A. History and Development of the Company Our legal name is Alpha Tau Medical Ltd. and our commercial name is Alpha Tau. We were founded in November 2015 by Uzi Sofer, our Chief Executive Officer and Chairman, along with the inventors of the Alpha DaRT® technology including Professor Itzhak Kelson and Professor Yona Keisari of Tel Aviv University, our late Chief Physics Officer and current Chief Scientific Officer, respectively. Together, they founded Alpha Tau with the goal of bringing this innovative technology out of the laboratory and into patients, in order to bring hope to cancer patients around the world. We are registered with the Israeli Registrar of Companies. Our registration number is 51-534453-9. The main address of our principal executive offices is 5 Kiryat HaMada St., Jerusalem, Israel 9777605 and our telephone number is +972 (3) 577-4115. Our agent for service of process in the United States is Alpha Tau Medical, Inc., 1 Union Street 3rd Floor, Lawrence, MA 01840. For a description of our principal capital expenditures and divestitures for the three years ended December 31, 2025 and for those currently in progress, see Item 5. “Operating and Financial Review and Prospects.” On July 7, 2021, we entered into the Merger Agreement with HCCC and Merger Sub. Pursuant to the Merger Agreement, Merger Sub merged with and into HCCC, with HCCC surviving the merger. Upon consummation of the Business Combination and the other transactions contemplated by the Merger Agreement on March 7, 2022, HCCC became a wholly owned subsidiary of Alpha Tau. In July 2022, we took the necessary actions to dissolve HCCC. The SEC maintains an Internet site that contains reports, proxy and information statements, and other information regarding issuers, such as we, that file electronically, with the SEC at www.sec.gov. Our website address is www.alphatau.com. Information contained on, or that can be accessed through, our website does not constitute a part of this Annual Report and is not incorporated by reference herein. We have included our website address in this Annual Report solely for informational purposes. B. Business Overview We are a clinical-stage oncology therapeutics company focused on harnessing the innate relative biological effectiveness and short range of alpha particles for use as a localized radiation therapy for solid tumors. Our proprietary Alpha DaRT® technology is designed to utilize the specific therapeutic properties of alpha particles while aiming to overcome, and even harness for potential benefit, the traditional shortcomings of alpha radiation’s limited range. We believe that our Alpha DaRT technology has the potential to be broadly applicable across multiple targets and tumor types. We are currently focused on developing the Alpha DaRT for use in a number of potential applications, particularly in refractory or unresectable localized tumors which are not being adequately addressed by standard of care, tumor types with a high unmet need (such as pancreatic adenocarcinoma or glioblastoma multiforme), and metastatic tumors in combination with systemic therapies such as checkpoint inhibitors. In our initial proof of concept of the Alpha DaRT technology, we have evaluated, and continue to evaluate, the feasibility, safety and efficacy of the Alpha DaRT technology for the treatment of superficial lesions, i.e., tumors of the skin, head or neck, in multiple clinical trials conducted in clinical sites around the world. On the basis of some of our clinical trials, we received marketing approval in Israel in August 2020 for the treatment of SCC of the skin or oral cavity using the Alpha DaRT. In June 2021, the U.S. Food and Drug Administration, or FDA, granted the Alpha DaRT Breakthrough Device Designation for the treatment of patients with SCC of the skin or oral cavity without curative standard of care. In October 2021, the FDA granted the Alpha DaRT a second Breakthrough Device Designation, in treating recurrent Glioblastoma Multiforme, or GBM, as an adjunct to standard medical therapies or as a standalone therapy after standard medical therapies have been exhausted. In the second half of 2021, we treated ten patients in the U.S. in a multi-center pilot feasibility trial conducted at Memorial Sloan Kettering Cancer Center and four other U.S. clinical sites, to explore the feasibility of delivering radiotherapy for malignant skin and superficial soft tissue tumors using Alpha DaRT. The study met its primary feasibility endpoint, as all patients had successful delivery of radiation by Alpha DaRT. At approximately 12 weeks and 24 weeks after treatment, all ten lesions treated demonstrated a complete response to treatment, with no product-related serious adverse events observed. In February 2026, on the basis of a clinical trial completed in Japan as well as data collected elsewhere in the world, we received shonin pre-market approval of Alpha DaRT for use in patients with unresectable locally advanced or locally recurrent head & neck cancer, from Japan’s Ministry of Health, Labour and Welfare, or MHLW. As part of the approval, we must conduct a post-market surveillance (PMS) study enrolling 66 patients in total at five selected leading clinical centers in Japan. To support our U.S. strategy, we are conducting a multi-center pivotal trial, which we refer to as the ReSTART trial, to explore the delivery of radiotherapy for up to 86 patients with recurrent cutaneous squamous cell carcinoma tumors using Alpha DaRT at clinical sites around the United States and selected other clinical sites outside the U.S. We anticipate completing recruitment of this trial imminently and receiving top-line results of the trial later in 2026 for potential submission to the FDA. 60 We have also evaluated and continue to evaluate the feasibility, safety and efficacy of the Alpha DaRT technology for the treatment of solid tumors in internal organs, including the pancreas, brain, lung, prostate, rectum and liver. In January 2025, we announced interim clinical data from multiple clinical trials, including safety and feasibility studies treating patients with pancreatic cancer, a combination study with pembrolizumab in patients with recurrent unresectable or metastatic head and neck squamous cell carcinoma (HNSCC), and other clinical trials. In a pooled interim data from three clinical trials of patients with pancreatic cancer, as of January 8, 2025, 41 patients had been treated with Alpha DaRT and 33 patients had a measured objective response and were examined for survival metrics. All patients were able to receive the Alpha DaRT treatment, and 151 adverse events, or AEs, were reported in total, of which 38 were possibly, probably or definitely associated with Alpha DaRT treatment, of which three were deemed serious adverse events, or SAEs. An analysis of best overall response in patients with a measured response showed an 18% objective response rate and 91% disease control rate, which is defined to include patients with stable disease or an objective response. An analysis using Kaplan-Meier statistics indicated median overall survival, or OS, across the 33 patients of 18.6 months from diagnosis or initiation of the previous round of chemotherapy, or 10.9 months from treatment with Alpha DaRT. In addition, ad-hoc analyses of pancreatic cancer population subgroups suggested meaningful improvement in median OS for patients treated with Alpha DaRT after prior therapy, compared to previously published studies of alternative monotherapies, across all analyzed subgroups, though caution should be exercised in comparing results from unrelated clinical studies due to differences in study designs, patient populations and other relevant factors. In January 2026, final results from our first-in-human study treating patients with pancreatic cancer, conducted in two sites in Montreal, Canada, were presented at the 2026 ASCO Gastrointestinal Cancers Symposium, demonstrating 22% objective response rate (“ORR”) and 81% disease control rate (“DCR”), across all 32 patients treated in the study, or 23% ORR and 87% DCR when excluding the first two patients, who were deliberately given low dosages in order to examine feasibility and safety only. In addition, investigators showed data from measurements of immune system markers before and after Alpha DaRT treatment, demonstrating immune system preservation not believed to be typical of conventional radiation therapy treatments. We also announced in January 2025 the approval of an investigational device exemption, or IDE, from the FDA, to conduct a clinical study examining the combination of Alpha DaRT and first-line chemotherapy in 12 patients with newly diagnosed metastatic pancreatic cancer, which was then further expanded by an IDE supplement to include a total of 30 patients across two cohorts of 15 patients each, one cohort of newly diagnosed metastatic pancreatic cancer and a second cohort of newly diagnosed locally advanced pancreatic cancer. In September 2025 we announced the successful treatment of the first patient in this study, which we expect to finish recruiting patients in the second quarter of 2026, with initial results expected in the second half of 2026. We also announced receipt of regulatory approval from France’s Ministry of Health to initiate a French multi-center study examining the use of Alpha DaRT alongside capecitabine in treating locally advanced pancreatic cancer in 40 patients who have responded or had stable disease with first-line FOLFIRINOX chemotherapy. We announced in April 2025 the approval of an IDE from the FDA to conduct a clinical study examining the use of Alpha DaRT in patients with recurrent GBM, an indication for which the Alpha DaRT has received Breakthrough Device Designation. The study is expected to enroll up to ten U.S. patients with recurrent glioblastoma not amenable for surgical resection who have undergone a prior course of central nervous system radiation. The primary objective of the study is to evaluate the feasibility and safety of the treatment following the Company’s promising results from pre-clinical studies. The first patient was treated in this study in December 2025. 61 We also announced in January 2025 interim data in our safety and efficacy study combining Alpha DaRT treatment with pembrolizumab in patients with recurrent unresectable or metastatic HNSCC, targeting a similar population as evaluated in Merck’s KEYNOTE-048 study and with a Combined Positive Score of at least 1. As of January 9, 2025, eight patients were treated with Alpha DaRT and pembrolizumab in the study. Of the eight patients treated, three demonstrated a systemic complete response, three demonstrated a systemic partial response, and two patients died before being evaluated, demonstrating a 37.5% systemic complete response rate and a 75% systemic objective response rate. In addition, no SAEs related to Alpha DaRT treatment were reported in these patients as of the data cutoff date of January 9, 2025. We have engaged with a number of prestigious medical and educational institutions and, as of December 31, 2025, have 11 clinical studies ongoing worldwide. Additionally, in our pre-clinical studies, we evaluated the Alpha DaRT on over 20 tumor models (both human and mouse). Alpha DaRT sources were observed to have killed multiple types of mouse and human tumors in vivo. The intensity of the killing activity varied between tumor types, and was dependent on the ability of the radioactive atoms to diffuse inside the tumor and on the intrinsic sensitivity of the tissue to DNA damage induced by the radiation, but all tumor types showed responsiveness to Alpha DaRT, i.e., there was no observed resistance. We therefore believe that our technology may potentially be relevant for treatment across a broad range of tumors. We are currently focused on developing the Alpha DaRT for use in a number of potential applications, particularly in refractory or unresectable localized tumors which are not being adequately addressed by standard of care, tumor types with a high unmet need (such as pancreatic adenocarcinoma or glioblastoma multiforme), and metastatic tumors in combination with systemic therapies such as checkpoint inhibitors. We are also investigating the potential of the Alpha DaRT to elicit an immune response as observed from previous pre-clinical data, as well as anecdotal evidence of response from untreated tumors, or abscopal effects, which may have the potential to inhibit or even reduce metastases, particularly when used in combination with immunotherapies such as checkpoint inhibitors. If approved, we expect to commercialize our Alpha DaRT technology first in a large-scale launch in the United States before other markets, including Israel, notwithstanding our existing marketing authorization in Israel (under which we have not yet commercialized the product) and in Japan (where we have post-marketing surveillance requirements that we are currently focused on satisfying). We hold exclusive rights to our proprietary Alpha DaRT technology in our core markets, including the United States and Europe, except for our agreement with HekaBio KK with respect to the commercialization of Alpha DaRT in Japan, which can be terminated with 90 days’ notice. While local radiation therapy has been a mainstay of cancer therapy for years, it has been mostly limited to modalities utilizing beta or gamma emissions, which primarily destroy cells through an indirect mechanism relying on oxygen and the generation of free radicals to cause single-strand DNA breaks. By contrast, alpha radiation has hundreds of times the linear energy transfer rate of beta-emitters. Additionally, alpha particles’ heavier mass and far shorter particle paths (less than 100 μm) relative to beta’s lighter mass and lengthier (up to 12 mm) path, have been shown to destroy radioresistant cells in clinical studies - causing multiple, irreparable, double-strand DNA breaks and other cellular damage upon direct impact - within a very short distance. Accordingly, we believe that alpha radiation has several significant potential advantages for use in cancer radiotherapy, including a high relative biological efficiency (potentially enabling it to destroy tumor cells with administration of lower levels of radiation), imperviousness to factors such as hypoxia, and a very well-defined range of travel with limited collateral damage. Nonetheless, its use has also been limited precisely due to alpha’s extremely short particle range in living tissue, as the range of less than 100 μm is insufficient to provide meaningful clinical utility. The Alpha DaRT technology employs a series of radioactive sources that are embedded with Radium-224 to enable a controlled, intratumoral release of alpha-emitting atoms which diffuse and decay throughout the tumor, seeking to kill cancerous cells with localized precision, while penetrating deeper into the tumor than can otherwise be reached by the limited ranges of the alpha particles themselves. Due to the inherent limited range of the alpha particles, we believe that the Alpha DaRT technology has the potential to deliver powerful and localized precise killing impact to the tumor without damage to surrounding healthy tissue. By combining the innate relative biological effectiveness and short range of alpha particles in a single-use disposable form, we believe that the Alpha DaRT could address tumors that have otherwise demonstrated poor response to radiation therapy or other standards of care, with the potential to apply to a wide range of tumors and clinical settings. 62 We have also devoted a significant amount of time and resources establishing a robust patent portfolio so as to gain a strong scientific and commercial foothold worldwide. As of December 31, 2025, our patent portfolio included 140 issued patents, 5 PCT applications pending and 240 pending patent applications, including 17 allowed patent applications, in the United States, Europe, the United Kingdom, Canada, Japan, Australia, China, South Korea, Israel, Russia, Mexico, India, Hong Kong, Taiwan, Singapore, South Africa and the African Regional Intellectual Property Organization, or the ARIPO. Our Therapeutic Focus While we believe the Alpha DaRT has the potential to revolutionize the treatment of nearly all solid tumors, we have identified three initial areas of therapeutic focus for the development of our Alpha DaRT technology: (1) Localized and Unresectable - Localized tumors of a type where either current treatment options are inadequate or unavailable for the patient, e.g., refractory or recurring tumors following surgery and/or radiation, unresectable tumors, or tumors in patients who are unable to withstand surgery. Some of these tumor types include SCC, head and neck SCC, and prostate tumors. (2) High Unmet Need. Tumor types with high unmet need, limited treatment options and generally poor prognosis, such as pancreatic adenocarcinoma and glioblastoma. (3) Metastatic. By combining our Alpha DaRT technology with systemic therapies, such as checkpoint inhibitors, we seek to boost the Alpha DaRT’s potentially immunogenic activity and trigger an immune response to detect and destroy metastatic cancers throughout the body. Development Pipeline We have a number of active clinical programs targeting a range of different tumor types. Our global clinical trial strategy involves evaluating the potential of Alpha DaRT in multiple clinical studies in parallel across a number of tumor types. Upon receipt of early initial results in internal organ cancers from our clinical studies outside the U.S., we undertook increased focus on broadening and accelerating our clinical studies in the U.S. in additional target indications, including internal organ cancers, and currently have five active IDE approvals in parallel from the FDA for clinical trials in the U.S. The following table summarizes our development pipeline: 63 Potential Advantages of the Alpha DaRT® Technology We believe the Alpha DaRT technology may offer the following potential advantages: ● Potential to destroy solid tumors and preserve health tissue. Proprietary technology designed to harness alpha radiation in an effort to destroy solid tumors irreparably with localized precision, while sparing surrounding healthy tissue and limiting systemic side effects. ● Broad potential utility across multiple tumors types supported by compelling safety data. Anti-tumor activity in clinical trials and pre-clinical studies has been observed across multiple tumor types, regardless of the size or location of the tumor or prior treatments, and the Alpha DaRT was generally well-tolerated in these studies and trials. We have also not observed any tumor types that demonstrated resistance to treatment with the Alpha DaRT technology. Taken together, we believe these results suggest the potential to treat patients with high unmet need. ● Promising preliminary efficacy results. In a first-in-human study of 28 tumors of locally advanced and recurrent SCC cancers of the skin and head and neck, results showed that Alpha DaRT achieved 100% objective response rate with over 78% complete response rate. Furthermore, in a U.S. multi-center pilot feasibility trial in ten patients with malignant skin or superficial soft tissue tumors, results showed that the Alpha DaRT achieved 100% complete response rate. In addition, promising initial efficacy results have previously been reported in tumors of the pancreas, lung, rectum and liver. ● Potential to treat patients with limited treatment options. Our Alpha DaRT technology is designed to deliver a powerful but conformal dose of radiation to a very targeted area, which we believe has the potential to address patients who have radio-resistant or recurring tumors, who are ineligible for surgery or for whom surgery would have a meaningful impact on quality of life, or who otherwise would have limited treatment options. ● Potential ease of use for patients and physicians. Potential to be convenient and efficient for both physician and patient alike: The Alpha DaRT technology is designed to be administered through a quick, minimally invasive, generally outpatient procedure, with minimal radioactive exposure, and to yield rapid results without the need for hospitalization or protective gear. We believe that, if approved and commercialized, physicians could easily adapt the customizable treatment to a wide patient profile range without the need to purchase special equipment. ● Potential stimulatory immune effect. Pre-clinical studies have demonstrated encouraging anti-tumor immune responses, cancer resistance and prolonged survival, with interim data from our study examining the combination of Alpha DaRT and pembrolizumab suggesting potential systemic cancer immune response in combination with immunotherapies or other systemic therapies. Our Strategy Our mission is to use our proprietary Alpha DaRT technology to transform the treatment of solid tumors and broaden the potential scope of local radiotherapy delivery across multiple clinical settings. Key elements of our strategy include: ● Complete our ongoing U.S. clinical trial evaluating the efficacy and safety of Alpha DaRT in treating recurrent cutaneous squamous cell carcinoma tumors. We are conducting a multi-center pivotal trial, which we refer to as the ReSTART trial, to explore the delivery of radiotherapy for up to 86 patients with recurrent cutaneous squamous cell carcinoma tumors using Alpha DaRT at up to 25 clinical sites around the United States and selected other clinical sites outside the U.S. We anticipate completing recruitment of this trial around the end of the first quarter of 2026 and receiving results of the trial in the second half of 2026 for potential submission to the FDA. ● Advance our global development pipeline by conducting pilot studies in tumors of high unmet need or metastatic diseases, with a particular focus on U.S. trials. We are seeking to develop the Alpha DaRT technology by conducting pilot studies in other indications and then generating potentially registrational data in other such indications, such as pancreas, brain and prostate cancers, as well as in patients with metastatic cancer. As of December 31, 2025, we have eleven clinical trials ongoing worldwide, with five active IDE approvals in parallel from the FDA for clinical trials in the U.S. 64 ● Continue to evaluate the potential systemic immune response generated by the Alpha DaRT, particularly in combination with immunotherapies. We have conducted extensive pre-clinical studies focused on the combination of Alpha DaRT with immunomodulators, which have demonstrated encouraging anti-tumor immune responses. By combining our Alpha DaRT technology with systemic therapies, we seek to harness the Alpha DaRT’s potential immunogenic activity and trigger an immune response to detect and destroy metastatic cancers. In January 2025 we first presented interim data from our combination study of Alpha DaRT and pembrolizumab (Keytruda) for the treatment of SCC of the head and neck, or HNSCC, in Israel, demonstrating a 75% objective response rate and 37.5% complete response rate in the first eight patients treated in the study as of January 9, 2025. We are exploring the possibility of conducting a similar clinical trial in the U.S. In addition, we conduct pre-clinical experiments in our own radioactive pre-clinical laboratory at our headquarters in Jerusalem, Israel to further explore potential combination therapies with Alpha DaRT. ● Expand our independent manufacturing capabilities across strategic geographical regions. We are establishing production sites in key regions around the world in order to supply sufficient radioactive sources with fast, reliable and cost-efficient delivery to our global clinical trials and core markets where we may seek additional marketing authorizations or certifications. We currently operate two manufacturing plants: one facility located in Jerusalem, Israel, where we manufacture our Alpha DaRTs, and a second facility located in the United States, in Lawrence, Massachusetts, which is currently focused on acquiring Thorium-228 and preparing generators for use in Jerusalem in preparing Alpha DaRT treatments. We are developing our first commercial-scale manufacturing facility in Hudson, New Hampshire, and announced in October 2025 the completion of the first phase of construction and receipt of a radioactive material license from the State of New Hampshire. We are exploring potential development of an additional manufacturing facility and headquarters on a plot of land in the Har Hotzvim Industrial Park in Jerusalem, for which we were awarded a discounted long-term leasehold by the Israel Land Authority. ● Pursue further marketing authorization and, if authorized, third-party payor coverage in multiple geographies, with a focus on the United States. We anticipate pursuing further marketing authorization, third-party payor coverage and reimbursement for the use of our Alpha DaRT technology in multiple geographies, with a focus on the United States. If approved, we expect to launch our first large-scale commercialization efforts for our Alpha DaRT technology in the United States before other markets, including Israel, notwithstanding our existing marketing authorization in Israel, which is currently in a renewal process, and Japan, where we are focused on satisfying post-marketing surveillance requirements. Background of Radiation-Based Cancer Treatment Solid tumors Tumors develop as an accumulation of mutated cells that are unable to regulate their growth, moving through the cell cycle uncontrollably and dividing excessively with properties that enable them to invade and destroy surrounding tissue. Cancer cells are able to co-opt the microenvironment, which enables the tumors to bypass the immune system and promote further growth and spread. Cancer cells can break away from the original tumor via the blood stream or the lymphatic system to form new cells elsewhere, called metastasis, and cause the growth of new blood vessels, a process called angiogenesis, which gives tumor cells a source of oxygen, nutrients and a mechanism to release waste products. In 2022 alone, there were approximately 20 million new cancer diagnoses and approximately 10 million cancer-related deaths worldwide, of which over 90% related to solid tumors, according to the World Health Organization’s International Agency for Research on Cancer. Radioactive decay Radioactive decay, the process by which a source emits energy that can penetrate certain materials, is well known for its extreme potency and capacity to destroy living cells when the radiation generated is at a sufficiently high intensity. Such sources include elements that possess an excess or imbalance of energy and consequently lack internal stability. As a result, such elements, termed radionuclides or radioisotopes, will naturally and spontaneously emit, or radiate, the excess energy in order to stabilize, in a random process which cannot be predicted. However, it is possible to define certain parameters such as the nature of the decay and its likelihood over a specified period of time. Amid the process of radioactive decay, the original element, with the excess energy stripped, will spin off into a new element, or a daughter atom. If this daughter atom is itself unstable, it, too, will shed its excess energy and generate its own daughter atom, setting into motion a decay chain until full stability is ultimately reached. While it remains unknown how long it will take an individual atom to fully stabilize, we can quantify how long it will take, on average, for half of a given quantity of an element to decay: known as a half-life, which can range among different radioisotopes from as little as infinitesimal fractions of a second, to billions of years. 