli Ministry of Health, except for certain
circumstances, is required to approve each trial as well. The institutional ethics committee must, among other things, evaluate the anticipated
benefits that are likely to be derived from the project to determine if it justifies the risks and inconvenience to be inflicted on the
human subjects, and the committee must ensure that adequate protection exists for the rights and safety of the participants as well as
the accuracy of the information gathered in the course of the clinical testing. Since we intend to perform a portion of the clinical studies
on certain of our therapeutic candidates in Israel, we will be required to obtain authorization from the ethics committee and head of
medical center of each institution in which we intend to conduct our clinical trials, and in most cases, from the Israeli Ministry of
Health.
Other Countries
In addition to regulations in the United States, the EU and Israel,
we and our collaborators are subject to numerous and a variety of regulatory requirements of other countries and jurisdictions regarding
quality, safety and efficacy governing, among other things, clinical trials, marketing authorization, manufacturing, commercial sales
and distribution of drugs in other countries. Whether or not our products receive approval from the FDA, approval of such products must
be obtained by the comparable regulatory authorities of countries other than the United States before we or our collaborators can commence
clinical trials, manufacturing or marketing of the product in those countries. The approval process varies from country to country and
may involve additional product testing and additional administrative review periods. As a result, the time may be longer or shorter than
that required for FDA approval. The requirements governing the conduct of clinical trials and product licensing vary greatly from country
to country. Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay
in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.
Related Matters
From time to time, legislation is drafted, introduced and passed
in governmental bodies that could significantly change the statutory provisions governing the approval, manufacturing and marketing of
products regulated by the FDA or EMA and other applicable regulatory bodies to which we are subject. In addition, regulations and guidance
are often revised or reinterpreted by the national agency in ways that may significantly affect our business and our therapeutic candidates.
It is impossible to predict whether such legislative changes will be enacted, whether FDA or EMA regulations, guidance or interpretations
will change, or what the impact of such changes, if any, may be. We may need to adapt our business and therapeutic candidates and products
to changes that occur in the future.
62
Pharmaceutical Coverage, Pricing and Reimbursement
Significant uncertainty exists as to the coverage and reimbursement
status of products approved by the FDA and other government authorities. Sales of products will depend, in part, on the extent to which
third-party payors, including government health programs in the United States such as Medicare and Medicaid, commercial health insurers
and managed care organizations, provide coverage, and establish adequate reimbursement levels for, such products. The process for determining
whether a payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that
the payor will pay for the product once coverage is approved. Third-party payors are increasingly challenging the prices charged, examining
the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party
payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products
for a particular indication.
In order to secure coverage and reimbursement for any product that
might be approved for sale, a company may need to conduct expensive pharmacoeconomic, health outcome studies in order to demonstrate the
medical necessity, quality of life benefits, and cost-effectiveness of the product, in addition to the costs required to obtain FDA or
other comparable regulatory approvals. Nonetheless, product candidates may not be considered medically necessary or cost effective in
light of cost-benefit analysis. Additionally, a payor’s decision to provide coverage for a drug product does not imply that an adequate
reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a drug product does not assure that
other payors will also provide coverage for the drug product. Third-party reimbursement may not be sufficient to maintain price levels
high enough to realize an appropriate return on investment in product development.
The containment of healthcare costs also has become a priority
of federal, state and foreign governments and the prices of drugs have been a focus in this effort. Governments have shown significant
interest in implementing cost-containment programs, including price controls, restrictions on reimbursement 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. Coverage policies and third-party reimbursement
rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which a company
or its collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
Outside the United States, ensuring adequate coverage and payment
for our therapeutic candidates will face challenges. Pricing of prescription pharmaceuticals is subject to governmental control in many
countries. Pricing negotiations with governmental authorities can extend well beyond the receipt of regulatory marketing approval for
a product and may require us to conduct studies that compare the cost effectiveness of our product candidates or products to other available
therapies. The conduct of such studies could be expensive and result in delays in our commercialization efforts.
Pricing and reimbursement schemes vary widely from country to country.
