Actinium Pharmaceuticals Inc

Previous wording

Actinium Pharmaceuticals, Inc. (“Actinium”, the “Company”, or ”we”) develops Antibody Radiation Conjugates (“ARCs”) and targeted radiotherapies intended to meaningfully improve outcomes for patients with relapsed or refractory cancer who have failed existing therapies. We are deploying our technology platform, which we believe to be industry-leading, and intellectual property with over 235 issued and pending patents worldwide, to develop ARCs and next-generation radiotherapies against validated cancer targets.

Current wording

Actinium Pharmaceuticals, Inc. (“Actinium”, the “Company”, or “we”) develops Antibody Radiation Conjugates (“ARCs”) and other targeted radiotherapies intended to meaningfully improve outcomes for patients with relapsed or refractory cancer who have failed existing therapies. We are deploying our technology platform, which we believe to be industry-leading, and intellectual property with over 230 issued and pending patents worldwide, to develop ARCs and next-generation radiotherapies against validated cancer targets.

Previous wording

Actinium’s strategy is to build an integrated, specialty radiotherapeutics company using the power of our platform to deliver new treatment options for patient populations living with high unmet medical needs in hematology and oncology. We believe our focus on relapsed or refractory disease in cancer indications with high unmet medical need, with limited or no competition, and where the primary delivery of care occurs in large comprehensive cancer care centers, is the appropriate strategy for our company. Radiotherapeutics leverage the cell-killing power of linear energy transfer, which we believe is unmatched by other technologies and we also believe that relapsed or refractory disease is an area where radiotherapeutics can succeed over other approaches. Our proven experience conducting multiple, late-stage clinical trials provides an advantage operating a radiotherapy company where barriers related to their utilization and supply chain are higher than those for other types of medicines due to the personalized, just-in-time nature of radiotherapies. We have accumulated extensive experience coordinating the manufacturing and clinical supply chain of radiotherapeutics resulting in the treatment of hundreds of patients across diverse treatment settings including the largest comprehensive cancer centers in North America that we intend to leverage in our ongoing and future development efforts. The potential of our approach is demonstrated by our product pipeline strategy, as well as the operating model that we are building for our ARC candidates.

Current wording

Actinium’s strategy is to build an integrated, specialty radiotherapeutics company using the power of our platform technologies to deliver new treatment options for patient populations living with high unmet medical needs in hematology and oncology. We believe our focus on relapsed or refractory disease in cancer indications with high unmet medical need, with limited or no competition, and where the primary delivery of care occurs in large comprehensive cancer care centers, is the appropriate strategy for our company. Radiotherapeutics leverage the cell-killing power of linear energy transfer, which we believe is unmatched by other technologies and we also believe that relapsed or refractory disease is an area where radiotherapeutics can succeed over other approaches. Our proven experience conducting multiple, late-stage clinical trials provides an advantage operating a radiotherapy company where barriers related to their utilization and supply chain are higher than those for other types of medicines due to the personalized, just-in-time nature of radiotherapies. We have accumulated extensive experience coordinating the manufacturing and clinical supply chain of radiotherapeutics, resulting in the treatment of hundreds of patients across diverse treatment settings, including the largest comprehensive cancer centers in North America, that we intend to leverage in our ongoing and future development efforts. The potential of our approach is demonstrated by our product pipeline strategy, as well as the operating model that we are building for our ARC candidates.

Previous wording

We are developing our lead product candidates, Iomab-B and Actimab-A, to potentially improve outcomes for patients with relapsed or refractory acute myeloid leukemia (“r/r AML”) to address the significant unmet need for better outcomes from treatment with therapeutics or from undergoing a bone marrow transplant (“BMT”).

Current wording

We have developed our lead product candidates, Iomab-B and Actimab-A, to potentially improve outcomes for patients with relapsed or refractory acute myeloid leukemia (“r/r AML”) to address the significant unmet need for better outcomes from treatment with therapeutics or from undergoing a bone marrow transplant (“BMT”).

Previous wording

Iomab-B is being developed as a targeted radiotherapy induction (disease control) and conditioning agent, comprised of the anti-CD45 monoclonal antibody apamistamab and the Iodine-131 (“I-131”) radioisotope payload, intended to enable patient access to BMT, the only potentially curative treatment option for patients with r/r AML. Iomab-B has been studied in over 400 patients and is supported by data in six blood cancer indications, including a randomized Phase 3 trial in patients with r/r AML.

Current wording

Iomab-B is a targeted radiotherapy induction (disease control) and conditioning agent, comprised of the anti-CD45 monoclonal antibody apamistamab and the Iodine-131 (“I-131") radioisotope payload, intended to enable patient access to BMT, the only potentially curative treatment option for patients with r/r AML. Iomab-B has been studied in over 400 patients and is supported by data in six blood cancer indications, including a randomized Phase 3 trial in patients with r/r AML.