65 Alpha, beta, and gamma radiation Specific radioactive elements will consistently undergo one or more types of radioactive decay with their own, fixed characteristics, and can result in the release of particles or photons. For example, the element Radium-224 will undergo decay by shedding two protons and two neutrons (an alpha particle), generating the element Radon-220, and in so doing, emit energy during the release of the alpha particle. This process is known as alpha radiation or alpha decay, and the alpha particle, bearing the mass-heavy, sloughed-off protons and neutrons, will itself be heavy (with an atomic mass of 4). By comparison, one form of beta decay occurs when an element emits an electron, with a negative charge and a relatively low mass. Alpha particles are far bulkier and slower than beta particle electrons: over 7,000 times heavier with approximately 200 times the linear energy transfer rate. Alpha and beta particles, being charged, interact with the charges of every atom they encounter and continually slow down as they travel. Because alpha particles have such a high mass and linear energy transfer rate, they dissipate their energy quickly and are unable to penetrate most surfaces, even as thin as a piece of paper. Alpha particles therefore have no clinical impact when delivered externally, since they cannot penetrate the skin. On the other hand, beta particles are more nimble than their alpha counterparts and can penetrate further into matter; however, because they have equally low mass as the electrons they encounter, beta particles transfer their energy and also fade quickly when encountering a surface of some thickness, such as being stopped by a sheet of aluminum. Gamma decay, by contrast, does not involve any transfer of charge but rather a reconfiguration of the existing subatomic particles, triggering the emission of high-energy photons in the form of gamma rays that can pass longer distances and are attenuated over lengths, depending on the medium being traversed. Radioactivity involves spontaneity, with high radioactivity corresponding to high likelihood of sporadic emissions towards stabilization. Clinical application of the emitted energy-the alpha particles, beta particles and gamma rays-from a radioactive source therefore demands the controlled harnessing of a spontaneous phenomenon, but with some predictable, key parameters, towards a specific desired outcome. Mechanisms of alpha, beta, and gamma radiotherapy Radiation, when aimed towards the destruction of cancerous or other damaged cells in the body, is known as radiotherapy. Depending on the patient’s particular condition, radiotherapy can be either an alternative or a complement to surgery or systemic therapies for the treatment of cancer. Cell death induced by radiotherapy can occur either through direct or indirect DNA damage. Alpha particles generate direct DNA damage, while beta particles and gamma rays destroy cancer cells primarily when they encounter oxygen: specifically, they rely on the presence of oxygen which, upon impact from the beta or gamma radiation, forcefully ejects electrons in a process known as ionization, wherein these atoms, now excited with unpaired electrons, become free radicals which are highly reactive. While the beta or gamma radiation will have little direct impact on the cells, the highly reactive free radicals will react with cellular machinery, including a strand of DNA should they encounter one, generating a single-strand break in the DNA. This is often a short-lived success, however, as the cancer cell may be able to reconstitute or repair the DNA damage after single-strand breaks, depending on its current position in the cell cycle. By contrast, alpha-emitters, with hundreds of times the linear energy transfer rate of beta-emitters, and alpha particles’ heavier mass and far shorter particle paths (less than 100 μm) relative to beta particles’ lighter mass and lengthier (up to 12 mm) path, generally destroyed radioresistant cells more effectively than other forms of radiation such as photons (e.g. X-rays) in pre-clinical studies - causing multiple, irreparable, DNA double-strand breaks and other cellular damage upon direct impact - within a very short distance. Alpha radiotherapy has approximately 500x more concentrated cytotoxic potency than beta particles, with radioactive potency that attenuates as they travel. Beta and gamma radiation are inherently limited in their use in radiotherapy, as their weaker potency and their reliance on multiple interactions demand significantly higher levels of radiation to destroy cancer cells, and these modalities have shown limited efficacy in hypoxic tumor tissue due to the lack of oxygen to generate free radicals. In addition, the relatively long range of beta and gamma increases the risk of greater imprecision, dissipation of potency, and potential collateral tissue damage. By contrast, we believe that alpha radiotherapy, owing to the nature of its high strength and very tightly controlled range, as well as the direct cellular impact not reliant on oxygen, has the potential to overcome treatment resistance to beta and gamma radiotherapy, and to offer a highly conformal and effective source of radiotherapy with very limited damage to surrounding tissues. We believe that alpha radiation may also have the potential to generate an immune-modulated systemic effect in the body when being used for localized treatment, given that it possesses several unique properties: (a) its high linear energy transfer, (b) rapid tumor cell destruction while sparing the surrounding lymphatic tissue, nearby tissues and blood vessels, and (c) the potential to release large amounts of tumor antigens and attract inflammatory and immune cells into the tumor vicinity. 66 Systemic vs. local radiotherapies Radiotherapy can be deployed as both a systemic agent and as a localized therapy. Systemic therapies are those which treat the entire body, and in the context of cancer therapies generally utilize pharmaceutical products, such as chemotherapy or immunotherapy drugs, injected into the body to damage (or stimulate the body to damage) cancer cells throughout the body preferentially over other cells. Local therapies, such as surgical excision, are those which address a disease or injury at a specific point, and in the context of cancer therapies will generally target a specific tumor or set of tumors to be treated. Localized radiotherapy is commonly performed by External Beam Radiotherapy, or EBRT, directing external beams of gamma radiation powerful enough to penetrate the body and damage or destroy cancer cells’ DNA if such cells are in the process of division. EBRT remains a widely used form of radiotherapy, but due to the high doses required for tumor control, results in normal tissue toxicity. While toxicity has been reduced due to technologic improvements such as Intensity-modulated radiation therapy, or IMRT, which allow for a more conformal treatment, significant side effects have continued to be observed in the clinic. Developments in the field of nuclear medicine have introduced the use of radiopharmaceuticals or radio-labeled antibodies, drugs containing a radiation-emitting radionuclide that is naturally absorbed into specific organs or binds to specific molecules to target specific organs, tissues or cells within the body. Systemic radiotherapy involves the use of isotopes such as beta-emitting Lutetium-177, Iodine-131, Strontium-89, or Samarium-153, or alpha-emitting Radium-223, Lead-212, or Actinium-225, alone or attached to targeting molecules and generally injected in liquid form into the body intravenously to travel through the bloodstream to kill cancerous cells, and are then ejected from the body via urine, sweat, and saliva. Limitations of systemic radiotherapy Systemic radiotherapy is beset by certain significant limitations. Although the radiopharmaceuticals or radio-labeled antibodies are armed with targeting mechanisms, certain amounts of radionuclide may still damage healthy tissue. Additionally, certain tumors may be beyond the reach of intravenously administered radiopharmaceuticals. Given the need for sufficient concentration of radiation at the tumor site to have an effect, systemic therapy has the potential to generate systemic toxicity and collateral damage to healthy tissue, critical organs and blood vessels, without sufficiently addressing the targeted tumor if the local concentration of radiation on site is insufficient. Limitations of local radiotherapy In contrast to systemic radiotherapies, local radiotherapies are targeted directly to the cancer and therefore may avoid the shortcomings of systemic treatment. By focusing on the tumor and sparing the healthy cells, there may be fewer debilitating side effects, and the cancerous cells may be destroyed while allowing healthy cells to utilize their superior repair mechanisms to recover from the impact of localized radiation. Local radiotherapy can be performed either externally, by directing one or more beams of EBRT, such as high-energy X-rays or gamma rays, towards the primary tumor and its immediate surroundings, or internally, through the insertion into the body of radiation in solid form, a procedure known as brachytherapy. EBRT and related therapies can be an effective method of destroying the tumor by irradiation but are prone to causing spillover damage in the surrounding healthy tissue and are therefore not practicable in every situation, as certain tumors may be unable to receive a sufficient therapeutic dose due to the surrounding normal tissue tolerance. Recent innovations in the field, such as IMRT, stereotactic radiosurgery and stereotactic body radiation therapy, have focused on improving the precision of gamma rays to concentrate more radiation in a tighter area, but ultimately face similar limitations from the innate characteristics of gamma rays. 67 In brachytherapy, small capsules containing a therapeutic dose of radiation, or seeds, are placed in or as close as possible to the tumor. By hewing closely to the tumor and utilizing the sharp dose falloff beyond the seed, physicians may more ably navigate around the healthy surrounding tissue. Brachytherapy, in being based on beta or gamma radiation, has similar concerns with respect to spillover damage in the surrounding healthy tissue. A less common form of internal radiotherapy is radioembolization, or selective internal radiation therapy, via tiny radioactive beads. The ability of these radioactive beads to adhere to small blood vessels has led to their use in the treatment of liver cancer. Given the unique differential blood supply of the liver, irradiating the tumor and concurrently blocking the blood supply may deprive the tumor of vital oxygen and nutrients. In any instance of radiotherapy, the total exposure must be carefully calibrated, as the human body has a fixed, maximum level of radiation tolerance before the onset of irreversible toxicity and debilitating side effects, such as impaired brain, spinal cord, kidney and bone marrow function and immune deficiency. With its higher relative biological efficiency enabling lower dose levels for anti-tumor activity, and very limited range, we believe alpha radiotherapy may offer an attractive treatment modality against this backdrop. Uses of alpha radiation in radiotherapy We believe alpha radiation has several significant advantages for use in cancer radiotherapy, including having a high relative biological efficiency (potentially enabling it to destroy tumor cells with administration of lower levels of radiation); it is impervious to factors such as hypoxia, and it has a very well-defined range of travel with limited collateral damage. Nonetheless, its use has also been limited precisely due to alpha’s extremely short particle range of less than 100 μm in living tissue, well below the threshold of clinical utility. For this reason, traditional attempts to deliver alpha radiation locally have failed to generate a clinically useful killing effect. The limited use to date of alpha radiation in radiotherapy has primarily been in systemic therapies using radiopharmaceuticals. For example, Xofigo, a salt of radium that naturally localizes to regions where cancer cells are infiltrating bone, has been approved by the FDA for the treatment of bone metastases associated with prostate cancer. Other experimental systemic alpha applications often rely on the conjugation of an alpha-emitting radioisotope with a targeting mechanism such as an antibody (creating an antibody-radionuclide conjugate), with the aim of preferential attachment to cancer cells throughout the body before the radionuclide decays. No solution has been approved that delivers local alpha particles able to penetrate into the depth of tumors, which we believe has hindered the local radiotherapeutic utility of alpha emitters. Our Solution: Alpha DaRT® Technology Mechanism of Action of the Alpha DaRT® Technology The Alpha DaRT technology is designed to act through the controlled release of alpha-emitting atoms directly into a tumor, relying on the innate decay chain of Radium-224 to release and propel multiple alpha emitters deeper into the tumor than can be achieved by the limited (less than 100 μm) ranges of the alpha particles themselves. Radium-224, with a decay chain releasing four alpha particles, has a half-life of approximately 3.7 days, while the remaining decay chain has a total half-life of approximately 12 hours, before eventually stabilizing in inert form. The Alpha DaRT utilizes stainless steel or titanium sources that are embedded with Radium-224. The Alpha DaRT source is designed to be injected into the tumor using one of the proprietary applicators we have developed. Once injected, the radium remains attached to the source, while its daughter atoms detach, spontaneously decay and recoil in succession, with the goal of emitting potentially cytotoxic alpha particle payloads as they move deeper into the tumor until eventually stabilizing. The sources are designed to be placed a few millimeters apart from each other in the tumor to fully utilize the range of each source, and the Alpha DaRT’s localized action is designed to kill the cancer cells while sparing the neighboring healthy cells. 68 The illustration below depicts the decay chain process of Radium-224, which is affixed to the Alpha DaRT source while its daughter atoms are designed to diffuse inside a tumor. The graphics below illustrate the radioactivity seen in a cross-section of a tumor grown in a mouse with a single Alpha DaRT source through the center, as well as the impact on the tumor from an adjacent slice under a histological stain. As illustrated, the Alpha DaRT delivered a high dose of radiation in a very conformal form, with near zero radiation detected outside of the 5mm range surrounding the source. This result is also seen clearly under histological stain, where the corresponding section of the tumor was destroyed while the surrounding environs continued to be unaffected by radiation. The radioisotopes are designed to disperse in the cancerous medium by diffusion and convection due to the tumor chaotic vascularity, as well as from ongoing recoil during the repeated alpha decays. Moreover, the blood vessels formed in tumors tend to have leaky walls, which we believe increases the chance of the radioactive isotopes staying in the tumor and potentially prolonging killing activity. The net result is that the potential range of cell killing in the tumor is up to five millimeters, which is up to 100 times the range of the alpha particles themselves. By contrast, healthy tissue has a highly organized vascular structure, with numerous, well-ordered blood vessels through which a radioisotope can be easily washed out. In our animal studies, the range of the Alpha DaRT was meaningfully more extensive in tumor tissue than it was in healthy tissue, as shown in the two images below comparing radioactivity visible on a radiograph when inserting the Alpha DaRT into SCC tissue and healthy tissue. Diffusion in SCC Diffusion in Healthy Tissue 69 Our Programs Clinical Development Plan Our development strategy is focused on evaluating the safety and efficacy of the Alpha DaRT technology across multiple solid tumor types through broad-ranging pre-clinical studies and into clinical trials. We have successfully completed a number of clinical trials, and are focused on continued clinical development as we seek FDA marketing authorization and other foreign regulatory approvals for use of the Alpha DaRT in these tumors, beginning with recurrent cutaneous squamous cell carcinoma. We are also generating additional clinical evidence regarding the Alpha DaRT technology in superficial and skin tumors from clinical sites around the world, to provide further support for a potential FDA marketing authorization and third-party payor coverage and reimbursement in the United States and around the world. In parallel, we are pursuing a similar approach towards developing the Alpha DaRT technology for other uses by conducting feasibility studies and then generating potentially registrational data in other indications, such as pancreas, brain, lung, and prostate cancers, or applications such as combinations with immunotherapies. We have engaged with a number of prestigious medical and educational institutions and, as of December 31, 2025, we have 11 clinical studies ongoing worldwide. Squamous Cell Carcinoma of the Skin, Head and Neck SCCs are cancers which grow out of squamous epithelial cells, commonly found on the skin or in the lining of bodily organs or respiratory and upper digestive tracts. According to the Skin Cancer Foundation, approximately 1.8 million cases of SCC of the skin are diagnosed every year in the United States. Over 50,000 cases of SCC of the head and neck are diagnosed every year in the United States, with SCC making up approximately 90% of head and neck cancers. We estimate that approximately 23% of cutaneous SCC cases have at least one high-risk factor, approximately 3.5% will result in local recurrence and/or nodal metastasis. We selected SCC of the skin, head and neck as an initial target for the Alpha DaRT because of the relative simplicity of delineation and delivery to superficial solid tumors, as well as the ability to easily assess the Alpha DaRT’s effects on the tumors and the surrounding tissue on an ongoing basis and to monitor for any potential serious adverse events. Rabin Medical Center, Israel, and IRST, Italy (completed; 2017 - 2019) We evaluated the feasibility, safety and efficacy of the Alpha DaRT technology in a first-in-human study of locally advanced and recurrent squamous cell carcinoma cancers of the skin and head and neck, the results of which were subsequently published in the International Journal for Radiation Oncology, Biology, Physics and which elected a positive editorial reaction in the same journal. The trial was conducted in an elderly (median age = 80.5 years) and largely pre-treated patient population, with 42% of the treated lesions having already received radiation therapy. Efficacy was evaluated in 28 tumors of the skin and head and neck, and results showed that Alpha DaRT achieved a >78% complete response rate. The Alpha DaRT was generally well-tolerated, with limited local toxicity and no systemic toxicity. Efficacy results Change in tumor size was assessed by physical examination when possible, or in most cases, by radiological imaging, including PET-CT or CT scans. Tumor response was assessed during a 30-to-45 day follow-up visit using RECIST. Only the irradiated tumor was considered a target lesion for response assessment. Response criteria were defined as follows: complete response, disappearance of the irradiated tumor, or CR; partial response, at least a 30% decrease in the longest dimension of the irradiated tumor, or PR; progressive disease, at least a 20% increase in the longest dimension of the irradiated tumor, taking as reference the smallest longest dimension recorded in radiotherapy, or PD; stable disease, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum since the treatment started. Four to six weeks following Alpha DaRT insertion, a biopsy was obtained if there was clinical suspicion of residual disease. Patients were subsequently evaluated every two months. 70 Twenty-eight target lesions were evaluable to determine tumor response. All evaluable target lesions responded to treatment, with CRs observed in 22 lesions (78.6%), and a PR (tumor reduction between 30% and 100%) was observed in the other six lesions (21.4%). An example of a CR observed in a patient with a newly diagnosed scalp tumor is shown in the figure below. Pre-Treatment Alpha DaRT Insertion 30 Days Post Alpha DaRT Insertion The Kaplan-Meier estimated local progression-free survival rate, or PFS, for all patients at one year was 44% (CI, 20.3-64.3%). Among patients with an initial CR to treatment, the Kaplan-Meier estimated local PFS rate at one year was 60%. Only 32% of the patients had a full year of follow-up. Patients who achieved an initial CR had significantly higher local PFS and OS rates at one year compared with those who achieved a PR (60.1% and 93% compared with 0% and 0%, respectively) (Fig). 