Some countries provide that drug products may be marketed only after a reimbursement price has been agreed. Some countries may require
the completion of additional studies that compare the cost-effectiveness of a particular drug candidate to currently available therapies
in order to obtain reimbursement. For example, the European Union provides options for its member states to restrict the range of drug
products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human
use. European Union member states may approve a specific price for a drug product, or it may instead adopt a system of direct or indirect
controls on the profitability of the company placing the drug product on the market. Other member states allow companies to fix their
own prices for drug products but monitor and control company profits and issue guidance to prescribers. The downward pressure on health
care costs in general, particularly prescription drugs, has become intense. As a result, increasingly high barriers are being erected
to the entry of new products. In addition, reference pricing and cross-border imports from low-priced markets exert competitive pressure
that may reduce pricing within a country. Any country that has price controls or reimbursement limitations for drug products may not allow
favorable reimbursement and pricing arrangements.
63
Other Healthcare Laws and Regulation
Healthcare providers and third-party payors play a primary role
in the recommendation and prescription of drug products that are granted regulatory approval. Arrangements with providers, consultants,
third-party payors and customers are subject to broadly applicable fraud and abuse and other healthcare laws and regulations that may
constrain our business and/or financial arrangements. Such restrictions under applicable federal and state healthcare laws and regulations
include the following:
• the federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, receiving or providing remuneration (including any kickback, bribe or rebate), directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, lease or order of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;
• the federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws, which prohibit individuals or entities from, among other things, 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 federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal laws that prohibit, among other things, knowingly and willingly executing, or attempting to execute, a scheme or making false statements in connection with the delivery of or payment for health care benefits, items, or services;
• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act and its implementing regulations, which also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information on covered entities and their business associates that associates that perform certain functions or activities that involve the use or disclosure of protected health information on their behalf;
• the Foreign Corrupt Practices Act, or FCPA, which prohibits companies and their intermediaries from making, or offering or promising to make improper payments to non-U.S. officials for the purpose of obtaining or retaining business or otherwise seeking favorable treatment; the Civil Monetary Penalty Act of 1981 imposes penalties against any person or entity that, among other things, is determined to have presented or caused to be presented a claim to a federal health care program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent, or offering or transferring remuneration to a federal health care beneficiary that a person knows or should know is likely to influence the beneficiary’s decision to order or receive items or services reimbursable by the government from a particular provider or supplier;
64
• the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, or collectively the ACA, which requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services, or CMS, within HHS, information related to payments and other transfers of value to certain healthcare providers and teaching hospitals and information regarding ownership and investment interests held by physicians and their immediate family members; and
• analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that are reimbursed by non-governmental third-party payors, including private insurers.
Some state laws require pharmaceutical companies to comply with
the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government
in addition to requiring drug manufacturers to report information related to payments to physicians and other health care providers or
marketing expenditures. State and foreign laws also govern the privacy and security of health information in some circumstances, many
of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.
U.S. Healthcare Reform
A primary trend in the U.S. healthcare industry and elsewhere is
cost containment. Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount
of reimbursement for particular medical products. For example, in March 2010, the ACA was enacted, which, among other things, increased
the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program; introduced a new methodology by which
rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted
or injected; extended the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care
plans; imposed mandatory discounts for certain Medicare Part D beneficiaries as a condition for manufacturers’ outpatient drugs
coverage under Medicare Part D; subjected drug manufacturers to new annual fees based on pharmaceutical companies’ share of sales
to federal healthcare programs; created a new Patient Centered Outcomes Research Institute to oversee, identify priorities in and conduct
comparative clinical effectiveness research, along with funding for such research; and established the Center for Medicare & Medicaid
Innovation at the CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending.
We expect that future changes or additions to the ACA, the Medicare
and Medicaid programs, and changes stemming from other healthcare reform measures, especially with regard to healthcare access, financing
or other legislation in individual states, could have a material adverse effect on the healthcare industry in the United States. For example,
the American Rescue Plan Act of 2021 eliminated the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average
manufacturer price, beginning on January 1, 2024.
Additionally, on December 20, 2019, the Further Consolidated Appropriations
Act for 2020 was signed into law (P.L. 116-94) and includes a piece of bipartisan legislation called the Creating and Restoring Equal
Access to Equivalent Samples Act of 2019, or the CREATES Act. The CREATES Act aims to address the concern articulated by both the FDA
and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking
the existence of a REMS for certain products, to deny generic product developers access to samples of brand products. Because generic
product developers need samples of an RLD to conduct certain comparative testing required by the FDA, some have attributed the inability
to timely obtain samples as a cause of delay in the entry of generic products. To remedy this concern, the CREATES Act establishes a private
cause of action that permits a generic product developer to sue the brand manufacturer to compel it to furnish the necessary samples on
“commercially reasonable, market-based terms.” Whether and how generic product developments will use this new pathway, as
well as the likely outcome of any legal challenges to provisions of the CREATES Act, remain highly uncertain and its potential effects
on any of our future commercial products are unknown.