Previous wording

Actimab-A is being developed as a targeted radiotherapeutic directed against CD33, a target expressed ubiquitously in patients with AML that uses the Actinium-225 (“Ac-225”) isotope payload. We are attempting to leverage the mutation-agnostic ability of Ac-225 to establish Actimab-A as a backbone therapy in AML, an extremely heterogenous and radiosensitive disease, as a single agent or in combinations with chemotherapy, targeted agents, cellular therapy and immunotherapy. Actimab-A has been studied in over 150 patients and is being developed in collaboration with the National Cancer Institute (“NCI”) under a Cooperative Research and Development Agreement (“CRADA”).

Current wording

Actimab-A is being developed as a targeted radiotherapeutic that uses the Actinium-225 (“Ac-225") isotope payload directed against CD33, a target expressed ubiquitously in patients with AML and expressed in other myeloid malignancies. We are attempting to leverage the mutation-agnostic ability of Ac-225 to establish Actimab-A as a backbone therapy in AML, an extremely heterogenous and radiosensitive disease, as a single agent or in combinations with chemotherapy, targeted agents, cellular therapy and immunotherapy. Actimab-A has been studied in over 150 patients and is being developed in collaboration with the National Cancer Institute (“NCI”) under a Cooperative Research and Development Agreement (“CRADA”).

Previous wording

The Phase 3 SIERRA trial enrolled 153 patients with r/r AML and compared outcomes of patients receiving Iomab-B and a BMT for patients receiving physician’s choice of care with salvage chemotherapies and standard allogeneic BMT in the control arm. In February 2023, Actinium announced that the SIERRA trial met the primary endpoint with statistical significance, as 22% of patients (13/76) on the Iomab-B arm achieved dCR compared to 0% of patients (0/77) on the control arm resulting in a p-value of <0.0001. The SIERRA trial was conducted in accordance with guidance from the End of Phase 2 meeting with the FDA, which stated that positive results for dCR as the primary endpoint would be an acceptable endpoint to support an Iomab-B BLA filing. SIERRA did not meet the secondary endpoint of OS on an ITT basis. Over the last several years, a majority of therapies for patients with AML have been approved based on the overall survival endpoint.

Current wording

Iomab-B is a targeted radiotherapy intended to provide both induction and conditioning in one agent. Iomab-B was evaluated in the randomized Study of Iomab-B in Elderly Relapsed and Refractory AML (“SIERRA”) trial. The Phase 3 SIERRA trial enrolled 153 patients with r/r AML and compared outcomes of patients receiving Iomab-B and a BMT for patients receiving physician’s choice of care with salvage chemotherapies and standard allogeneic BMT in the control arm. The SIERRA trial was conducted in accordance with guidance from the End of Phase 2 meeting with the FDA, which stated that positive results for durable Complete Remission (“dCR”) as the primary endpoint would be an acceptable endpoint to support an Iomab-B Biologics License Application (“BLA”) filing. The Iomab-B dose in the SIERRA trial was also individualized for each patient, based on the dosimetric infusion findings, to deliver 24 Gy radiation to the dose-limiting organ (typically the liver), or 48 Gy to the bone marrow, whichever was predicted to receive the highest estimated dose of radiation.

Previous wording

Iomab-B Regulatory Update on Planned BLA Filing and Future Development

Current wording

Iomab-B Regulatory Status Update and Future Development

Previous wording

Actinium has now concluded both its clinical and Chemistry, Manufacturing and Controls (“CMC”) interactions with the FDA regarding the BLA pathway for Iomab-B based on the positive SIERRA trial results. As previously disclosed, we received positive feedback from the FDA regarding our CMC package for Iomab-B and were also assigned a BLA number. However, the FDA has now provided definitive feedback regarding the clinical portion that the SIERRA trial alone is not adequate to support a BLA filing for Iomab-B despite the SIERRA trial meeting the primary endpoint of durable Complete Remission (dCR) with statistical significance (p-value<0.0001) and other positive secondary endpoints including Event Free Survival (“EFS”) and safety. The FDA now requires that demonstrating an overall survival benefit in a randomized head-to-head trial is necessary and has advised us to conduct a study to evaluate allogeneic bone marrow transplant (“BMT”) using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation (“Flu/TBI”) versus allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI. This proposed additional study will differ from the SIERRA trial, which allowed physician’s choice of salvage chemotherapies and heterogenous conditioning regimens in the control arm. Additionally, the proposed new study will not allow patients to cross over from the control arm, which was allowed in the SIERRA trial and confounded the overall survival analysis in the intent to treat (“ITT”) patient population, as nearly 60% of patients crossed over from the control arm.