71 Local Progression-Free Survival Stratified by Response Status OS rates to 12 months post-Alpha DaRT implantation were 75% (95% CI, 46.14-89.99%) among all patients and 93% (95% CI, 59.08-98.96%) among complete responders. The median follow-up was 6.7 months (range, 1.45-23.36 months). One patient who was treated twice for skin SCC exhibited a unique response, as each time a lesion was treated, a second, non-target lesion responded as well, manifesting as CR to the treatment. The details of this patient’s unique response were published in a 2019 case report in the Journal of Contemporary Brachytherapy. The publication concluded that Alpha DaRT treatment may play a very important role because it could stimulate an anti-tumor immune reactivity with more ease than low-LET radiation that is used with conventional EBRT. Furthermore, the destruction of the tumor by Alpha DaRT maintains an intact vasculature around the tumor, enabling an influx of immune cells to recognize and destroy tumor cells. Following these initial positive results, we expanded our clinical evaluations to a wider patient population and initiated follow-on trials at multiple clinical sites in Israel and around the world. These trials are designed to evaluate Alpha DaRT in cancers of the skin, superficial soft tissue, or oral cavity, regardless of cell type, which includes SCC as well as basal cell carcinoma, melanoma, skin metastases, and others. We also initiated a trial to evaluate the retreatment of patients who previously were treated with the Alpha DaRT. The data from these first trials led to the FDA granting Breakthrough Device Designation to the Alpha DaRT for the treatment of patients with SCC of the skin or oral cavity without curative standard of care. Memorial Sloan Kettering Cancer Center, NY / Multi-Center (completed; 2021) Following receipt of an investigational device exemption, or IDE, from the FDA, we conducted a U.S. pilot clinical study to evaluate the feasibility of Alpha DaRT in treating malignant skin and superficial soft tissue tumors, at Memorial Sloan Kettering Cancer Center, New York and four other clinical sites around the U.S. All ten patients in this trial were treated in the second half of 2021. 72 Study design The initial IDE study was a pilot feasibility trial in which 10 subjects were enrolled. The primary objectives were to explore the feasibility of delivering radiotherapy for malignant skin and superficial soft tissue tumors using Alpha DaRT, with a goal of achieving successful delivery in at least 7 of the 10 patients, as well as to determine the frequency and severity of acute adverse events. Secondary objectives included assessments of radiotherapy-related adverse events, tumor response, radiation safety, stability of device placement, and quality of life measures. Eligible patients had a malignant skin or superficial soft tissue tumor 1-5 cm in size that is suitable for percutaneous interstitial brachytherapy, a form of radiotherapy, with a minimum longest dimension for the tumor of 1 cm and a minimum tumor thickness of 4 mm. After enrolling in the trial, eligible subjects underwent a volumetric assessment of the tumor by a CT planning scan. Volumetric images were used to generate the plan for delivering Alpha DaRT by defining the optimal number, size and location for Alpha DaRT source placement. After radiation planning is completed, the Alpha DaRT sources were inserted using pre-planned radiotherapy parameters (with a specified number and size of Alpha DaRT sources). Immediately after placement of the Alpha DaRT sources, a standard planning CT was performed to assess source positions within the tumor. A physical dose of 10 Gy was prescribed, which is equivalent to a weighted radiation dose of 200 CGyE. Approximately two to three weeks after placement of the Alpha DaRT sources, the placement of the sources was reassessed by volumetric imaging, and then they were removed. Tumor response was assessed periodically three months after removal of the Alpha DaRT source. Feasibility and safety evaluation The study met its primary feasibility endpoint, as all patients had successful delivery of radiation by Alpha DaRT. 22 AEs were reported across seven patients, and 13 of the AEs were considered unrelated to the Alpha DaRT. There were only 2 reported SAEs, both in a single patient, but both events were deemed unrelated to the Alpha DaRT. The most common AEs were dermatitis and pruritus over the implanted area, which subsequently resolved when treated with conservative measures. No Alpha DaRT-related SAEs were reported, and no long-term toxic effects were observed. Efficacy results At approximately 12 weeks, all ten lesions treated demonstrated a complete response to treatment. Computerized tomography scans, or CT, obtained at 24 weeks posttreatment showed no evidence of recurrent disease in any of the ten patients. An example of a CR observed in a patient with a recurrent nose tumor is shown in the figure below. Pre-Treatment 12 weeks after Alpha DaRT Removal 73 ReSTART - U.S. multi-center pivotal study in recurrent cutaneous SCC (recruiting) Following receipt of a conditional IDE from the FDA, whose conditions were subsequently satisfied, we initiated a trial to evaluate the efficacy and safety of Alpha DaRT in the treatment of certain patients with recurrent cutaneous squamous cell carcinoma, a development program supported by a Breakthrough Device Designation from the FDA. We refer to this trial as the ReSTART trial, for Recurrent SCC Treatment with Alpha DaRT Radiation Therapy. The IDE permits us to treat up to 86 patients in up to 25 clinical sites around the U.S., in addition to clinical sites that may be added outside the U.S. Our first patient in this trial was treated in March 2023. We anticipate completing recruitment of this trial around the end of the first quarter of 2026 and receiving results of the trial in the second half of 2026. Following completion of this trial, and pending further discussion with the FDA, we plan to submit the data collected during this clinical trial in our application for marketing authorization from the FDA, which has been initiated in the form of a modular PMA and for which we have already submitted a module regarding non-clinical studies. Study design The pivotal study is a prospective, multi-center, single-arm, open label trial enrolling up to 86 patients with recurrent cutaneous squamous cell carcinoma. The primary objectives are to determine the objective response rate, or ORR, established by the confirmed best overall response, or BOR, following treatment with the Alpha DaRT, as well as to assess the duration of response, or DOR, at 6 months from initial response. Secondary objectives are to assess the safety of Alpha DaRT, and to assess the PFS, OS, overall duration of response, local control, and quality of life, or QOL, for patients treated with Alpha DaRT. U.S. multi-center study in recurrent cutaneous SCC in immunocompromised patients (recruiting) Following receipt of IDE approval from the FDA, we are recruiting patients in a trial to evaluate the efficacy and safety of Alpha DaRT in the treatment of recurrent cutaneous SCC in immunocompromised patients. The clinical study has been approved to enroll up to 28 U.S. patients at up to 8 institutions in the U.S., and will focus on patients with recurrent cSCC who have a weakened immune system due to any primary or secondary immunodeficiencies, excluding diabetes. A 2015 article in Journal of Clinical Medicine noted that non-melanoma skin cancers represent a major cause of morbidity for patients after organ transplantation, and cSCC is the most common skin cancer seen in this population, with a 65-100 fold greater incidence in organ transplant recipients compared to the general population. In addition, a 2003 article in the New England Journal of Medicine cited a number of sources indicating that 50% or more of Caucasian transplant recipients will ultimately develop cutaneous carcinomas. The primary efficacy endpoint of the study is the ORR to the treatment, as measured by best overall response. Secondary efficacy endpoints include progression-free survival, overall survival and local control up to twelve months after treatment, and the safety objective is the measurement of any related AEs. France multi-center - skin cancer (recruiting) We have initiated a multi-center study at up to six cancer centers in France to investigate the safety and efficacy of Alpha DaRT for the treatment of malignant cutaneous tumors. The target population will consist of two cohorts: newly diagnosed patients (up to 49 subjects), and patients with recurrent disease or aggressive pathology (i.e., melanoma) (36 subjects). The primary effectiveness endpoint is the assessment of the ORR using Response Evaluation Criteria in Solid Tumors criteria, or RECIST, 9 to 11 weeks after Alpha DaRT source insertion. The secondary effectiveness endpoints include assessment of the reduction in tumor volume based on CT / ultrasound / physical examination-measured tumor volume at 9 to 11 weeks, assessment of Alpha DaRT source placement using CT imaging on the day of Alpha DaRT insertion, patient-reported health-related QoL outcomes, and Disease-Free Survival at 12- and 24-months post-Alpha DaRT source insertion. Safety objectives include assessment of acute AEs both related and unrelated to Alpha DaRT administration, according to Common Terminology Criteria for Adverse Events, or CTCAE, version 5.0, all vital signs, blood and urine tests, and subject external radiation levels, and assessment of chronic AEs related to Alpha DaRT at 12- and 24-months post-source insertion. The first patient was treated in this trial in June 2022. 74 Long-term safety and efficacy data In August 2023, we released long-term safety and efficacy data that were collected from patients treated with Alpha DaRT across four feasibility trials of head and neck or skin cancers conducted at six institutions across the world. These data were then published in a journal article in June 2024. Between February 2017 and December 2022, 81 lesions in 71 patients were treated with Alpha DaRT in four prospective feasibility trials whose objective was to assess early toxicity and tumor response outcomes. The median follow-up was 14.1 months, with a range of 2-51 months. A CR was observed in 89% of treated lesions, 10% demonstrated a PR, and one patient was not evaluable. The two-year actuarial local recurrence-free survival was 77%, with a 95% confidence interval of 63-87%. Variables including recurrent vs. non-recurrent lesions, baseline tumor size, or histology did not impact long-term outcomes. 27% of patients developed treatment-related acute grade 2 toxicity (such as dermatitis radiation, local pain at the treatment site or pruritus), which subsequently resolved with conservative treatment; there were no grade 3 or higher related acute toxicities. There was no grade 2 or higher late toxicities observed in this cohort, defined as toxicities occurring six months or later after Alpha DaRT treatment. Pancreatic Cancer According to the American Cancer Society, pancreatic cancer accounts for 3% of cancer incidences in the U.S. but about 8% of cancer deaths. It is associated with an extremely poor prognosis, reflected by a five-year survival probability of approximately 13% when all stages are combined. Pancreatic cancer is particularly deadly due to the fact that there are no unique symptoms in its early stages, and, since the pancreas is obscured by other organs in the abdomen and is difficult to visualize clearly on imaging tests, it is therefore typically not detected before having already metastasized to regional lymph nodes, the liver, the lungs or other visceral organs such as the stomach or colon. We selected pancreatic cancer as a target for the Alpha DaRT technology in light of the poor prognosis associated with this particular cancer, as well as our pre-clinical research in which the Alpha DaRT showed activity against pancreatic adenocarcinoma cells. Montréal, Canada (recruitment completed – in follow-up) We are conducting a multi-center clinical study at Centre Hospitalier de l’Université de Montréal, or CHUM, and Jewish General Hospital, both in Montréal, Canada, to investigate the feasibility, safety and preliminary efficacy of Alpha DaRT for the treatment of advanced pancreatic cancer. Recruitment has completed for 32 patients with locally advanced (Stage II or Stage III) or metastatic (Stage IV) pancreatic adenocarcinoma which has been histologically and/or cytologically proven and which is not amenable to surgery, with a tumor lesion of less than four cm in the longest dimension. There are two short-term objectives of this study: to evaluate the feasibility and safety of Alpha DaRT as assessed by the incidence of device-related AEs and SAEs, and to evaluate the preliminary efficacy of Alpha DaRT for pancreatic cancer patients, as measured by ORR following the insertion of the sources, and any observable change in CA19-9 as a marker of tissue damage. The long-term objectives include evaluating overall survival following Alpha DaRT sources insertion, stent durability after Alpha DaRT source insertion, and change in quality of life as measured by patient questionnaires. The primary endpoints of the study are: feasibility, as measured by the successful placement of the Alpha DaRT sources within the tumor or less than 5 mm from the tumor, to be determined based on CT scan performed immediately following the insertion procedure; and safety, by assessing the frequency, severity and causality of acute AEs and SAEs related to Alpha DaRT sources insertion. AEs and SAEs will be assessed and graded according to CTCAE version 5.0. Other safety endpoints include all AEs and SAEs related and unrelated to the study treatment, vital signs, blood and urine tests, and subject and personnel radiation levels. 75 Secondary endpoints include: preliminary efficacy, measured by assessing the ORR four to six weeks after Alpha DaRT sources insertion as assessed by CT scan, changes in CA19-9, which serves as a marker of tissue damage (elevation during treatment, and reduction as a result of tumor ablation), and assessments of overall survival, local control, regional control, distal metastases following Alpha DaRT sources insertion for 24 months, or until patients are lost to follow-up or disease progression, stent durability (assessed by the time elapsed from Alpha DaRT insertion to the need for follow up referral for endoscopic retrograde cholangiopancreatograph, or ERCP, for stent change due to tumor ingrowth), and change in patient-reported quality of life measures 35 and 60 days after Alpha DaRT source insertion. For the first five patients, only one patient was recruited on a four-week basis to allow for assessment of AEs and SAEs before the next patient was recruited, with an interim analysis conducted after five patients were enrolled. In January 2026, the investigators in this trial presented results of this trial at the 2026 ASCO Gastrointestinal Cancers Symposium, as recruitment has been completed but follow-up remains ongoing. A total of 32 patients (13 male, 19 female), median age 73, were enrolled from 2023-2024. Fourteen patients had locally advanced pancreatic cancer and 18 had metastatic pancreatic cancer. Successful placement of Alpha DaRT sources in or around the pancreas tumor was achieved in all cases (100%). A total of 52 device-associated AEs were observed in 13 (41%) patients, with 49 grade 1-2 and 3 grade 3 AEs. Two AEs (biliary obstruction and bacteremia) were deemed to be serious AEs, both of which subsequently resolved. Tumor response data, reported as best overall response, were available for all 32 treated patients. 81% demonstrated disease control, with 56% (18) of patients demonstrating stable disease, 16% (5) with partial response, and 9% (3) had complete response, yielding an ORR of 25%. Excluding the first two patients who had low, sub-optimal Alpha DaRT delivered for safety run-in, the disease control rate and ORR were 87% and 27%, respectively. In addition, at the same symposium, investigators in this trial presented results showing the immune-preserving profile of Alpha DaRT in PDAC, based on immune markers as well as inflammatory indices known to be negative prognostic indicators, and which typically worsen after other forms of radiation therapy. In a study of 23 PDAC patients treated with Alpha DaRT who had complete laboratory data, one month following Alpha DaRT treatment, investigators observed no significant change in Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, CD4/CD8 T-cell ratio, or C-Reactive Protein levels, demonstrating immune system preservation not believed to be typical of conventional radiation therapy treatments. Hadassah Medical Center, Israel (recruitment completed – in follow-up) We are conducting a clinical study at Hadassah Medical Center in Jerusalem, Israel, to investigate the feasibility, safety and preliminary efficacy of Alpha DaRT for the treatment of advanced pancreatic cancer. Recruitment has been completed for 20 patients with locally advanced (Stage II or Stage III) or metastatic (Stage IV) pancreatic adenocarcinoma which has been histologically and/or cytologically proven and which tumor or patient is not amenable to surgery and which has already had chemotherapy or is ineligible for chemotherapy, with a tumor lesion of less than five centimeters in the longest dimension. The objectives of this study are similar to those of the study being conducted in Montréal, Canada to evaluate the use of Alpha DaRT in treating advanced pancreatic cancer. The primary endpoints of the study are: feasibility, as measured by the successful placement of the Alpha DaRT sources, and safety, by assessing the frequency, severity and causality of acute SAEs related to Alpha DaRT source insertion. AEs and SAEs will be assessed and graded according to CTCAE version 5.0, and radioactivity levels will also be measured using blood and urine tests. Secondary endpoints include: preliminary efficacy, measured by assessing the ORR at one and three months after Alpha DaRT source insertion according to RECIST v. 1.1 criteria, changes in CA19-9, which serves as a marker of tissue damage, and tumor dose coverage. Exploratory objectives include changes in immune markers and tumor response using endoscopic ultrasound. Interim Pooled Results of January 2025 In pooled interim data from three clinical trials of patients with pancreatic cancer, as of a cutoff date of January 8, 2025, 41 patients had been treated with Alpha DaRT and 33 patients had a measured objective response and were examined for survival metrics. The Alpha DaRT treatment was successfully administered to all patients, and 151 adverse events were reported in total, of which 38 were possibly, probably or definitely associated with Alpha DaRT treatment, of which three were deemed SAEs. An analysis of best overall response in patients with a measured response indicated an 18% objective response rate and 91% disease control rate, or 19% and 97%, respectively, when excluding the first two patients, who were deliberately given low dosages in order to examine feasibility and safety only. An analysis using Kaplan-Meier statistics indicated median overall survival across the 33 patients of 18.6 months from diagnosis or initiation of the previous round of chemotherapy, or 10.9 months from treatment with Alpha DaRT. In addition, ad-hoc analyses of pancreatic cancer population subgroups suggested meaningful improvement in median overall survival from diagnosis or initiation of the previous round of chemotherapy across all analyzed subgroups, for patients treated with Alpha DaRT after prior therapy, compared to previously published studies of alternative monotherapies, though caution should be exercised in comparing results from unrelated clinical studies due to differences in study designs, patient populations and other relevant factors. 76 Specifically, as of January 8, 2025: ● For patients who could not or would not receive chemotherapy (n=8), patients treated with Alpha DaRT demonstrated median OS of 7.5 months after diagnosis, with four of eight treated patients still alive. ● For metastatic patients whose cancer progressed after receiving first-line FOLFIRINOX chemotherapy (n=10), median OS was not yet reached after 15.1 months of median overall follow-up since the initiation of FOLFIRINOX, with eight of ten treated patients still alive. ● For patients whose cancer progressed after receiving second-line Gemcitabine-Abraxane chemotherapy (n=7), findings showed a median OS of 23.0 months since the initiation of Gemcitabine-Abraxane, and a median OS of 9.0 months since being treated with Alpha DaRT, with three of seven treated patients still alive. IMPACT Trial - U.S. multi-center pilot Study in pancreatic cancer (recruiting) Following the approval of an IDE by the FDA, we initiated a clinical study in the U.S. to evaluate the safety, feasibility and efficacy of Alpha DaRT in combination with chemotherapy for the treatment of newly diagnosed locally advanced or metastatic pancreatic cancer. We refer to this trial as the IMPACT trial, for Intratumoral Pancreatic Alpha Combination Trial. We expect to recruit up to 30 patients at up to 10 U.S. institutions, in two cohorts: (1) 15 patients with newly diagnosed locally advanced inoperable pancreatic cancer, and (2) 15 patients with newly diagnosed metastatic pancreatic cancer. Patients will begin modified FOLFIRINOX chemotherapy and will undergo Alpha DaRT treatment during the first four cycles of chemotherapy. The primary objective of the study is to evaluate the safety of Alpha DaRT in combination with chemotherapy, based on the cumulative incidence rate, severity and outcome of treatment-emergent AEs, which are classified according to CTCAE version 5.0. Secondary objectives include the assessment of efficacy of the Alpha DaRT sources in combination with chemotherapy, determined by overall and progression-free survival, pain control, and the rate of surgical resection in the cohort with locally advanced pancreatic cancer. The primary endpoint of the study is the incidence, rate and severity of treatment-emergent AEs, graded according to CTCAE v5.0. Secondary endpoints include overall survival, progression-free survival using RECIST version 1.1, pain response at 30 days and 2 months post treatment as compared to baseline, based on average pain scale using the brief pain inventory short form, and, for the cohort of patients with locally advanced disease, the percentage of patients with tumors that became surgically resectable after Alpha DaRT treatment. Exploratory endpoints include change in CA 19-9 biomarker levels, a user experience questionnaire, and pain response per the brief pain inventory short form. We announced treatment of the first patient in this trial in September 2025. We anticipate completing recruitment of this trial during the second quarter of 2026, and receiving initial results of the trial in the second half of 2026. Italian Single-Center Study (recruiting) Following receipt of authorization from the Italian Ministry of Health, we have initiated a clinical study at a single center in Italy examining the use of Alpha DaRT in treating patients with pancreatic cancer. The trial is expected to recruit up to 15 patients with unresectable locally advanced pancreatic cancer, who have previously received or are ineligible for chemotherapy. The primary objective of the study is to evaluate the feasibility and safety of Alpha DaRT for the treatment of locally advanced pancreatic cancer, as determined by the rate of successful placement of Alpha DaRT sources and the overall incidence of treatment-related SAEs, with severity graded according to CTCAE version 5.0 criteria. The secondary objective of the study is to evaluate the efficacy of the Alpha DaRT treatment, as determined tumor local control according to RECIST version 1.1 criteria, CA19-9 biomarker levels, and tumor coverage during treatment. The exploratory objective is to evaluate changes in immune markers one month after treatment with Alpha DaRT, by measuring levels of CD3, CD4, CD8, CD69, and CD137 biomarker levels. 77 French Multi-Center Study (recruiting) Following receipt of authorization of a clinical investigation from the ANSM, we are currently recruiting patients in a multi-center clinical study in France examining the use of Alpha DaRT alongside capecitabine in treating locally advanced pancreatic cancer patients who have responded or had stable disease with first-line modified FOLFIRINOX chemotherapy. Up to 40 patients who have been previously treated with 8 - 12 cycles of modified FOLFIRINOX are expected to undergo Alpha DaRT insertion, and then three days later they will receive Capecitabine for 2 months. Every 2 months after Alpha DaRT insertion, the patient will be assessed to determine if their tumor is surgically resectable, if they should continue with therapy, or if they should pause therapy. The primary objective of the study will be to evaluate the safety of Alpha DaRT in combination with chemotherapy for the treatment of locally advanced pancreatic cancer in subjects who have non-progressive disease following treatment with modified FOLFIRINOX, and the primary safety endpoint is expected to be the overall incidence of treatment-related SAEs, with severity graded according to CTCAE version 5.0 criteria. Secondary endpoints include tumor ORR, OS, PFS, and percentage of patients with certain resected tumors or tumors that become surgically resectable after Alpha DaRT treatment. Exploratory endpoints include changes in PET scan metrics, CA19-9 biomarker levels and quality of life. French Single-Center Study (planning) Following receipt of authorization of a clinical investigation from the ANSM, we are also working to initiate a clinical study at a single center in France examining the use of Alpha DaRT delivered via Fine Needle System, or FNS, in the treatment of locally advanced pancreatic cancer. The primary objective of the study will be to evaluate the feasibility of the Alpha DaRT for the treatment of locally advanced pancreatic cancer, and the primary endpoint is Alpha DaRT insertion feasibility. Other endpoints include local control rate according to RECIST v. 1.1 criteria, and the incidence of AEs and treated-related AEs. Brain Cancer In preclinical experiments, clinicians have successfully demonstrated the ability to deliver Alpha DaRT sources into the brain cortex and subcortex. No unexpected abnormalities were detected in blood or cerebral spinal floor samples, and MRI and CT scans revealed no evidence of major bleeding or infection. Minimal spatial and temporal movements of the sources were noted. Histopathological analysis demonstrated locally confined findings in brain parenchyma in a very close proximity to the sources. According to the American Cancer Society, approximately 25 thousand malignant tumors of the brain or central nervous system are diagnosed per year, and have a particularly poor prognosis, as they make up only about 1% of cancer diagnoses each year but lead to approximately 3% of annual cancer deaths. GBM remains the deadliest such tumor, with a five-year relative survival rate of only 6% when diagnosed in patients aged 40 or older. We selected recurrent GBM as a target for the Alpha DaRT technology in light of the poor prognosis associated with this cancer, our pre-clinical research in which the Alpha DaRT showed activity against GBM cells, and the particular sensitivity to the potential damage to healthy brain cells surrounding the tumor when using forms of radiation with a longer treatment range. 