65
In August 2022, President Biden signed into the law the Inflation
Reduction Act of 2022, or the IRA. The IRA has multiple provisions that may impact the prices of drug products that are both sold into
the Medicare program and throughout the United States. Starting in 2023, a manufacturer of a drug or biological product covered by Medicare
Parts B or D must pay a rebate to the federal government if the drug product’s price increases faster than the rate of inflation.
This calculation is made on a drug product by drug product basis and the amount of the rebate owed to the federal government is directly
dependent on the volume of a drug product that is paid for by Medicare Parts B or D. Additionally, starting in payment year 2026, CMS
will negotiate drug prices annually for a select number of single source Part D drugs without generic or biosimilar competition. CMS will
also negotiate drug prices for a select number of Part B drugs starting for payment year 2028. If a drug product is selected by CMS for
negotiation, it is expected that the revenue generated from such drug will decrease. CMS has begun to implement these new authorities
and entered into the first set of agreements with pharmaceutical manufacturers for negotiated prices of 10 products, which became applicable
for payment year 2026. However, the IRA’s impact on the pharmaceutical industry in the United States remains uncertain, in part
because multiple large pharmaceutical companies and other stakeholders (e.g., the U.S. Chamber of Commerce) have initiated federal lawsuits
against CMS arguing the program is unconstitutional for a variety of reasons, among other complaints. Those lawsuits are currently ongoing.
To date, President Trump has signed an Executive Order to require
drug prices to be transparent. In addition, the President reversed certain policies by the Biden Administration. President Trump eliminated:
Medicare $2 drug list model, cell and gene therapy access model to improve high-cost drugs for Medicaid enrollees, and accelerate clinical
evidence model for new drug. Additionally, in 2025, HHS began implementation of “Most Favored Nation” drug pricing by setting
the Medicare price of single-source brand drugs without generic or biosimilar competition to the lowest price available in wealthy countries
with a per capita GDP of at least 60% of that in the United States. It is not clear what additional changes may be implemented, but President
Trump does want disclosure of transparency in prices.
Individual states in the United States have also increasingly passed
legislation and implemented regulations designed to control pharmaceutical product 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. For example, in recent years, several states have formed prescription
drug affordability boards (PDABs). Much like the IRA’s drug price negotiation program, these PDABs have attempted to implement upper
payment limits (UPLs) on drugs sold in their respective states in both public and commercial health plans. In August 2023, Colorado’s
PDAB announced a list of five prescription drugs that would undergo an affordability review. The effects of these efforts remain uncertain
pending the outcomes of several federal lawsuits challenging state authority to regulate prescription drug payment limits. In December
2020, the U.S. Supreme Court held unanimously that federal law does not preempt the states’ ability to regulate pharmaceutical benefit
managers, or PBMs, and other members of the healthcare and pharmaceutical supply chain, an important decision that may lead to further
and more aggressive efforts by states in this area. The Federal Trade Commission (FTC) in mid-2022 also launched sweeping investigations
into the practices of the PBM industry that could lead to additional federal and state legislative or regulatory proposals targeting such
entities’ operations, pharmacy networks, or financial arrangements. On February 3, 2026, Congress enacted the Consolidated Appropriations
Act of 2026, which limits the fees charged by PBMs, as well as requiring PBMs to fully pass through manufacturer rebates to a Medicare
Part D plan sponsor. Significant efforts to change the PBM industry as it currently exists in the U.S. may affect the entire pharmaceutical
supply chain and the business of other stakeholders, including pharmaceutical product developers like us.
We expect that additional foreign, federal and state healthcare
reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare
products and services, which could result in limited coverage and reimbursement and reduced demand for our products, once approved, or
additional pricing pressures.