78 U.S. feasibility study (recruiting) Following receipt of both IDE approval and Breakthrough Device Designation from the FDA, we initiated a clinical trial to evaluate the feasibility and safety of using Alpha DaRT to treat patients with recurrent GBM, at the Ohio State University Center in Columbus, Ohio. The clinical trial is expected to enroll up to ten U.S. patients with recurrent glioblastoma not amenable for surgical resection who have undergone a prior course of central nervous system radiation. We anticipate examining the safety results after treatment of the first three patients, and if supportive we may add another clinical trial site for the second part of the trial. The primary objective of the study is to evaluate the feasibility and safety of the treatment, as measured by the successful rate of Alpha DaRT source placement and the incidence of AEs according to CTCAE v. 5.0 criteria. Secondary objectives include the valuation of radiographic local tumor control and pseudo-progression rate, using standardized RANO criteria, as well as overall survival of the patients. The first patient was treated in this trial in December 2025. Prostate Cancer According to the American Cancer Society, prostate cancer is the most frequently diagnosed cancer in men in the U.S., and according to the International Agency for Research on Cancer, approximately 1.5 million new cases are diagnosed each year. We believe there are several potential benefits to delivering neoadjuvant radiation therapy specifically with Alpha DaRT in patients with prostate cancer. First, we believe that Alpha DaRT may be able to elicit an immune response, as suggested by previous pre-clinical data that showed immune activity, as well as data from our clinical studies that showed anecdotal evidence of a potential abscopal effect, which we believe would have the potential to inhibit the development of future metastases. Second, while prostate cancer is a heterogeneous disease, it appears that local recurrences emanate from the dominant lesion. Therefore, we believe treating these lesions with Alpha DaRT could decrease the risk of recurrence. Third, these dominant lesions can create hypoxic microenvironments, which are associated with worse outcomes for traditional radiation therapy. Alpha radiation cytotoxic activity has been observed to be independent of oxygen levels and therefore we believe may be better suited to treating these lesions. Rambam Health Care Campus, Israel (recruiting) Following initial exploration of the use of Alpha DaRT in a neoadjuvant setting for prostate cancer patients indicated for radical prostatectomy, we have initiated a clinical trial at the Rambam Health Care Campus in Israel, to examine the use of Alpha DaRT for focal treatment of recurrent prostate cancer tumors. The trial aims to recruit up to 10 patients with recurrent, non-metastatic prostate adenocarcinoma. The primary objective of the study is to evaluate the feasibility and the safety of intratumoral insertion of Alpha DaRT sources into prostate adenocarcinoma. The secondary objectives include evaluation of efficacy using biochemical and radiological response, as well as patient-reported quality of life measures. The first patient in this trial was treated in May 2024. U.S. multi-center pilot study (planning) Following the approval of an IDE by the FDA, we are currently working to initiate a clinical study in the U.S. to evaluate the safety and efficacy of Alpha DaRT in treating patients with locally recurrent prostate cancer. The study is expected to enroll up to 12 U.S. patients with locally recurrent prostate cancer who have demonstrated biochemical recurrence by the Phoenix definition (a rise of levels of the biomarker known as prostate-specific antigen, or PSA, by 2 ng/mL from the PSA nadir). The primary objective of the study is to evaluate the safety of the treatment, and the secondary objective of the study is to evaluate the efficacy of Alpha DaRT as assessed by biochemical and clinical evaluation of disease progression as well as overall survival. 79 Liver Metastases The liver is the most common site for metastatic disease from the gastrointestinal tract. It is also one of the most commons sites for metastases of other malignancies such as breast cancer, lung cancer, and melanoma. In colorectal cancer, about two thirds of 600,000 annual deaths are related to liver metastases. Liver metastases are diagnosed in more than 50% of colorectal cancer patients during the course of their disease. During the last two decades, treatment paradigms of metastatic disease have changed dramatically. While surgical resection of metastases was once considered futile, today surgical resection of liver metastases is a well-established therapeutic strategy and offers the best chance for long term survival for suitable patients. Colorectal liver metastases are the most common indication for liver resection, but selected patients with neuroendocrine, breast, lung and melanoma also benefit from resection of liver metastases. Other common indications for liver resection include primary liver tumors such as hepatocellular carcinoma and intra-hepatic cholangiocarcinoma. Montréal, Canada (recruiting) We have initiated, in collaboration with McGill University Health Center in Montréal, Canada, a clinical study to evaluate the feasibility and safety of intratumoral Alpha DaRT for the treatment of liver metastases of colorectal cancer in approximately 10 patients. We plan to test the effect of the Alpha DaRT technology on liver metastases during a two-staged hepatectomy. This unique clinical scenario is designed to allow us to implant Alpha DaRT sources in right-sided liver metastases during the first operation and resect the right liver containing the sources during the second operation. Thus, we believe a complete histopathological evaluation of liver metastases following Alpha DaRT administration can be performed, after which we will be able to evaluate the effect of Alpha DaRT sources on liver metastases with different histopathological growth patterns. The rationale for evaluating Alpha DaRT with this approach is multi-fold. First, we believe Alpha DaRT may elicit an immunological response, thus through treatment of a single liver metastasis, we believe there could be reduction in metastases throughout the remaining liver. We believe a reduction in metastases may also reduce the risk of future metastases from arising. Secondly, during the time between the two stages of the hepatectomy, patients are normally not receiving metastasis-directed therapy, but in this study their remaining lesions will be receiving Alpha DaRT during the period between surgical procedures. Third, we believe there may be synergy between Alpha DaRT and chemotherapy, which could further improve outcomes. The study’s primary objectives are to evaluate the safety and feasibility of Alpha DaRT implanted in liver metastases. The secondary objectives are to evaluate the pathological and radiological response of liver metastases to Alpha DaRT. Exploratory objectives include the immunological effects of Alpha DaRT treatment and stratification of the differences in response to Alpha DaRT by histopathological growth patterns. The first patient in this trial was treated in May 2024. The clinicians observed a reduction of 18% in dimension of a treated lesion after one week, and at the same time also saw a reduction of over 25% in dimension of an untreated lesion elsewhere in the liver. The patient was discharged as planned and had an uneventful recovery. Histopathological analysis suggested a pronounced adaptive immune response in the treated lesion. Lung Cancer According to the World Health Organization’s International Agency for Research on Cancer, lung cancer is the leading cause of cancer death, with an estimated 1.8 million deaths in 2022. The term lung cancer, or bronchogenic carcinoma, refers to malignancies that originate in the airways or pulmonary parenchyma. Approximately 95% of all lung cancers are classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) based upon histologic examination. A mediastinal tumor is a tumor in the mediastinum, the cavity that separates the lungs from the rest of the chest. It contains the heart, esophagus, trachea, thymus, and aorta. Lung cancer typically spreads to the lymph nodes in the mediastinum. 80 In preclinical experiments, clinicians have successfully demonstrated the ability to deliver Alpha DaRT sources into the lung and mediastinum using an endobronchial ultrasound procedure. A total of 158 Alpha DaRT sources were inserted successfully in the lung parenchyma and mediastinum of five swine. No adverse event or change in the health and general condition of animals was observed. Hematologic evaluation did not show any clinically significant abnormality related to the Alpha DaRT sources. Histopathology demonstrated local mild inflammatory changes, minimal fibrosis, and dystrophic mineralization with giant cells. Minimal movement and no migration of Alpha DaRT sources were observed. Recurrent lung cancer - Hadassah Medical Center, Israel (recruiting) We have initiated a clinical study at Hadassah Medical Center in Jerusalem, Israel, for the treatment of mediastinal tumors from recurrent lung cancer. Recruitment is open for up to 10 patients with recurrent tumors of the mediastinum of up to 3cm in the longest dimension. The primary endpoints of the study are feasibility, as measured by the successful placement of the Alpha DaRT sources, and safety, by assessing the frequency, severity and causality of acute SAEs related to Alpha DaRT source insertion, according to CTCAE version 5.0. Secondary endpoints include preliminary efficacy, measured by assessing the ORR at one and three months after Alpha DaRT source insertion according to RECIST v. 1.1 criteria, and tumor coverage. The first patient in this trial was treated in October 2024. Ten Alpha DaRT sources were delivered into a lymph node metastasis in the mediastinum, leading to a 41.6% reduction in observed tumor volume after one month, and a 52.7% reduction in observed tumor volume after two months, as well as a reduction in FDG uptake during a PET scan, with no treatment-related adverse events as of Jan 15, 2025. Other Cancers SCC of the vulva - Cambridge University Addenbrooke’s Hospital, UK (completed) We have completed, in collaboration with the Addenbrooke’s Hospital of the Cambridge University Hospitals NHS Trust, a study to evaluate the safety and efficacy of the Alpha DaRT technology for the treatment of primary and recurrent SCC of the vulva. A total of eight patients were treated in this study between 2023 and 2025, with the primary objective being the safety, feasibility and tolerability, and the secondary objective being the effectiveness of the treatment. All patients completed Alpha DaRT treatment as planned, with no adverse impact on patient pain and no grade 3 or higher AEs associated with the Alpha DaRT treatment, which we believe is unique as compared to the standard of care in such a sensitive location. 75% of the patients demonstrated a clinical partial response at four weeks, however they did not meet criteria for a response when examined on MRI. Basket Trial - Hadassah Medical Center, Israel (recruiting) In lieu of ad hoc compassionate use treatments, we have initiated a clinical study at Hadassah Medical Center, Jerusalem, Israel, with recruitment open for up to 100 patients with malignant tumors of up to 7 centimeters in the longest dimension, which we refer to as our ALL study. The study objectives are to collect data on the general safety and efficacy of Alpha DaRT among patients who do not fit the entry criteria of existing investigational trials. The primary endpoint of the study is to assess the frequency, severity and causality of acute AEs related to the Alpha DaRT treatment, according to CTCAE version 5.0. The secondary endpoint is to assess the tumor response to Alpha DaRT treatment assessed using RECIST version 1.1, approximately 3 months after Alpha DaRT treatment. Additional Pipeline Indications In addition to the trials and clinical pathways described above, we are currently planning a number of other clinical studies, both to generate additional data from the tumor types we are already exploring in humans, as well as to test the use of Alpha DaRT in additional tumor types, including breast cancer and rectal cancer. 81 Exploration of Potential Systemic Immune Benefit Combination study: Alpha DaRT + checkpoint inhibitor (recruiting) In November 2021, we initiated a combination study of the Alpha DaRT and pembrolizumab (Keytruda) for the treatment of HNSCC, in Israel. We chose to evaluate the Alpha DaRT in combination with pembrolizumab for the treatment of HNSCC because in our pre-clinical studies (discussed below), the combined use of Alpha DaRT with immunomodulators resulted in decreased metastatic burden and improved survival in treated animals. Further, the results indicated that this activity was modulated by activation of the immune system. Both pembrolizumab, a humanized antibody targeting the PD-1 receptor of lymphocytes, and Alpha DaRT have shown positive results in clinical studies in the treatment of HNSCC. Consequently, we are aiming to explore the combination of these interventions as a potential treatment for metastatic or recurrent HNSCC. Study objectives and design The primary objectives of this study are to evaluate efficacy of Alpha DaRT in combination with pembrolizumab via the Confirmed BOR as defined by RECIST. Secondary objectives include assessments of the frequency, severity and causality of acute adverse events related to the Alpha DaRT treatment in combination with pembrolizumab. Patients enrolled in the trial will receive pembrolizumab cycles every three weeks both before and after receiving Alpha DaRT treatment. The study uses a two-stage adaptive design and can recruit up to 48 patients, with a planned interim analysis after the first 18 patients have been treated. Adverse events will be assessed and graded according to CTCAE version 5.0. PFS will be defined as the time from pembrolizumab treatment start date to progressive disease according to RECIST or death due to any cause, whichever occurs first. OS is defined as the time from pembrolizumab treatment start date to death due to any cause or lost to follow up. DOR is defined as the interval from the time measurement criteria are first met for CR, PR, or stable disease (whichever is first recorded) until the first date recurrent or progressive disease is objectively documented. Exploratory objectives include the assessment of immunological parameters as a result of Alpha DaRT administration in combination with pembrolizumab. The image below illustrates the trial design for this combination study: Interim Results In January 2025, we announced interim data from this study. As of January 9, 2025, eight patients were enrolled for treatment with Alpha DaRT and pembrolizumab in the study. Of the eight patients treated, three demonstrated a systemic complete response, three demonstrated a systemic partial response, and two patients died before being evaluated, demonstrating a 37.5% systemic complete response rate and a 75% systemic objective response rate. In addition, no SAEs related to Alpha DaRT treatment were reported in these patients as of the data cutoff date of January 9, 2025. We are exploring a potential U.S. study similar to the trial described above, and are also exploring other pre-clinical and clinical studies of the combination of Alpha DaRT and systemic therapies, including through pre-clinical testing at our pre-clinical GLP-certified animal laboratory in Jerusalem. 82 Summary of Our Pre-Clinical Findings We consider pre-clinical research as a source of strong and ongoing support for our core thesis and for potential expansion into a wide range of proposed indications. To that end, we continue to invest, both internally and with leading universities and academic centers around the world, in conducting robust pre-clinical research with particular focus on potential supra-additive combinations of Alpha DaRT with other therapies such as immunotherapies and chemotherapies. Among other things, we have completed construction of our own pre-clinical laboratory at our headquarters in Jerusalem, Israel, which has received the necessary certifications to initiate pre-clinical studies, to facilitate our own examination of such combinations. The extensive pre-clinical research conducted on Alpha DaRT has generally focused on three core areas: (1) evaluating the potency of Alpha DaRT in destroying tumors, measured across a broad range of cell lines, (2) evaluating combinational treatments with standard of care / FDA approved therapies such as chemotherapy and antiangiogenic agents, and (3) evaluating the immunostimulatory potential of the Alpha DaRT and optimizing the combination of Alpha DaRT and immunotherapy. Pre-clinical research, including both in vitro and in vivo experiments as well as physical, biological and computational modeling of the diffusion or biokinetic properties of Alpha DaRT, have led to the publication of 28 articles in peer-reviewed journals. Alpha DaRT is Designed to Efficiently Destroy a Tumor Pre-clinical studies were performed in vitro and in vivo with mouse tumor models and human derived tumors, to evaluate the diffusion properties and potential therapeutic activity of Alpha DaRT: Summary of Pre-Clinical Studies Histology Murine Cells in Mice or in Vitro Human Cells in Athymic Mice or in Vitro Skin SCC X Lung SCC X HNSCC X X Lung Adenocarcinoma X X Pancreas Adenocarcinoma X X Prostate Adenocarcinoma X X Breast Carcinoma X X Glioblastoma Multiforme X X Cervical Carcinoma X Melanoma X X Colon Carcinoma X X Fibrosarcoma X Bladder Carcinoma X In vitro studies were performed to evaluate the impact of alpha particles on tumor cell viability. Cell lines investigated in vitro included squamous cell, lung, colon, prostate, breast, pancreatic and cervical carcinomas, glioblastoma and melanoma. All cell lines were sensitive to alpha particles (typically dying within days after exposure), with a mean lethal dose in the range 0.7 - 1.5 Gy. In vivo studies using various tumor types were consistent with the in vitro findings and showed that Alpha DaRT sources destroyed tumors and achieved a high degree of local control. As shown in the figure below regarding observed tumor growth in mice, in a pre-clinical study using a sealed Alpha DaRT source designed to prevent radon recoil, no ablative effect was observed, suggesting that the ablation was caused primarily by alpha radiation from the recoiling alpha emitters, rather than the low level of gamma/beta radiation emitted from the source, which had a minor effect. 83 The complex DNA damage induced by alpha radiation, namely clustered double-strand breaks, is nearly impossible to repair and is largely unaffected by the presence of oxygen or by cell cycle phase, which may indicate the potential for alpha particles to kill hypoxic cells which might otherwise be resistant to conventional radiation treatments based on photons or electrons. Consistent with this understanding, mouse and human cells showed lower survival following treatment with alpha radiation compared to x-ray in the same dose. The figure below demonstrates in vitro survival curves for Panc1 (A) and FaDu (B) cancer cell lines after exposure to X-rays or to alpha particles generated from Thorium-228. Alpha DaRT sources were observed to have killed multiple types of mouse and human tumors in vivo. The extent of the tumor killing varied between tumor types and was dependent on the ability of the radioactive atoms to diffuse inside the tumor and on the intrinsic sensitivity of the cancer cells to DNA damage induced by the radiation, but all tumor types showed responsiveness to Alpha DaRT, i.e., there was no observed resistance. The figure below compares the growth of tumors in groups of mice who received a Radium-224-loaded Alpha DaRT vs. an inert wire (control), in athymic mice bearing colonic HCT15 (A), prostatic PC3 (B) or glioblastoma U87 (C) tumors, as well as representative mice in the HCT15 group treated with a Radium-224-loaded Alpha DaRT source (D) and an inert source (E). 84 Alpha DaRT was evaluated in combination with chemotherapy (e.g., cisplatin), locally and systemically, which extended host survival. The figure below shows the development of tumor growth (A) and survival curve (B) for BALB/c mice bearing SQ2 tumors who were each treated with two sources that were either loaded with Radium-224 or inert, where some received Cisplatin and others did not. 85 Notably, in many of our combination pre-clinical experiments only a single Alpha DaRT source was used for the treatment of a tumor, despite that the alpha-emitting atoms released from this single source would not be expected to cover the whole tumor. The purpose of using a single source is to avoid a complete response of the tumor only by virtue of the direct impact of the alpha radiation. Deliberately under-dosing Alpha DaRT enables the investigation of the combination and potential synergy between Alpha DaRT and the drug. The figure below demonstrates the metastatic lung burden using hematoxylin-eosin-stained lung cross-sections from this experiment, comparing representative mice from the Inert group (A) and Radium-224 + Cisplatin group (B), as well as a graph (C) of the ratio of total average gray pixel value for each group vs. normal healthy lungs from mice without tumors, when images were analyzed with Image J software. 86 In human xenografts in nude mice of Glioblastoma Multiforme, or GBM, Alpha DaRT was combined with the chemotherapy drug Temozolomide. As seen in Figure A below, the combination led to significantly increased tumor growth retardation compared to each of the treatments alone. Moreover, as seen in Figure B below, the rate of animals that reached the maximal allowed tumor size before sacrifice was significantly decreased in Alpha DaRT-treated mice and in the combination-treated mice, which may indicate a potential of Alpha DaRT to extend lifespan. 87 Notably, in our combination pre-clinical experiments only a single Alpha DaRT source was used for the treatment of a tumor, despite that the alpha-emitting atoms released from this single source would not be expected to cover the whole tumor. The purpose of using a single source is to avoid a complete response of the tumor only by virtue of the direct impact of the alpha radiation. Deliberately under-dosing Alpha DaRT enables the investigation of the combination and potential synergy between Alpha DaRT and the drug. GBM-bearing mice were also treated with Alpha DaRT in combination with the anti-angiogenic agent Avastin (bevacizumab), where Avastin was injected 3 times per week for 3 weeks from day 5 after insertion of the Alpha DaRT. The combination treatment prevented tumor regrowth following treatment, and tumor size was stable for a longer period than in either of the treatments alone. Additionally, in the mice treated with the combination or with Alpha DaRT, 4 of 14 or 3 of 13 mice, respectively, saw their tumors disappear completely without late relapse, potentially indicating an ability to prevent GBM recurrence. We have seen evidence that the Avastin-induced decrease in angiogenesis may reduce the clearance of radioisotopes from the tumor, consequently expanding the “effective range” of Alpha DaRT in the tumor. Alpha DaRT as a Potential Immunostimulator Radiation is traditionally considered to produce damage-associated molecular patterns, or DAMPs, that activate dendritic cells; in the presence of an antigen this may lead to specific T cell responses. During the escape phase, melanoma cells acquire deficient antigen presentation machinery, masking them from the immune system. 88 A published third-party study recently reported that, apart from the potential to efficiently kill tumor cells relative to other radiation types, alpha-emitting radium significantly enhanced T cell-mediated tumor lysis that was accompanied by augmented protein expression of MHC-I and calreticulin, molecules that are essential for efficient antigen presentation and immune activation. The figure below illustrates the potential effect of irradiation to release antigens from the tumor, which, in turn, may be able to harness the dendritic cells to generate T cell response to detect and target the specific tumor cells for destruction. Tumor antigens released by irradiated tumor cells can be taken up by antigen-presenting cells, or APCs, such as dendritic cells and phagocytic cells. The APCs may then interact with tumor antigens and then migrate to the lymph nodes where they present antigens to T cells, a process that is mediated by the MHC pathway and other co-stimulatory signals, such as CD80 and CD28. After activation by multiple signals, T cells, especially the CD8+ T cells, may be activated and begin to propagate. As a result, activated effector T cells may exit the lymph nodes and home to tumors, including primary tumors and non-irradiated tumor metastases, to exert their effect of killing tumor cells. However, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) competitively combines with CD80/86 and inhibits the activation of T cells. Following T cell activation, programmed cell death 1 (PD-1) receptors that are expressed on the T cell surface bind primarily to PD-L1 and inhibit immune responses. Hence, we believe the administration of immune checkpoint blockades of CTLA-4, PD-1, and PD-L1 may be able to enhance the anti-tumor immunity induced by radiotherapy. Source: Journal of Hematology & Oncology available at: https://pubmed.ncbi.nlm.nih.gov/30115069/ Previously reported studies have demonstrated that ablation treatments, such as radiotherapy, have the potential to expose the body to large amounts of tumor antigens and danger signals and thus may trigger anti-tumor immunity. Consistent with this thesis, we observed that Alpha DaRT rendered the studied animals resistant to a second tumor challenge in two tumor models, colon carcinoma and breast carcinoma. In the immunogenic colon carcinoma tumor model CT26, mice that were treated with Alpha DaRT developed resistance to tumor re-challenge in the opposite lateral side of the back or to experimental metastases in the lungs, suggesting that a systemic immune memory was induced following treatment. The figure below demonstrates the tumor development (A) and survival (B) of mice who were challenged with CT26 cancer cells, where those mice were previously treated for CT26 tumors with Alpha DaRT or with inert sources, compared to naïve mice that did not previously have tumors. 89 Inhibition of regulatory T cells by low-dose cyclophosphamide, inhibition of Myeloid-derived Suppressor Cells, or MDSCs, by sildenafil, or immuno-stimulation by CpG further enhanced the tumor retardation induced by Alpha DaRT, providing further evidence of immune response. As seen in the figure below, mice bearing breast DA3 tumors demonstrated the least tumor development when treated with the Alpha DaRT together with CpG (as compared to phosphate-buffered saline, or PBS). In addition, as seen in the figures below, the combination of sildenafil (A) or cyclophosphamide (B) with Alpha DaRT, led to greater tumor growth inhibition compared to any of the monotherapy groups. As can be seen in the figure below showing survival curves for the different groups, the combination of cyclophosphamide, sildenafil, CpG and Alpha DaRT led to 51% long-term tumor rejection of the CT26 bearing mice, while the combination of cyclophosphamide, sildenafil, CpG and an inert source in lieu of Alpha DaRT mostly led to tumor recurrence. 90 In addition, as shown in the figure below, when repeating the previously described challenge tests four months after a previous treatment, the previous treatment that included Alpha DART and immunomodulation (CpG, cyclophosphamide and sildenafil) led to the most meaningful tumor inhibition. It was observed that the anti-tumor immune memory evidenced following combination treatment (Alpha DaRT and immunomodulators) was specific to CT26 tumor cells and did not provide any protection against other tumor cell lines. In addition, this specific anti-tumor immune memory was transferable to naïve mice, as splenocytes isolated from treated mice were able to protect naïve mice from the CT26 tumor cells, yet not from other tumor cells. In a range of tumors, including triple negative breast cancer, pancreatic and squamous cell carcinoma, a synergy in tumor/metastases development was observed between Alpha DaRT and the delivery of viral dsRNA into the cytoplasm of tumor cells by intratumoral injection of polyIC complexed with polyethylenimine, or PEI. As shown in the figure below, under neoadjuvant settings and following long-term follow-up in mice with 4T1 breast tumors, it was observed that metastases were not formed in the lungs of 75% of studied mice which underwent the combined before surgery treatment, while metastases-related death was observed in the other animals. 91 In light of the observed potential of Alpha DaRT to induce antigen-specific immune memory and to demonstrate synergy with immunomodulation, we have investigated the use of the Alpha DaRT in combination with an inhibitor of programmed cell death protein 1, or PD1. As there are many patients who do not demonstrate a response to such therapies, we wish to understand whether the Alpha DaRT may demonstrate immunostimulatory traits that can potentially enhance response rates or efficacy of response to anti-PD1 therapies, thereby offering a potential mechanism for reducing recurrence rates or enhancing systemic effects in addition to the local therapeutic effect. Recent data support this hypothesis, shown in the figure below, in mice bearing SCC tumors which were treated with the Alpha DaRT, and then a PD1 inhibitor was injected 4 times from day 2 to day 12 after Alpha DaRT treatment. Alpha DaRT demonstrated the potential to increase the response of tumors otherwise unresponsive to a PD-1 inhibitor, where the tumor growth of SCC tumors in mice was meaningfully inhibited in mice that received both the Alpha DaRT as well as a PD-1 inhibitor, as compared to mice that received either the Alpha DaRT or the PD-1 inhibitor alone. Whereas anti-PD-1 therapy did not affect tumor progression on its own, adding anti-PD-1 therapy to Alpha DART further increased the growth retardation induced by Alpha DaRT, suggesting that Alpha DART may induce responsiveness to anti-PD-1 therapy. Furthermore, as shown below both graphically and in representative immunohistochemistry cryo-sections, it was observed that the density of tumor-infiltrating lymphocytes (CD3+ TILs) in the tumor, which is often used to define a “hot tumor” and as a predictor for treatment response, is higher in the combination treatment relative to anti-PD-1 alone, further suggesting that Alpha DART may activate T-cell function when used with anti-PD-1 therapy. 92 anti PD-1 Alpha DaRT + anti PD-1 Similar effects were seen with respect to the density of the lymphocyte effector sub population (CD8+ TILs) and Granzyme B, a serine protease most commonly found in the granules of natural killer cells and cytotoxic T cells, as seen in the figures below. 93 In the pancreatic tumor model, as seen below in the figure of average tumor volume measured at day 14 after treatment, a similar trend was observed in response to the combination of Alpha DaRT with anti-PD1, which led to better tumor control than either therapy alone or the standard of care chemotherapy gemcitabine. This result was further explored in a pre-clinical study that examined the growth of untreated distant pancreatic cancer tumor models in mice. When mice were inoculated intracutaneously with two pancreatic cancer model tumors (from the KPC or Panc02 tumor models) and treated with Alpha DaRT sources instead of inert sources in one pancreatic cancer tumor, a statistically significant decline in secondary tumor growth rate was seen, as can be seen in the figure below. This was true for both the KPC and Panc02 models independently. 94 Components of the Alpha DaRT® Technology Alpha DaRT technology is delivered in a kit comprising radioactive stainless steel or titanium hollow wires or tubes of 5-20 mm length and <1mm diameter, known as “sources,” and applicators to administer the sources. Each source is impregnated with Radium-224, which generates the decay chain of alpha emitters that are designed to recoil into the tumor. These proprietary applicators have been specially designed and developed by us for dispensing the sources based upon the tumor’s location in the body in order to facilitate clinicians’ access to hard-to-reach tumors or tumors which are extremely close to major organs or blood vessels. We believe the applicators are a key component to maximizing the potential advantages of localized alpha radiotherapy. Our Alpha DaRT kit comprises three main components: the radioactive source, specialized applicators, and accessories. We have developed the applicators and accessories with input from clinicians across a variety of specialties in an effort to optimize the Alpha DaRT technology for clinical use. Our Alpha DaRT Sources Our Alpha DaRT sources utilize a hollow tube or rod, made of either stainless steel or titanium, to which Radium-224 is affixed. Titanium is our preferred material of choice for use in internal organs, especially those that may require enhanced MRI compatibility, such as the brain. Our Alpha DaRT sources are designed to be customized to multiple sizes (depending on their intended use) and designed as temporary implants (for use in and removal from superficial tumors) or permanent implants (for use in internal organs). Our R&D department is constantly examining enhancements to future versions of the Alpha DaRT sources, including the use of additional materials that we believe could offer advantages in flexibility, biocompatibility or biodegradability, more advanced anchoring and fixation, or enhanced properties of desorption of the alpha-emitting decay chain. 95 Our Applicators and Accessories Our applicators The Alpha DaRT applicator is composed of a needle or tube (with an attached hub) with the Alpha DaRT sources placed inside for deployment into a tumor, and a stylet (with an attached hub) which functions like a plunger in the needle or tube to eject the source(s) towards the appropriate location within the tumor. A protective cap is attached to the needle to prevent inadvertent damage or loss of a source, and a safety screw is used to fasten the needle and the stylet firmly together. Additionally, the sources are encapsulated with glycerin, a biocompatible material which is designed to act as a sealant to trap the decay product Radon-220 gas from release until it is ejected into the tumor by the applicator. Each applicator can hold multiple sources, often up to six in one applicator, for deployment in a single injection. We have developed seven applicators designed to cover a range of potential applications, including the treatment delivery method, the duration of the sources’ implantation, and on the location of the tumor. For the temporary implantation of sources into superficial tumors, we have developed the following three categories of applicators: ● Alpha DaRT Needle Applicator - a rigid, hypodermic needle designed in various lengths. In this applicator, the sources are affixed to a biocompatible suture and loaded inside the needle; ● Alpha DaRT Flex Applicator - designed for difficult geometry insertions. This applicator is in the form of a flexible (Kapton) tube, wherein the sources are strung upon a biocompatible suture and loaded inside the tube. The Flex Applicator is designed to be used in conjunction with a rigid hypodermic needle, which may be straight or curved, depending upon the specific geometry of the patient’s tumor and the physician’s preference; and ● Alpha DaRT Template Applicator - designed to be used together with a custom-fitted 3D-printed template molded to the patient’s tumor. The template is used as a guiding channel for rigid hypodermic needles. The sources are attached to a stainless-steel wire and loaded inside the needle. This applicator is designated for deeper tumors. All of the foregoing applicators are designed to be supplied preloaded, sealed and ready for immediate use in the procedure room. We have also developed a number of applicators for implantation of sources into tumors inside the body: ● Alpha DaRT Plant Applicator - designed for percutaneous delivery (delivery through the skin) to tumors located in organs such prostate and liver. This applicator is designed to be preloaded with the radioactive sources in accordance with a specific treatment plan. ● Alpha DaRT Scope Applicator - designed to be attached to an existing endoscope or bronchoscope for endoscopic delivery to tumors located in the upper and peripheral lungs. This applicator is also preloaded with the radioactive sources. ● Loading Device - designed to be fitted to existing needles such as standard FNA needles, for the administration of Alpha DaRT to GI organs such as the pancreas or the mediastinum. While our other applicators come preloaded and ready for deployment, the Loading Device is designed to allow the clinician to load the radioactive sources into the delivery device, such as the FNA needle, in the procedure room before or during treatment, to select how many sources to deliver into the treatment area. ● Radial Applicator - designed to be fitted to existing stereotactic biopsy needles, for the administration of Alpha DaRT to the brain and potentially for other organs as well. This applicator is designed to be adapted to specific constraints in the brain, including minimizing movement in the brain when deploying Alpha DaRT sources in a circular pattern. Our goal is to ensure that such adaptor is appropriately sterilized and does not release any undesired radioactivity into the brain. 96 Below are images of several applicators within our range: The Alpha DaRT Needle Applicator and components (18 gauge needle, 140 mm in length) The Alpha DaRT Flex Applicator 97 The Alpha DaRT Template Applicator Loading Device 98 Our Accessories In addition to our sources and applicators, we have also developed a number of ancillary accessories specially designed for use with our Alpha DaRT sources, including grids for guiding deployment, surgical buttons and clips. We have also developed and printed personalized bolus templates for use in specific clinical cases, designed to allow the clinician to execute the treatment plan accurately and seamlessly in conjunction with the Alpha DaRT Template Applicator. Under a collaboration agreement signed in August 2022 with MIM Software Inc. (“MIM”) we collaborate with MIM on the use of MIM’s radiation treatment planning software suite, including MIM Symphony and MIMcloud®, for development of new features and support for the Alpha DaRT across multiple potential indications, integration into all clinical trials involving the Alpha DaRT, and bundling the MIM software with the Alpha DaRT for future commercial sales in territories where the Alpha DaRT and MIM’s software are both approved. The agreement contemplates certain payments to be made by us to MIM in the future upon further development of MIM’s software and integration with the Alpha DaRT in new geographies or sites or with additional features, and upon commercial sales of the Alpha DaRT bundled with MIM software. Our Manufacturing and Supply Infrastructure The Alpha DaRT technology utilizes sources enriched with Radium-224, a radioactive material with a half-life of only 3.7 days. As each treatment requires a different number of sources and applicators tailored for the specific patient, a reliable and timely delivery of the personalized Alpha DaRT kit to the hospital is required. We therefore plan to develop production sites in key regions around the world. We have already built two sites in the United States and Israel which are currently operational, have finished construction of the first phase of a third site in the U.S., have started the planning process for additional potential sites in Israel and Japan, and anticipate that we may build another facility in Europe. Our global manufacturing plan is designed to ensure a sufficient supply of radioactive sources with fast and cost-efficient delivery to our core markets. Our key input for production of the Alpha DaRT is Thorium-228, a readily available radioisotope that can be purchased from licensed vendors around the world. Thorium-228 naturally decays into the Radium-224 that is collected onto the sources. We acquire Thorium-228 from the Oak Ridge National Laboratory of the United States Department of Energy. We are also aware of or have spoken with other potential suppliers of Thorium-228, such that we anticipate steady supply of thorium for the production of the Alpha DaRT given sufficient lead time, although we note the increased demand for Thorium-228 and its daughter atoms in light of the increasing interest in exploring the use of Lead-212 in systemic radiopharmaceuticals. We currently operate two manufacturing plants. One, located in Jerusalem, Israel, is currently operational and contains sufficient capacity for approximately 200,000 sources for local use at current capacity. Our second facility, in Lawrence, Massachusetts, was completed in 2020 and began producing Thorium-228 generators at the start of 2021. In July 2023, we were awarded a discounted long-term leasehold from the Israel Land Authority on a plot of land of approximately 6,660 square meters (1.65 acres) in the Har Hotzvim Industrial Park in Jerusalem, near the Company’s current headquarters leased in an existing facility in the same park, where we expect to develop the land toward a future standalone global headquarters and lead manufacturing site, including significantly expanded areas for Alpha DaRT manufacturing, staff, and R&D facilities. In October 2023 we entered into a long-term lease agreement for a standalone building of over 14,000 rentable square feet in Hudson, New Hampshire, where we are currently developing our second U.S. manufacturing site, which will be focused on the manufacturing of Alpha DaRT sources in the U.S. Construction on the first phase of the facility has been completed, and we received a radioactive material license from the State of New Hampshire Bureau of Public Health Protection in October 2025, allowing us to proceed to equipping the facility, verification and validation, and introducing thorium generators, aiming to produce Alpha DaRT treatments in the facility during the course of 2026. The first phase has a total expected capacity of approximately 400,000 sources for local use from the first phase when at full capacity. We have also entered into a lease for a building in Togane, Japan where we are exploring a potential facility of a similar size as our current Jerusalem facility at scale. The modular nature of our manufacturing capacity allows us to initiate manufacturing more swiftly and then scale up to full capacity over time. We believe these facilities will enable us to maintain sufficient quantities of Thorium-228 securely, to safely produce and capture radium from thorium’s alpha-emitting decay, to affix the radium onto the sources, and to ship the sources with their suitable applicator(s) to various destinations efficiently. 99 In our manufacturing facilities, we employ different methods to produce extractable radium for scalable use. One such method, in a dry setup, utilizes an electrostatic field to attract and isolate radium atoms. Specifically, we use the thorium as a flux-generating surface source to create a collecting unit in which we place the Alpha DaRT sources for charging. The thorium decays into ionized radium atoms, which recoil from the thorium generator and can be attracted or repelled using their inherent charge. The source is placed at a precise distance from the thorium generator and an electrostatic field is placed across it to attract the radium to adhere to the source. After the radium is collected, each source is thermally treated or coated with a polymer to embed the radium securely on the outermost layers of the metallic matrix of the source, while allowing the Radon-220 and subsequent daughter atoms to desorb, or detach from the source and enter the tumor. Each Alpha DaRT source is individually measured to determine the overall Radium-224 activity on it and the desorption probability of Radon-220, to calculate how much Radon-220 will diffuse into the tumor. It is then placed in an applicator to fit the prescribed treatment profile. We have also devised a newer method of radium production, which entails the collection of Radium-224 via a liquid solution of Thorium-228, allowing for more efficient production with a higher output by significantly increasing the percentage yield of Radium-224 which is collected, as well as shortening the time to collect Radium-224 onto each source. This method has the potential of increasing our existing capacity by a factor of 2 to 3. Alpha DaRT sources are prepared upon receiving an order from the clinician and are designed specifically for the treatment of an individual patient; specifically, the number of active sources in each applicator is made to order to match the prescribed treatment plan. Supply of the Alpha DaRT sources is carefully coordinated to account for a usable window up to 24 hours after receipt of the Alpha DaRT sources by the hospital, accounting for the natural decay of the Radium-224 during shipment and intake. Pursuant to the United Nations guidance regarding the transport of radioactive materials, the Alpha DaRT sources can be shipped by standard courier in Excepted Packages, which are used to transport material with extremely low levels of radioactivity, and do not require special handling or protective gear in transit, or they can be shipped in Type A Packages, which are commonly used for shipping intermediate amounts of radioactive material. Prior to shipment, our clinical operations team ensures that all relevant clinicians undergo sufficient training as to proper handling, storage, and disposal of the Alpha DaRT sources. Our Marketing and Commercialization Strategies We have yet to commercialize in any geographical market, even though we presently have received marketing approval in Israel for the treatment of squamous cell carcinoma of the skin or oral cavity using the Alpha DaRT, as well as in Japan for the treatment of unresectable locally advanced or locally recurrent head and neck cancer, and expect that our existing clinical trials, if completed successfully, may be sufficient to satisfy the regulatory requirements for marketing authorization in the United States and Europe. As we believe that the Alpha DaRT technology has the potential address the majority of solid tumors, including in potential combination with immunotherapies, we are focused on evaluating that potential in these various tumors by conducting clinical trials across multiple indications, to be incorporated into a future plan of commercial launch, sequencing and pricing if we obtain marketing authorization(s) in the future. We aim to generate clinical and healthcare economic data to support marketing authorization and third-party payor coverage and reimbursement in the United States, which we see as our primary market, and we anticipate seeking to commercialize initially in the United States before other markets, including Israel, notwithstanding our existing marketing approvals in Japan and Israel. We also believe that our clinical trials being conducted in leading sites around the world will ultimately serve our commercial purposes as well, as we believe those clinical sites may ultimately become lead commercial end-users or centers of excellence in the commercial setting. While we ultimately envision leading much of the commercialization of the Alpha DaRT in core markets such as the United States, we may choose to enter into distribution agreements in other geographies with parties who have exemplary local sales and marketing capabilities. To that end, we have entered into binding term sheets with Medison Pharma Ltd., one of the largest commercial partners of leading global biotech companies in international markets, and its affiliates, to lead the potential commercialization of the Alpha DaRT in Canada and Israel. We intend to enter into definitive commercial agreements covering the commercialization, distribution and sales of the Company’s future products in Canada and Israel. Under these term sheets, effective for a 15-year term following the approval to sell our products, Medison will be responsible for performing regulatory submissions, marketing and distribution directly to clinicians. In March 2026, we entered into a commercial agreement with HekaBio K.K. related to the distribution of the Alpha DaRT in Japan, providing for terms related to the roles and responsibilities of each party as well as defining a split of potential revenues and liabilities, with a focus on treating patients under the pre-market approval in the context of the PMS study. The agreement can be terminated with 90 days’ notice. 