66
Israeli Government Programs
Israel Innovation Authority
Before we in-licensed motixafortide, Biokine had received $2.7
million in funding for the project from the IIA (formerly the OCS). As a condition for the IIA’s consent to our in-licensing of
motixafortide, we were required to agree to abide by any obligations resulting from such funding under the Israeli Encouragement of Industrial
Research, Development and Technological Innovation Law, 1984, and related regulations, as amended (the Research Law). Under the Research
Law and the terms of IIA grants, royalties on the revenues derived from sales of products (and associated services) developed with IIA
funding are payable to the Israeli government, generally at the rate of 3% (and at an increased rate under certain circumstances, as described
below). The obligation to make these royalty payments terminates upon repayment of the amount of grants, linked to the U.S. dollar, plus
interest (in accordance with IIA regulations), which amount may be increased under certain circumstances, as described below.
Under the Research Law, the transfer or license to third parties
outside of Israel of know-how or technologies developed under IIA-funded programs, or the transfer to third parties outside of Israel
of manufacturing or rights to manufacture based on IIA-funded know-how, requires the consent of the IIA in certain circumstances, and
may result in increased payments to the IIA. Specifically, for the transfer of manufacturing outside of Israel, royalty payments can be
up to three times the amount of the IIA grants received, linked, plus interest, and the royalty repayment rate may increase. For the transfer
of IIA-funded know-how outside of Israel, the payment may be up to six times the amount of the IIA grants, linked, plus interest. In connection
with the IIA’s approval of the out-licensing transactions with Gloria and Ayrmid, the IIA determined that we are required to pay
the IIA 3.9% on any sub-license consideration, up to six times the IIA grant, linked, plus interest. Additionally, in December 2024, we
received IIA approval to transfer the manufacturing of motixafortide outside of Israel, which requires us to pay the IIA 4% of proceeds
on any direct product sales, up to three times the IIA grant, linked plus interest. As of December 31, 2025, $1.3 million in aggregate
royalties had been paid to the IIA on account of the motixafortide program and there was a contingent liability to the IIA (including
interest) of $2.5 million (without taking into account the potential repayment requirement of up to six times the amount as detailed above).
In any event, under our agreement with Biokine, we have a full right of offset for amounts payable to the IIA for the motixafortide program
from any payments that we may owe to Biokine in the future.
Should we wish to further out-license motixafortide in the future,
there is no assurance that we will be able to obtain the IIA’s consent on terms acceptable to us, or at all. Even following the
full repayment of IIA grants, we must nevertheless continue to comply with the requirements of the Research Law. If we fail to comply
with any of the conditions and restrictions imposed by the Research Law and regulations and guidelines thereunder, or by the specific
terms of the IIA grants, we may be required to refund any IIA grants that Biokine previously received together with interest and penalties,
and, in certain circumstances, may be subject to criminal charges. In any event, under our agreement with Biokine, we have a full right
of offset for amounts payable to the IIA for the motixafortide program from any payments that we may owe to Biokine in the future.
Environmental Matters
We are subject to various environmental, health and safety laws
and regulations, including those governing air emissions, water and wastewater discharges, noise emissions, the use, management and disposal
of hazardous, radioactive and biological materials and wastes and the cleanup of contaminated sites. We believe that our business, operations
and facilities are being operated in compliance, in all material respects, with applicable environmental and health and safety laws and
regulations. Based on information currently available to us, we do not expect environmental costs and contingencies to have a material
adverse effect on us. The operation of our facilities, however, entails risks in these areas. Significant expenditures could be required
in the future if we are required to comply with new or more stringent environmental or health and safety laws, regulations or requirements.
See “Business - Government Regulation and Funding - Israel Ministry of Environment - Toxin Permit.”
67
C. Organizational Structure
Our corporate structure consists of BioLineRx Ltd., one wholly
owned subsidiary, BioLineRx USA, Inc. and we own 40% of the shares of Tetragon.
D. Property, Plant and Equipment
We are headquartered in Modi’in, Israel. We entered into
a lease agreement in August 2014, for an aggregate of 1,663 square meters (approximately 17,900 square feet) of space. Monthly rent is
NIS 137,000 (approximately $39,700), including maintenance fees and parking. The initial term of the lease expired in June 2020, and we
exercised our options to extend the lease through June 30, 2028. We have the option to extend the lease for one additional period of two
years, at a 5% increase to the preceding lease payment amount.
This facility houses both our administrative and research operations
and our central laboratory. The central laboratory consists of approximately 380 square meters (approximately 4,200 square feet) and includes
a bioanalytical laboratory, a formulation laboratory and a tissue culture laboratory. Our bioanalytical laboratory has received GLP certification.