100 We remain focused on performing investigational studies to evaluate the potential efficacy of the Alpha DaRT as a monotherapy and an immuno-stimulating combination therapy, and on supplementing our robust patent portfolio across a broad range of tumor applications, as we continue to navigate the regulatory pathways towards commercialization. We believe that these studies will also allow us to better explore the question of which clinicians are ultimately our end customer for commercial purposes, given the involvement of multiple practitioners including the radiation oncologist, medical physicist, and the clinician delivering the Alpha DaRT such as the oncology surgeon or interventional radiologist. Competition The biotechnology, medical device and pharmaceutical industries are characterized by the rapid evolution of technologies and understanding of disease etiology, intense competition and a strong emphasis on intellectual property. We face potential competition from many different sources, including major pharmaceutical, medical device, specialty pharmaceutical and biotechnology companies, academic research institutions, governmental agencies and public and private research institutions. In the field of local therapy for solid tumors, we face competition from new or continually improving surgical techniques, as well as a number of radiation therapies - EBRT, stereotactic body radiation therapy, intensity-modulated radiation therapy, brachytherapy, and others, as well as particle therapies such as proton therapy, neutron therapy and carbon ion therapy. There are several companies developing improved or new forms of local radiation therapy, including Varian Medical Systems, Inc. (a subsidiary of Siemens Healthineers), Elekta AB, BTG plc (a subsidiary of Boston Scientific Corporation), ViewRay, Inc., Accuray, Inc., RefleXion Medical, Inc., or developing radiosensitizers or other products to improve the effect of local radiation therapy, such as Nanobiotix S.A. There are also other forms of local energy delivery being developed in various forms, including the Tumor-Treating Fields developed by Novocure Ltd., and local treatments relying on radiofrequency waves, ultrasound waves, and thermal changes. In addition, in the field of systemic therapy for cancer, commercial and academic clinical trials are being pursued by a number of parties in the field of radiopharmaceuticals, some of which involve the use of alpha radiation as well. Early results from these trials have fueled continued interest in radiopharmaceuticals, which is being pursued by several biotechnology companies as well as by large pharmaceutical companies. There are several companies developing targeted alpha-based radiopharmaceuticals for the treatment of cancer, including Bayer AG, or Bayer, Novartis AG, Fusion Pharmaceuticals Inc. (which has been acquired by AstraZeneca plc), RayzeBio, Inc. (which has been acquired by Bristol-Myers Squibb Co.), Actinium Pharmaceuticals, Inc., Perspective Therapeutics, Inc., RadioMedix, Inc., Orano SA and Telix Pharmaceuticals Limited. These companies are targeting a wide range of solid and hematologic malignancies using various alpha emitting isotopes, including Radium-223, Actinium-225, Lead-212 and Thorium-227. The first and only approved alpha particle-based therapy is Bayer’s Xofigo, a salt of Radium-223 that cannot easily and robustly be attached to a targeting molecule, but naturally localizes to regions where cancer cells are infiltrating bone. Xofigo was approved in 2013 for the treatment of bone metastases associated with prostate cancer. Many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, pre-clinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. Mergers and acquisitions in the pharmaceutical, medical device and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient enrollment in clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. We could see a reduction or elimination in our commercial opportunity if our competitors develop and commercialize treatments that are safer, more effective, have fewer or less severe side effects, are more convenient to administer, are less expensive or have a more favorable label than our Alpha DaRT technology. Our competitors also may obtain FDA or other regulatory approval for their treatments more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of all of our product candidates, if approved, are likely to be their efficacy, safety, convenience and ease of use, price, the effectiveness of imaging diagnostics, the level of generic competition and the availability of reimbursement from government and other third-party payors. 101 Seasonality Our business historically has not been subject to seasonal variations. Our Intellectual Property As of December 31, 2025, our patent portfolio included 140 issued patents, 5 pending PCT applications and 240 pending patent applications, including 17 allowed patent applications. Pursuant to an Intellectual Property Purchase Agreement dated February 2, 2016, we acquired from Althera Medical Ltd. a patent portfolio, including some patent applications whose prosecution was completed following our acquisition. These patents were all assigned to us and are recorded in our name. The patents relate primarily to a device, method of treatment, or method of production of the Alpha DaRT product itself, specifically, to intratumoral diffusing alpha-emitter radiation therapy wherein a probe is loaded with radioisotopes which undergo a process of alpha-emitting radioactive decay solely in proximity to and/or within a tumor. Three of these patents are currently valid, including two U.S. patents and one Japanese patent, and are expected to expire between 2026 and 2029, without accounting for any potential patent term adjustments or extensions or other forms of exclusivity. We have eleven issued patents, and five pending patent applications, relating to the use of a polymer allowing daughter atoms to escape the source and penetrate the tumor where they emit alpha particles by diffusion. This increases the percentage of daughter radionuclides that reach the tumor. The eleven issued patents have been issued in the U.S., Australia, Japan, India, Korea, South Africa, the African Regional Intellectual Property Organization (ARIPO), Russia, Singapore, and Mexico. Five patent applications are pending in Europe, Canada, China and Japan. These patents or patents issuing from the pending applications will begin to expire in 2038, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have ten issued patents, and six pending patent applications, relating to the potential controlled release of a certain amount of Radium-224 from the Alpha DaRT source into the tumor. The ten issued patents have been issued in the U.S., Australia, South Africa, India, Korea, China, ARIPO, Hong Kong, Japan and Mexico. Six patent applications are pending in Europe, Japan, Canada, Russia, Singapore and India. These patents or patents issuing from these pending applications will begin to expire in 2039, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have 17 issued patents, and 14 pending patent applications, of which two applications are allowed, relating to a number of our applicators and other accessories that are used in the Alpha DaRT source itself or in its delivery. The 17 issued patents have been issued in the U.S., Korea, South Africa, India, China, Hong Kong, Japan, ARIPO, Australia and Russia. Fourteen patent applications are pending in the U.S., Europe, Canada, Mexico, Singapore, Japan, Australia, Korea, China and Hong Kong, of which the patent applications in Europe and Singapore have been allowed. These patents or patents issuing from these pending applications will begin to expire in 2039, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have 22 issued patents, and ten pending patent applications, of which one application is allowed, relating to a therapeutic substance administered to a tumor as a medicant, which triggers cytoplasmatic sensors to the presence of an intracellular pathogen, followed by intratumoral Alpha DaRT thereafter. The 22 issued patents have been issued in China, Russia, Hong Kong, Europe, UK, Australia and a unitary patent. Ten patent applications are pending in the U.S., India, Europe, Japan, China, Canada, Australia, Korea, Singapore and Hong Kong, of which the patent application in the U.S. has been allowed. These patents or patents issuing from these patent applications begin to expire in 2039, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have 13 issued patents, and ten pending patent applications, of which two applications have been allowed, relating to our newer liquid method of radium production, as described above. The 13 issued patents have been issued in the U.S., South Africa, Singapore, China and ARIPO, Australia, Russia and Japan. Ten patent applications are pending in the U.S., Europe, Japan, China, Hong Kong, Mexico, Singapore, Korea, Canada and India, of which the patent applications in Hong Kong and Japan have been allowed. These patents or patents issuing from these pending applications will begin to expire in 2040, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have three issued patents and 15 pending patent applications, of which three applications have been allowed, relating to tailored amounts of radioactivity levels to a tumor in a radiotherapy treatment. The three issued patents have been issued in the U.S., Australia, and South Africa. The 15 patent applications are pending in the U.S., Europe, Taiwan, China, Korea, Japan, India, Singapore, Australia, Canada, Mexico, Russia, ARIPO, Israel and Hong Kong, of which the patent applications in China, Hong Kong, and Australia have been allowed. These patents or patents issuing from these pending applications will begin to expire in 2041, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. 102 We have three issued patents, and 15 pending patent applications, of which three applications have been allowed, relating to an applicator for delivery of radiotherapy sources to a tumor of a patient through an elongate needle. The three issued patents have been issued in the U.S., South Africa, and Australia. The 15 patent applications are pending in the U.S., Europe, Taiwan, China, Korea, Japan, India, Singapore, Australia, Canada, Mexico, Russia, ARIPO, Israel and Hong Kong, of which the patent applications in Taiwan, Israel, and Australia have been allowed. These patents or patents issuing from these pending applications will begin to expire in 2041, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have nine issued patents, and four pending patent applications, relating to a template assembly to grasp a body organ during radiotherapy. The nine issued patents have been issued in the U.S., Japan, Australia, South Africa, Hong Kong, China, Russia and Taiwan. Four patent applications are pending in India, Singapore, Canada and Mexico. These patents or patents issuing from these pending applications will begin to expire in 2041, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have four issued patents, and 15 pending patent applications, including one allowed patent application, relating to a modified Alpha DaRT source with higher activity levels and lower desorption probability for enhanced effects of beta radiation. The four issued patents have been issued in the U.S., South Africa and Australia. The 15 patent applications are pending in the U.S., Europe, Taiwan, Japan, China, Korea, India, Singapore, Australia, Canada, Mexico, Russia, ARIPO, Israel and Hong Kong, of which the patent application in Europe has been allowed. These patents or patents issuing from these pending applications will begin to expire in 2042, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have 28 issued patents and ten pending patent applications, including one allowed patent application, relating to an apparatus for planning an Alpha DaRT treatment session. The 28 issued patents have been issued in the U.S., Japan, Korea, China, Australia, Russia, Hong Kong, Taiwan, UK and Europe, and one unitary patent. Ten patent applications are pending in Europe, Japan, India, Singapore, Australia, Canada, Mexico, ARIPO, South Africa and Israel, of which the patent application in Israel has been allowed. These patents or patents issuing from these pending applications will begin to expire in 2041, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have two issued patents, and 15 pending patent applications, relating to a designated applicator which dispenses radioactive sources in a radial configuration. The two issued patents have been issued in the U.S. and Australia. The 15 patent applications are pending in the U.S., Taiwan, Europe, China, Hong Kong, Japan, Korea, India, Singapore, Canada, Russia, ARIPO, South Africa, Mexico and Israel. This patent or patents issuing from these pending applications will begin to expire in 2042, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have twelve issued patents, and 24 pending patent applications, including three allowed patent applications, relating to Alpha DaRT as used in tumor-specific treatment applications. The twelve issued patents have been issued in the U.S., Australia and Taiwan. The 24 pending patent applications are pending in the U.S., Japan, Europe, China, Hong Kong, Australia, Taiwan, of which a patent application in each of Hong Kong, China, and Australia has been allowed. These patents or patents issuing from these pending applications will begin to expire in 2041, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. We have one issued patent, and 29 pending patent applications, including one allowed patent application, relating to the combination of Alpha DaRT with checkpoint inhibitor or vasculature inhibitor immunotherapies. The issued patent has been issued in South Africa. The 29 pending patent applications are pending in the U.S., Europe, China, Japan, Korea, ARIPO, Israel, Mexico, Singapore, Australia, Canada, South Africa, Taiwan and Russia, of which the patent application in Australia has been allowed. The patents issuing from these pending applications will begin to expire in 2042, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. 103 We have two issued patents, and twelve pending patent applications, relating to a calculation for automatic estimation of radiotherapy source positions. The two issued patents were issued in Australia and South Africa. Twelve patent applications are pending in the U.S., Taiwan, Europe, China, Hong Kong, Japan, Korea, India, Singapore, Canada, Russia and Mexico. The patents issuing from these pending applications will begin to expire in 2042, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. In addition, we have 56 pending patent applications, five PCT applications, and four provisional patent applications, which relate to other potential approaches for our products. Patents issuing from these applications will begin to expire in 2043, exclusive of possible patent term adjustments or extensions or other forms of exclusivity. Grants Under the Innovation Law Under the Encouragement of Research, Development and Technological Innovation in the Industry Law 5744-1984, and the provisions of the applicable regulations, rules, IIA directives and benefit tracks, (collectively, the “Innovation Law”), research and development programs that meet specified criteria and are approved by a committee of the IIA are eligible for grants. The grants awarded are typically up to 50% of the project’s expenditures, as determined by the research committee and subject to the benefit track under which the grant was awarded. A company that receives a grant from the IIA, or a grant recipient, is typically required to pay royalties to the IIA on income generated from products incorporating know-how developed using such grants (including income derived from services associated with such products), until 100% of the U.S. dollars-linked grant plus annual interest is repaid, based on the LIBOR interest rate, and since January 1, 2024 based on the 12 month Term SOFR interest rate. The rate of royalties under the regular benefits tracks varies between 3% to 5% of the income generated from the IIA-supported products. The obligation to pay royalties is contingent on actual income generated from such products and services. In the absence of such income, no payment of such royalties is required. The terms of the grants under the Innovation Law also generally require that the products developed as part of the programs under which the grants were given be manufactured in Israel and that the know-how developed thereunder may not be transferred outside of Israel, unless a prior written approval is received from the IIA (such approval is not required for the transfer of a portion of the manufacturing capacity which does not exceed, in the aggregate, 10% of the portion declared to be manufactured outside of Israel in the applications for funding, in which case only notification is required) and additional payments are required to be made to the IIA. It should be noted, that this does not restrict the export of products that incorporate the funded know-how. With respect to transfer of know how out of Israel, when an approval is received from the IIA, a redemption fee must be paid to the IIA. The Innovation Law provides a formula for the calculation of such redemption fee, based on the value of the transferred know-how, multiplied by the amount of grants received from the IIA (including the accrued interest), and divided by the total amounts expended by the grant recipient on R&D. To the extent any royalties were paid to the IIA on account of the grants, such royalties will be deducted from the calculation. The redemption fee is subject to a cap of six times the total amount of the IIA grants, plus interest accrued thereon, and a floor of equal to the total amounts of the IIA grants, plus the interest accrued. Upon payment of the redemption fee, the know-how and manufacturing rights developed under the IIA funding cease to be subject to the Innovation Law. See “Risk Factors- Risks Related to Our Incorporation and Location in Israel” for additional information. Since our incorporation, we have received grants from the IIA relating to various projects, of both royalty-bearing and non-royalty-bearing varieties. No royalties have been paid to the IIA in respect of any grant. Our total outstanding obligation to the IIA at December 31, 2025, including grants received by the Company, grants assumed from Althera Medical Ltd. and the associated interest accrued on all such grants, amounts to approximately $7.69 million, of royalty-bearing grants. In addition, through December 31, 2025, we received IIA participation payments in the aggregate amount of $1,652 thousand under non-royalty-bearing programs from the IIA. Government Regulation Our products and operations are subject to extensive regulation by the U.S. Food and Drug Administration, or FDA, and other federal and state authorities in the United States, as well as comparable authorities in foreign jurisdictions. Our product candidates are subject to regulation as medical devices in the United States under the Federal Food, Drug, and Cosmetic Act, or FDCA, as implemented and enforced by the FDA. United States Regulation of Medical Devices The FDA regulates the development, design, non-clinical and clinical research, manufacturing, safety, efficacy, labeling, packaging, storage, installation, servicing, recordkeeping, premarket clearance or approval, adverse event reporting, advertising, promotion, marketing and distribution, and import and export of medical devices to ensure that medical devices distributed domestically are safe and effective for their intended uses and otherwise meet the requirements of the FDCA. 104 FDA premarket clearance and approval requirements Unless an exemption applies, each medical device commercially distributed in the United States requires either FDA clearance of a 510(k) premarket notification, or approval of a premarket approval, or PMA, application. Under the FDCA, medical devices are classified into one of three classes-Class I, Class II or Class III-depending on the degree of risk associated with each medical device and the extent of manufacturer and regulatory control needed to ensure its safety and effectiveness. Class I includes devices with the lowest risk to the patient and are those for which safety and effectiveness can be assured by adherence to the FDA’s General Controls for medical devices, which include compliance with the applicable portions of the Quality Management System Regulation, or QMSR, facility registration and product listing, reporting of adverse medical events, and truthful and non-misleading labeling, advertising, and promotional materials. Class II devices are subject to the FDA’s General Controls, and special controls as deemed necessary by the FDA to ensure the safety and effectiveness of the device. These special controls can include performance standards, post-market surveillance, patient registries and FDA guidance documents. While most Class I devices are exempt from the 510(k) premarket notification requirement, manufacturers of most Class II devices are required to submit to the FDA a premarket notification under Section 510(k) of the FDCA requesting permission to commercially distribute the device. The FDA’s permission to commercially distribute a device subject to a 510(k) premarket notification is generally known as 510(k) clearance. Devices deemed by the FDA to pose the greatest risks, such as life-sustaining, life-supporting or some implantable devices, or devices that have a new intended use, or use advanced technology that is not substantially equivalent to that of a legally marketed device, are placed in Class III, requiring approval of a PMA. Some pre-amendment devices are unclassified, but are subject to FDA’s premarket notification and clearance process in order to be commercially distributed. 510(k) Clearance marketing pathway To obtain 510(k) clearance, a manufacturer must submit to the FDA a premarket notification demonstrating that the proposed device is “substantially equivalent” to a predicate device already on the market. A predicate device is a legally marketed device that is not subject to premarket approval, i.e., a device that was legally marketed prior to May 28, 1976 (pre-amendments device) and for which a PMA is not required, a device that has been reclassified from Class III to Class II or I, or a device that was found substantially equivalent through the 510(k) process. The FDA’s 510(k) clearance process usually takes from three to twelve months, but may take longer. The FDA may require additional information, including clinical data, to make a determination regarding substantial equivalence. In addition, FDA collects user fees for certain medical device submissions and annual fees and for medical device establishments. For fiscal year 2026, the standard user fee for a 510(k) premarket notification application is $26,067. If the FDA agrees that the device is substantially equivalent to a predicate device currently on the market, it will grant 510(k) clearance to commercially market the device. If the FDA determines that the device is “not substantially equivalent” to a previously cleared device, the device is automatically designated as a Class III device. The device sponsor must then fulfill more rigorous PMA requirements, or can request a risk-based classification determination for the device in accordance with the “de novo” process, which is a route to market for novel medical devices that are low to moderate risk and are not substantially equivalent to a predicate device. 105 After a device receives 510(k) clearance, any modification that could significantly affect its safety or effectiveness, or that would constitute a major change or modification in its intended use, will require a new 510(k) clearance or, depending on the modification, PMA approval or de novo reclassification. The FDA requires each manufacturer to determine whether the proposed change requires submission of a 510(k), de novo request or a PMA in the first instance, but the FDA can review any such decision and disagree with a manufacturer’s determination. If the FDA disagrees with a manufacturer’s determination, the FDA can require the manufacturer to cease marketing and/or request the recall of the modified device until 510(k) marketing clearance or PMA approval is obtained or a de novo request is granted. Also, in these circumstances, the manufacturer may be subject to significant regulatory fines or penalties. PMA approval pathway Class III devices require PMA approval before they can be marketed, although some pre-amendment Class III devices for which FDA has not yet required a PMA are cleared through the 510(k) process. The PMA process is more demanding than the 510(k) premarket notification process. In a PMA, the manufacturer must demonstrate that the device is safe and effective for its intended use(s), and the PMA must be supported by extensive data, including data from pre-clinical studies and human clinical trials. The PMA must also contain a full description of the device and its components, a full description of the methods, facilities, and controls used for manufacturing, and proposed labeling. Following receipt of a PMA, the FDA determines whether the application is sufficiently complete to permit a substantive review. If FDA accepts the application for review, it has 180 days under the FDCA to complete its review of a PMA, although in practice, the FDA’s review often takes significantly longer, and can take up to several years. An advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to the FDA as to the approvability of the device. The FDA may or may not accept the panel’s recommendation. In addition, the FDA will generally conduct a pre-approval inspection of the applicant or its third-party manufacturers’ or suppliers’ manufacturing facility or facilities to ensure compliance with the QMSR. PMA applications are also subject to the payment of user fees, which for fiscal year 2026 includes a standard application fee of $579,272. The FDA will approve the new device for commercial distribution if it determines that the data and information in the PMA constitute valid scientific evidence and that there is reasonable assurance that the device is safe and effective for its intended use(s). The FDA may approve a PMA with post-approval conditions intended to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution, and collection of long-term follow-up data from patients in the clinical study that supported PMA approval or requirements to conduct additional clinical studies post-approval. The FDA may condition PMA approval on some form of post-market surveillance when deemed necessary to protect the public health or to provide additional safety and efficacy data for the device in a larger population or for a longer period of use. In such cases, the manufacturer might be required to follow certain patient groups for a number of years and to make periodic reports to the FDA on the clinical status of those patients. Failure to comply with the conditions of approval can result in material adverse enforcement action, including withdrawal of the approval. Certain changes to an approved device, such as changes in manufacturing facilities, methods, or quality control procedures, or changes in the design performance specifications, which affect the safety or effectiveness of the device, require submission of a PMA supplement. PMA supplements often require submission of the same type of information as a PMA, except that the supplement is limited to information needed to support any changes from the device covered by the original PMA and may not require as extensive clinical data or the convening of an advisory panel. Certain other changes to an approved device require the submission of a new PMA, such as when the design change causes a different intended use, mode of operation, and technical basis of operation, or when the design change is so significant that a new generation of the device will be developed, and the data that were submitted with the original PMA are not applicable for the change in demonstrating a reasonable assurance of safety and effectiveness. 106 De novo classification process Medical device types that the FDA has not previously classified as Class I, II, or III are automatically classified into Class III regardless of the level of risk they pose. The Food and Drug Administration Modernization Act of 1997 established a route to market for low-to-moderate risk medical devices that are automatically placed into Class III due to the absence of a predicate device, called the “Request for Evaluation of Automatic Class III Designation,” or the de novo classification procedure. This procedure allows a manufacturer whose novel device is automatically classified into Class III to request down-classification of its medical device into Class I or Class II on the basis that the device presents low or moderate risk, rather than requiring the submission and approval of a PMA application. Pursuant to the Food and Drug Administration Safety and Innovation Act, or FDASIA, manufacturers may request the de novo classification pathway by permitting manufacturers to request de novo classification directly without first submitting a 510(k) pre-market notification to the FDA and receiving a not-substantially-equivalent determination. De novo classification requests are subject to the payment of user fees, which for fiscal year 2026, includes a standard fee of $173,782. Under FDASIA, FDA is required to classify the device within 120 days following receipt of the de novo request, although the process may take significantly longer. If the manufacturer seeks reclassification into Class II, the manufacturer must include a draft proposal for special controls that are necessary to provide a reasonable assurance of the safety and effectiveness of the medical device. If FDA grants the de novo request, the device may be legally marketed in the United States. However, the FDA may reject the request if the FDA identifies a legally marketed predicate device that would be appropriate for a 510(k) notification, determines that the device is not low-to-moderate risk, or determines that general controls would be inadequate to control the risks and/or special controls cannot be developed. After a device receives de novo classification, any modification that could significantly affect its safety or efficacy, or that would constitute a major change or modification in its intended use, will require a new 510(k) clearance or, depending on the modification, another de novo request or even PMA approval. Clinical trials Clinical trials are almost always required to support a PMA or a de novo request, and are sometimes required to support 510(k) submissions. All clinical investigations of devices to determine safety and effectiveness must be conducted in accordance with the FDA’s investigational device exemption, or IDE, regulations which govern investigational device labeling, prohibit promotion of the investigational device, and specify an array of recordkeeping, reporting and monitoring responsibilities of study sponsors and study investigators. If the device presents a “significant risk” to human health, as defined by the FDA, the FDA requires the device sponsor to submit an IDE application to the FDA, which must become effective prior to commencing human clinical trials. If the device under evaluation does not present a significant risk to human health, then the device sponsor is not required to submit an IDE application to the FDA before initiating human clinical trials, but must still comply with abbreviated IDE requirements when conducting such trials. A significant risk device is one that presents a potential for serious risk to the health, safety or welfare of a patient and either is implanted, used in supporting or sustaining human life, substantially important in diagnosing, curing, mitigating or treating disease or otherwise preventing impairment of human health, or otherwise presents a potential for serious risk to a subject. An IDE application must be supported by appropriate data, such as animal and laboratory test results, showing that it is safe to test the device in humans and that the testing protocol is scientifically sound. The IDE application will automatically become effective 30 days after receipt by the FDA unless the FDA notifies the company that the investigation may not begin. If the FDA determines that there are deficiencies or other concerns with an IDE for which it requires modification, the FDA may permit a clinical trial to proceed under a conditional approval. Regardless of the degree of risk presented by the medical device, clinical studies must be approved by, and conducted under the oversight of, an Institutional Review Board, or IRB, for each clinical site. The IRB is responsible for the initial and continuing review of the IDE, and may pose additional requirements for the conduct of the study. If an IDE application is approved by the FDA and one or more IRBs, human clinical trials may begin at a specific number of investigational sites with a specific number of patients, as approved by the FDA. If the device presents a non-significant risk to the patient, a sponsor may begin the clinical trial after obtaining approval for the trial by one or more IRBs without separate approval from the FDA, but must still follow abbreviated IDE requirements, such as monitoring the investigation, ensuring that the investigators obtain informed consent, and labeling and record-keeping requirements. Acceptance of an IDE application for review does not guarantee that the FDA will allow the IDE to become effective and, if it does become effective, the FDA may or may not determine that the data derived from the trials support the safety and effectiveness of the device or warrant the continuation of clinical trials. An IDE supplement must be submitted to, and approved by, the FDA before a sponsor or investigator may make a change to the investigational plan that may affect its scientific soundness, study plan or the rights, safety or welfare of human subjects. 107 During a study, the sponsor is required to comply with the applicable FDA requirements, including, for example, trial monitoring, selecting clinical investigators and providing them with the investigational plan, ensuring IRB review, adverse event reporting, record keeping and prohibitions on the promotion of investigational devices or on making safety or effectiveness claims for them. The clinical investigators in the clinical study are also subject to FDA’s regulations and must obtain patient informed consent, rigorously follow the investigational plan and study protocol, control the disposition of the investigational device, and comply with all reporting and recordkeeping requirements. Additionally, after a trial begins, we, the FDA or the IRB could suspend or terminate a clinical trial at any time for various reasons, including a belief that the risks to study subjects outweigh the anticipated benefits. Expedited development and review programs Following passage of the 21st Century Cures Act, the FDA implemented the Breakthrough Devices Program, which is a voluntary program offered to manufacturers of certain medical devices and device-led combination products that may provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. The goal of the program is to provide patients and health care providers with more timely access to qualifying devices by expediting their development, assessment and review, while preserving the statutory standards for PMA approval, 510(k) clearance and de novo classification. The program is available to medical devices that meet certain eligibility criteria, including that the device provides more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions, and that the device meets one of the following criteria: (i) the device represents a breakthrough technology, (ii) no approved or cleared alternatives exist, (iii) the device offers significant advantages over existing approved or cleared alternatives, or (iv) the availability of the device is in the best interest of patients. Breakthrough Device Designation provides certain benefits to device developers, including more interactive and timely communications with FDA staff, use of post-market data collection, when scientifically appropriate, to facilitate expedited and efficient development and review of the device, opportunities for efficient and flexible clinical study design, and prioritized review of premarket submissions. Post-market regulation After a device is cleared or approved for marketing, numerous and pervasive regulatory requirements continue to apply. These include: ● establishment registration and device listing with the FDA; ● QMSR requirements, which require manufacturers, including third-party manufacturers, to follow stringent design, testing, control, documentation and other quality assurance procedures during all aspects of the design and manufacturing process; ● labeling regulations and FDA prohibitions against the promotion of investigational products, or the promotion of “off-label” uses of cleared or approved products; ● requirements related to promotional activities; ● clearance or approval of product modifications to cleared devices or devices authorized through the de novo classification process that could significantly affect safety or effectiveness, or that would constitute a major change in intended use of such devices, or approval of certain modifications to PMA-approved devices; ● medical device reporting regulations, which require that a manufacturer report to the FDA if a device it markets may have caused or contributed to a death or serious injury, or has malfunctioned and the device or a similar device that it markets would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur; ● correction, removal and recall reporting regulations, which require that manufacturers report to the FDA field corrections and product recalls or removals if undertaken to reduce a risk to health posed by the device or to remedy a violation of the FDCA that may present a risk to health; ● complying with the laws and regulations requiring Unique Device Identifiers on devices and also requiring the submission of certain information about each device to the FDA’s Global Unique Device Identification Database; ● the FDA’s recall authority, whereby the agency can order device manufacturers to recall from the market a product that is in violation of governing laws and regulations; and ● post-market surveillance activities and regulations, which apply when deemed by the FDA to be necessary to protect the public health or to provide additional safety and effectiveness data for the device. 108 Manufacturing processes for medical devices are required to comply with the applicable portions of the QMSR, which cover the methods and the facilities and controls for the design, manufacture, testing, production, processes, controls, quality assurance, labeling, packaging, distribution, installation and servicing of finished devices intended for human use. The QMSR also requires, among other things, maintenance of a medical device file and complaint files. Medical device manufacturers are subject to periodic scheduled or unscheduled inspections by the FDA. Failure to maintain compliance with the QMSR requirements could result in the shutdown of, or restrictions on, manufacturing operations and the recall or seizure of marketed products. The discovery of previously unknown problems with marketed medical devices, including unanticipated adverse events or adverse events of increasing severity or frequency, whether resulting from the use of the device within the scope of its marketing authorization or off-label by a physician in the practice of medicine, could result in restrictions on the device, including the removal of the product from the market or voluntary or mandatory device recalls. The FDA has broad regulatory compliance and enforcement powers. If the FDA determines that a manufacturer has failed to comply with applicable regulatory requirements, it can take a variety of compliance or enforcement actions, which may result in any of the following sanctions: ● warning letters, untitled letters, fines, injunctions, consent decrees and civil penalties; ● recalls, withdrawals, or administrative detention or product seizures; ● operating restrictions or partial suspension or total shutdown of production; ● refusing or delaying requests for marketing authorization of new products or modified products; ● withdrawing marketing authorizations that have already been granted; ● refusal to grant export approvals for; or ● criminal prosecution. Regulation of Medical Devices in the European Union In the European Union, or EU, until May 25, 2021, medical devices were regulated by the Council Directive 93/42/EEC, or the EU Medical Devices Directive, which has been repealed and replaced by Regulation (EU) No 2017/745, or the EU Medical Devices Regulation. Unlike directives, regulations are directly applicable in all EU member states without the need for member states to implement into national law. In the EU, there is currently no premarket government review of medical devices. However, all medical devices placed on the EU market must meet general safety and performance requirements, including the requirement that a medical device must be designed and manufactured in such a way that, during normal conditions of use, it is suitable for its intended purpose. Medical devices must be safe and effective and must not compromise the clinical condition or safety of patients, or the safety and health of users and - where applicable - other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art. Compliance with the general safety and performance requirements is a prerequisite for European conformity marking, or CE mark, without which medical devices cannot be marketed or sold in the EU. To demonstrate compliance with the general safety and performance requirements medical device manufacturers must undergo a conformity assessment procedure, which varies according to the type of medical device and its (risk) classification. Except for low-risk medical devices (Class I), where the manufacturer can self-assess the conformity of its products with the general safety and performance requirements (except for any parts which relate to sterility, metrology or reuse aspects), a conformity assessment procedure requires the intervention of a notified body. Notified bodies are independent organizations designated by EU member states to assess the conformity of devices before being placed on the market. A notified body would typically audit and examine a product’s technical dossiers and the manufacturer’s quality system. If satisfied that the relevant product conforms to the relevant general safety and performance requirements, the notified body issues a certificate of conformity, which the manufacturer uses as a basis for its own declaration of conformity. The manufacturer may then apply the CE mark to the device, which allows the device to be placed on the market throughout the EU. 109 Throughout the term of the certificate of conformity, the manufacturer will be subject to periodic surveillance audits to verify continued compliance with the applicable requirements. In particular, there will be a new audit by the notified body before it will renew the relevant certificate(s). All manufacturers placing medical devices into the market in the EU must comply with the EU medical device vigilance system. Under this system, serious incidents and Field Safety Corrective Actions, or FSCAs, must be reported to the relevant authorities of the EU member states. Manufacturers are required to take FSCAs defined as any corrective action for technical or medical reasons to prevent or reduce a risk of a serious incident associated with the use of a medical device that is made available on the market. An FSCA may include the recall, modification, exchange, destruction or retrofitting of the device. The aforementioned EU rules are generally applicable in the European Economic Area, or EEA, which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland. Brexit Since January 1, 2021, the MHRA has become the sovereign regulatory authority responsible for the Great Britain (i.e. England, Wales and Scotland) medical device market according to the requirements provided in the UK Medical Devices Regulations that broadly continues to give effect to the three pre-existing EU directives governing active implantable medical devices, general medical devices and in vitro diagnostic medical devices whereas Northern Ireland continues to be governed by EU rules according to the Northern Ireland Protocol. Following the end of the Brexit transition period on January 1, 2021, all medical devices are required to be registered with the MHRA before being placed on the Great Britain market. Manufacturers based outside the UK need to appoint a UK responsible person that has a registered place of business in the UK to register devices with the MHRA. Furthermore, on June 16, 2025, an amendment to the UK Medical Devices Regulations came into force intended to clarify and strengthen the post-market surveillance requirements for medical devices in Great Britain. This amendment aims to facilitate greater traceability of incidents and trends enabling the MHRA to act swiftly when needed to address safety issues and support the entire health system in better protecting patients. In addition, the MHRA launched a consultation between November 14, 2024 and January 5, 2025 on proposals to update the pre-market requirements for medical devices in Great Britain, covering four topics, namely: (1) a new international reliance scheme to enable swifter market access for certain devices that have already been approved in a comparable regulator country; (2) the new UKCA mark and, in particular, proposals to remove the requirement to place such UKCA marking on devices; (3) conformity assessment procedures for in vitro diagnostic devices; and (4) maintaining in UK law certain pieces of “assimilated” EU law. This consultation builds on the MHRA’s previous consultation between September and November 2021, and the UK government’s response to that consultation which was published on June 26, 2022. On July 22, 2025, the MHRA published a response to the consultation confirming that it will incorporate feedback to this consultation into new legislation on pre-market requirements for medical devices in Great Britain. A draft of the new legislation is expected this year and aims to enable greater international collaboration and practices, with more patient-centered, proportionate requirements for medical devices which are responsive to technological advances. Under the UK Medical Devices Regulations, in order to be lawfully placed on the Great Britain market, class I (non-sterile, non-measuring or non-re-useable) medical devices need to be “UKCA” self-certified, and other medical devices need to be “UKCA” certified by a UK approved body. However, certain medical devices in compliance with: (1) the EU Medical Devices Directive can continue to be placed on the Great Britain market until the sooner of certificate expiration or June 30, 2028; or (2) the EU Medical Devices Regulation can continue to be placed on the Great Britain market until June 30, 2030. On February 16, 2026, the MHRA launched a targeted consultation on proposals for recognizing such devices in Great Britain, which will run until April 10, 2026. In particular, the consultation includes a proposal to extend the recognition of EU Medical Devices Regulation-compliant devices in Great Britain indefinitely. 110 In addition, the trade deal between the UK and the EU generally provides for cooperation and exchange of information between the parties in the areas of product safety and compliance, including market surveillance, enforcement activities and measures, standardization-related activities, exchanges of officials, and coordinated product recalls. As such, processes for compliance and reporting should reflect requirements from regulatory authorities. Under the terms of the Northern Ireland Protocol, Northern Ireland follows EU rules on medical devices and devices marketed in Northern Ireland require assessment according to the EU regulatory regime. Such assessment may be conducted by an EU notified body, in which case a CE mark is required before placing the device on the market in the EU or Northern Ireland. Alternatively, if a UK notified body conducts such assessment, a ‘UKNI’ mark and a CE mark are applied and the device may only be placed on the market in Northern Ireland and not the EU. Israel’s Regulations of our Products Our product candidates require approval by the Israeli Ministry of Health for sale and distribution in Israel. Our manufacturing activities in Israel are also subject to regulation by the Israeli Ministry of Health, in addition to the radioactive aspect of our manufacturing which is subject to regulation by the Israeli Ministry of Environmental Protection. In addition to approvals related to marketing and selling our products, once approved, we or our clinical trial partner sites also must obtain pertinent approvals or permits to perform our clinical trials in the countries in which we perform such trials, such as in compliance with an international guideline for the ethical conduct of clinical research known as the Declaration of Helsinki. In Israel, our clinical trials require a permit for a research plan (protocol) by the Helsinki Committee, operating under the Israeli Public Health Regulations (Clinical Trials in Human Subject Research), 1980. Japan’s Regulations of Medical Devices Medical devices are defined as “appliances or instruments, etc. which are intended for use in the diagnosis, treatment or prevention of disease…,” which are classified into 85 broad product categories under the implementing Cabinet Order, such as “physical diagnostic and treatment devices” or “radioactive material treatment devices”, based on product features and functionalities. If a product falls under any of these categories, it will be regulated as a medical device For regulatory purposes, the medical devices are given classification of Class I through IV, based upon their potential safety concerns and health risks. For example, a simple device such as blood pressure meter is Class I, whereas products with potential health risks but for which technology is well established in the form of ISO specifications are Class II (e.g., a pulse oximeter). More advanced products with significant safety concerns are Class III (e.g., a heart pacemaker). Finally, the Ministry of Health, Labor and Welfare (“MHLW”) designates part of Class III devices as Class IV which covers those invasive items with significant safety concerns which may impair human lives (e.g., a balloon cardiovascular catheter). These classifications are compiled in a classification table describing thousands of product subcategories, which is updated from time to time by the MHLW, reflecting introduction of new medical device. For introduction to the Japanese market, new Class I medical devices do not require any pre market regulatory action. In contrast, it is mandatory, for both Class III and Class IV devices, to obtain pre marketing product approval which the MHLW grants on the basis of safety testing information, as well as clinical trial information, when required. Class II devices (and part of Class III devices) are subject to the certification requirement for compliance with the applicable product specifications, which are often developed under the ISO, before introduction into Japan. Certification for most of these Class II devices is granted by private sector laboratories accredited in Japan, pending precedent set by a similar, predicate device. At present, no mutual recognition agreement is in force with either the United States or the European Union for medical device registration. Foreign registration of a medical device, therefore, does not exempt products registered in these regions from the Japanese registration requirement. However, the MHLW will accept foreign electric or other safety data as well as foreign clinical trial data for the purpose of Japanese registration when such data meets Japanese standards (e.g., Good Clinical Practice (GCP)). 111 Approval and clinical trial For approval of a new Class III/IV medical device product, the applicant (which can be either a foreign manufacturer or its distributor in Japan) is required to submit a package of information required by the Japanese regulations which are largely consistent with the Global Harmonization Task Force (“GHTF”)’s regulatory recommendations. For example, the manufacturer is required to prepare documentation and test results demonstrating compliance with the Essential Principles of Safety and Performance, which are largely identical to the general safety and performance requirements of the European Union, such as a risk management program and safety and efficacy documentation. Unlike the case of pharmaceuticals, not all new medical devices are required to submit clinical trial data to prove safety and efficacy. In particular, new products without “evident” improvement from existing products may be approved with clinical information of a limited size, if they do not pose a new, material clinical risk. On the other hand, truly innovative medical devices have to be tested through a clinical trial, but the domestic clinical trial can be limited or waived if the foreign/international pivotal clinical trial source data are accessible and the study was conducted under GCP. Importantly, the authorities’ guidance document provides that “clinical significance”, or operability by Japanese healthcare providers (“HCPs”) in the Japanese clinical environment and applicability in the Japanese patient population are important points of reference for a new medical device. For this reason, even when domestic clinical trial data is required, the scope of the trial is limited to applicability of the new technology to the Japanese clinical environment, the number of subjects can be limited, and comparative data is not essential. Separately, in order to expedite introduction of new medical devices from overseas, the authorities may accept, in lieu of clinical trial results, a “clinical evaluation report” which proves the risks and benefits of the new medical device based on published professional information on the mechanism and operation of the device. Quality management systems In addition to the approval requirements, manufacturers of Class III/IV medical devices, either domestic or foreign, are required to observe the Japanese quality management systems (QMS) requirements and obtain certification of compliance from the authorities. The QMS requirements are largely identical to those under ISO 13485, and cover matters including adequate documentation of manufacturing processes in the form of SOPs, adequate staffing and the PDCA cycle procedure. Post-marketing surveillance and “data exclusivity” In contrast to new pharmaceuticals, which are typically given a post marketing surveillance period for a certain number of years to assess the safety and efficacy of the new product upon approval, not all newly approved medical devices are subject to the post marketing surveillance requirement. Since 2014, the MHLW requires post marketing surveillance only for “evidently” new medical devices in terms of its mechanical structure, usage, operative procedures, or efficacy, and which have not been used either in Japan or abroad. The post marketing surveillance period is, in principle, 3 years, and generally 5 years for implanted products or orphan products which require a long term observation or a larger number of clinical cases to fully assess the product profile. These determinations are made by the MHLW on a case by case basis, and the Ministry may set the period up to 8 years if it finds necessary. Notably, when a new product is assigned a post marketing surveillance period, it is the policy of the MHLW to require similar follow-on products to submit the equivalent set of data (in particular clinical trial data) to obtain approval, as the right of reference is not automatically granted to competitors. This operation of the post marketing surveillance to block follow-on applications is known as the “data exclusivity.” However, the data exclusivity is less important for medical devices than in the case of the pharmaceuticals which are typically given a much longer post marketing surveillance period (8 years for a new API). Indeed, unlike chemical compounds or biological preparations, medical device manufacturers frequently improve and update device models and software to compete in the market, rather than relying on the patents or data exclusivity. 112 Safety reports After approval, incidents impacting on safety and efficacy of the medical device products marketed in Japan must be reported within 15 days or 30 days of the date when the Japanese distributor becomes aware of the incident. These periods begin counting on the date the relevant information is received by the Japanese distributor, and not the date when the foreign manufacturer has found the incident. In the past, quite a few Japanese distributors sometimes failed to collect overseas information and file a timely report, resulting in regulatory penalties. In addition, the distributor is also required to file a periodic safety report to the authorities collecting information on serious incidents as well as unexpected incidents. Reimbursement Reimbursement for medical devices in Japan is centralized, as it is covered by the Japanese National Health Insurance (NHI). Institutions who purchased the reimbursable medical devices receive monetary compensation either in the form of price reimbursement (for consumable medical devices), or through their professional/technical fees (for non-consumables such as CT scanners, automated surgical robotics). When a new Class III/IV non-consumable device product is granted approval, the manufacturer who wishes to obtain the reimbursement status under the NHI must submit a reimbursement proposal to the MHLW. Upon receipt of the proposal, the Ministry will task the advisory body to evaluate if the new medical device would require a new technical fee for reimbursement, or would be reimbursable under the existing technical fee. If the product is entirely new, a new technical fee will be created, under which the fee will be payable to the institution when the device is used for treatment. On the other hand, the authorities may determine that the existing (generic) technical fee covers the new technology, and simply add the new medical device as being eligible for NHI reimbursement under the technical fee. In the latter case, the new product will have to compete with the existing products for compensation from the same technical fee payable to the institution. Compliance, promotion and advertisement The law in Japan was amended in 2020 to strengthen the compliance mechanism inside the corporate structure of the holder of the product approval. Specifically, the approval holder is required to nominate an officer in charge of the medical device matters who shall bear overall responsibilities for compliance, as well as a qualified individual who supervises the operational issues of safety and efficacy of the medical device it distributes. The law also requires the approval holder to organize the compliance structure and allocate and document necessary responsibilities among its staff. Another major change from the previous law is the introduction of a regulatory surcharge designed to strip the companies of the profits they gain from “false or excessive” advertisement or promotion. The amount of the surcharge will be 4.5 percent of the sales volume of the particular product it unlawfully promoted. Promotional incentives to the HCPs are governed by the industry association in the form of a fair competition code. For example, the prices of meals offered to the HCPs may not exceed the ceiling under the code. Advertisement is subject to detailed regulatory guidance of the MHLW. Notably, it is not permitted to distribute academic publication articles to the HCPs when the product is yet to be approved in Japan. Other U.S. Regulatory Requirements Medical device and pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states in which they conduct their business and may constrain the financial arrangements and relationships through which we research, as well as sell, market and distribute any products for which we obtain marketing authorization. Such laws include, without limitation, state and federal anti-kickback, fraud and abuse, false claims, data privacy and security, and transparency laws and regulations related to drug pricing and payments and other transfers of value made to physicians and other healthcare providers. If their operations are found to be in violation of any of such laws or any other governmental regulations that apply, they may be subject to penalties, including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, the curtailment or restructuring of operations, integrity oversight and reporting obligations, exclusion from participation in federal and state healthcare programs and imprisonment. 113 Coverage and Reimbursement In the United States, our commercial success will depend in part on the extent to which governmental authorities, private health insurers and other third-party payors provide coverage for and establish adequate reimbursement levels for our product candidates, if cleared or approved by the FDA. Failure by physicians, hospitals, ambulatory surgery centers and other users of our products to obtain coverage and adequate reimbursement from third-party payors for our product candidates, or adverse changes in government and private third-party payors’ coverage and reimbursement policies, may adversely impact demand for our product candidates if cleared or approved. A substantial portion of our revenue will depend on the extent to which the costs of our products purchased by our customers (or services provided with our products) will be reimbursed by third-party payors, including Medicare, Medicaid, other U.S. government sponsored programs and private payors. These third-party payors exercise significant control over patient access and increasingly use their enhanced bargaining power to secure discounted rates and impose other requirements that may reduce demand for our product candidates, if cleared or approved. Our potential customers’ ability to obtain adequate reimbursement for products and services from these third-party payors affects the selection of products they purchase and the prices they are willing to pay. In addition, demand for new products may be limited unless we obtain favorable reimbursement (including coverage, coding and payment) from governmental and private third-party payors at the time of the product’s introduction, which will depend, in part, on our ability to demonstrate that our products have a positive impact on clinical outcomes. Third-party payors continually review their coverage policies for existing and new products and procedures and can deny coverage for our products or revise payment policies such that payments do not adequately cover the cost of our products. Even if third-party payors make coverage and reimbursement available, that reimbursement may not be adequate, which may have an adverse effect on our business, results of operations, financial condition and cash flows. No uniform policy of coverage and reimbursement among payors in the United States exists and coverage and reimbursement for procedures can differ significantly from payor to payor. Some third-party payors must approve coverage for new or innovative devices or procedures before they will reimburse healthcare providers who use the products or therapies. Even though a new product may have been approved for commercial distribution by the FDA, we may find limited demand for the product unless and until reimbursement approval has been obtained from governmental and private third-party payors. We can provide no assurances that we will be successful in obtaining coverage from Medicare or any other governmental or commercial third-party payor. Moreover, we may be required to seek new billing codes for the components of the Alpha DaRT, and regulatory authorities may not approve the creation of separate codes. Additionally, even if we are successful, these billing codes or the payment amounts associated with such codes may change in the future. In addition to uncertainties surrounding coverage policies, there are periodic changes to reimbursement levels. Third-party payors regularly update reimbursement amounts and also from time to time revise the methodologies used to determine reimbursement amounts. This includes routine updates to payments to physicians, hospitals and ambulatory surgery centers for procedures during which our products are used. These updates could directly impact the demand for our products. See “Risk Factors - Risks Related to Government Regulation - Healthcare policy changes, including recently enacted legislation reforming the U.S. healthcare system, could harm our business, financial condition and results of operations.” We believe the overall escalating cost of medical products and services being paid for by the government and private health insurance has led to, and will continue to lead to, increased pressures on the healthcare and medical device industry to reduce the costs of products and services. Third-party payors are developing increasingly sophisticated methods of controlling healthcare costs through prospective reimbursement and capitation programs, group purchasing, redesign of benefits, and exploration of more cost-effective methods of delivering healthcare. In the United States, some insured individuals enroll in managed care programs, which monitor and often require pre-approval of the services that a member will receive. Some managed-care programs pay their providers on a per capita (patient) basis, which puts the providers at financial risk for the services provided to their patients by paying these providers a predetermined payment per member per month and, consequently, may limit the willingness of these providers to use our products. It is possible that third-party payor coding, coverage and reimbursement policies will affect the need or prices for our products in the future, which could significantly affect our financial performance and our ability to conduct our business. 114 In international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted price ceilings on specific product lines and procedures. EU member states and UK impose controls on whether products are reimbursable by national or regional health service providers and on the prices at which devices are reimbursed under state-run healthcare schemes. More and more, local, product specific reimbursement law is applied as an overlay to medical device regulation, which has provided an additional layer of clearance requirement. Healthcare Reform The United States government has enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our products profitably. Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality or expanding access. Current and future legislative proposals to further reform healthcare or reduce healthcare costs may limit coverage of or lower reimbursement for our product candidates, if cleared or approved, and the procedures associated with the use of such products. The cost containment measures that payors and providers are instituting and the effect of any healthcare reform initiative implemented in the future could impact our revenue from the sale of our products. The implementation of the Affordable Care Act, or ACA, in the United States, for example, has changed healthcare financing and delivery by both governmental and private insurers substantially, and affected medical device manufacturers significantly. The ACA, among other things, provided incentives to programs that increase the federal government’s comparative effectiveness research and implemented payment system reforms including national pilot program on payment bundling to encourage hospitals, physicians and other providers to improve the coordination, quality and efficiency of certain healthcare services through bundled payment models. Additionally, the ACA expanded eligibility criteria for Medicaid programs and 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. Since its enactment, there have been judicial, executive and political challenges to certain aspects of the ACA. On June 17, 2021, the U.S. Supreme Court dismissed the most recent judicial challenge to the ACA without specifically ruling on the constitutionality of the ACA. In addition, other legislative changes have been proposed and adopted since the ACA was enacted. For example, the Budget Control Act of 2011, among other things, reduced Medicare payments to providers, effective on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2032, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022, unless additional Congressional action is taken. Additionally, the American Taxpayer Relief Act of 2012, among other things, further reduced Medicare payments to several providers, including hospitals, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. More recently, the One Big Beautiful Bill Act, which was enacted in July 2025, imposes significant reductions in the funding of the Medicaid program. Such reductions are expected to decrease the number of persons enrolled in Medicaid and reduce the services covered by Medicaid, which could adversely affect our sales of any product candidate that we commercialize. We expect additional state, federal and foreign healthcare reform measures to 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 reduced demand for our products or additional pricing pressure. For instance, on December 13, 2021, the EU Regulation No 2021/2282 on Health Technology Assessment, or HTA, amending Directive 2011/24/EU, was adopted. The Regulation entered into force in January 2022 and has been applicable since January 2025, with phased implementation based on the type of product i.e., certain high-risk medical devices as of 2026. The Regulation intends to boost cooperation among EU member states in assessing health technologies, including certain high-risk medical devices, and providing the basis for cooperation at the EU level for joint clinical assessments in these areas. It will permit EU member states to use common HTA tools, methodologies, and procedures across the EU, working together in four main areas, including joint clinical assessment of the innovative health technologies with the highest potential impact for patients, joint scientific consultations whereby developers can seek advice from HTA authorities, identification of emerging health technologies to identify promising technologies early, and continuing voluntary cooperation in other areas. Individual EU member states will continue to be responsible for assessing non-clinical (e.g., economic, social, ethical) aspects of health technologies, and making decisions on pricing and reimbursement. 115 Data Privacy and Security Laws Numerous state, federal and foreign laws, regulations and standards govern the collection, use, access to, confidentiality and security of health-related and other personal information, and could apply now or in the future to our operations or the operations of our partners. In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure, and protection of health-related and other personal information. In addition, certain foreign laws govern the privacy and security of personal data, including health-related data. Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing. C. Organizational Structure Alpha Tau Medical Ltd. was incorporated in 2015 under the Israel Companies Law of the State of Israel and commenced operations on that date. We have three wholly-owned subsidiaries: Alpha Tau Medical, Inc., which is incorporated in the United States, Alpha Tau Medical Canada, which is incorporated under the laws of Quebec, and Alpha Tau Medical KK, which is incorporated under the laws of Japan. D. Property, Plants and Equipment Our principal facilities are located in Jerusalem, Israel and consist of approximately 3,000 square meters (approximately 32,000 square feet) of leased office space and a manufacturing facility. These facilities currently accommodate our principal executive offices, research and development, account management, marketing, design, business development, finance, and other administrative activities. Of our total 130 employees as of December 31, 2025, 112 are located in Israel. The lease for these facilities expires in May 2035. In addition, we operate a manufacturing facility in Lawrence, MA, USA, which began producing Thorium-228 generators at the start of 2021. We also have a long-term leasehold on a plot of land of approximately 6,660 square meters (1.65 acres) in the Har Hotzvim Industrial Park in Jerusalem, and are currently developing a commercial-scale manufacturing facility in a leased standalone building of over 14,000 rentable square feet in Hudson, NH, USA. Construction on the first phase of the facility has been completed, and we received a radioactive material license from the State of New Hampshire Bureau of Public Health Protection in October 2025, allowing us to proceed to equipping the facility, verification and validation, and introducing thorium generators, aiming to produce Alpha DaRT treatments in the facility during the course of 2026. The first phase has a total expected capacity of approximately 400,000 sources for local use from the first phase when at full capacity. We believe that our facilities are adequate to meet our needs for the immediate future, and that, should it be needed, suitable additional space will be available to accommodate any such expansion of our operations. We have also constructed our own radioactive pre-clinical laboratory at our headquarters in Jerusalem, Israel, which is conducting pre-clinical studies, to explore potential combination therapies with Alpha DaRT.