Current wording

On August 5, 2024, Actinium announced that it concluded both its clinical and Chemistry, Manufacturing and Controls (“CMC”) interactions with the FDA regarding the BLA pathway for Iomab-B based on the SIERRA trial results. As previously disclosed, we had received positive feedback from the FDA regarding our CMC package for Iomab-B and were also assigned a BLA number. However, in the third quarter of 2024, the FDA provided definitive feedback that the SIERRA trial alone is not adequate to support a BLA filing for Iomab-B, despite (a) the SIERRA trial meeting the primary endpoint of dCR with statistical significance (p-value<0.0001) and other positive secondary endpoints including Event Free Survival (“EFS”) and safety, and (b) our presentation of several additional analyses from the SIERRA study, including long-term follow-up demonstrating a trend towards improved overall survival and evidence of survival benefit in patients with high-risk TP53 mutations, to support Iomab-B’s impact on overall survival. The FDA indicated that demonstrating an overall survival benefit in a randomized head-to-head trial is necessary and has advised us to conduct a study to evaluate allogeneic BMT using Iomab-B plus a reduced intensity conditioning regimen of fludarabine and total body irradiation (“Flu/TBI”) versus allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI. This proposed additional study differs from the SIERRA trial, which allowed physician’s choice of salvage chemotherapies and heterogenous conditioning regimens in the control arm. Additionally, the proposed new study will not allow patients to cross over from the control arm, which was allowed in the SIERRA trial and confounded the overall survival analysis in the ITT patient population, as nearly 60% of patients crossed over from the control arm.

Previous wording

We have an industry-leading clinical development program investigating our alpha-particle therapy Actimab-A, a CD33 targeting ARC conjugated to the potent alpha radiation emitting isotope Ac-225. Actimab-A has been studied in approximately 150 patients over six clinical trials as both a single agent and in combination with other modalities such as chemotherapy and targeted therapy. The potent linear energy transfer emitted by Ac-225 has no known resistance mechanism and there is no known repair mechanism to the double strand DNA breaks it is capable of causing with a single alpha particle hit to a cell. Actimab-A is currently being developed in combination with other regimens, including chemotherapies such as CLAG-M and targeted agents such as venetoclax utilizing its potential mechanistic synergies. We are attempting to leverage the mutation-agnostic ability of Ac-225 to establish Actimab-A as a backbone therapy in AML, an extremely heterogenous and radiosensitive disease.

Current wording

We have an industry-leading clinical development program investigating our alpha-particle therapy Actimab-A, a CD33 targeting ARC conjugated to the potent alpha radiation emitting isotope Ac-225. Actimab-A has been studied in over 150 patients across six clinical trials as both a single agent and in combination with other modalities such as chemotherapy and targeted therapy. The potent linear energy transfer emitted by Ac-225 has no known resistance mechanism and there is no known repair mechanism to the double strand DNA breaks it is capable of causing with a single alpha particle hit to a cell. Actimab-A is currently being developed in combination with other regimens, including chemotherapies such as CLAG-M and targeted agents such as venetoclax utilizing its potential mechanistic synergies. We are attempting to leverage the mutation-agnostic ability of Ac-225 to establish Actimab-A as a backbone therapy in AML, an extremely heterogenous and radiosensitive disease.

Previous wording

In 2023, we announced the NCI Cooperative Research and Development Agreement (“CRADA”) to develop Actimab-A for the treatment of patients with AML and other hematologic malignancies. The NCI will serve as the regulatory sponsor for any clinical trials mutually approved by both parties to study Actimab-A, and the CRADA will provide extensive support for and accelerate the development of Actimab-A alone or in combination with chemotherapy, immunotherapy, targeted agents and other novel combinations. The CRADA studies will be overseen by the NCI in collaboration with Actinium’s clinical development team, where we have the right to review and approve all protocols and has full rights to all data. The NCI CRADA provides for us to supply Actimab-A and for NCI to cover all clinical trial execution and development expenses. The NCI CRADA is anticipated to have a balance sheet sparing impact over the next several years. We expect the NCI to initiate further development of Actimab-A in combination with CLAG-M and other targeted agents to broaden the scope of its development in r/r AML.

Current wording

In 2023, we entered into a CRADA with NCI to develop Actimab-A for the treatment of patients with AML and other hematologic malignancies. The NCI will serve as the regulatory sponsor for any clinical trials mutually approved by both parties to study Actimab-A, and the CRADA will provide extensive support for and accelerate the development of Actimab-A alone or in combination with chemotherapy, immunotherapy, targeted agents and other novel combinations. The CRADA studies will be overseen by the NCI in collaboration with Actinium’s clinical development team, where we have the right to review and approve all protocols and have full rights to all data. The NCI CRADA provides for us to supply Actimab-A and for NCI to cover all clinical trial execution and development expenses. The NCI CRADA is anticipated to have a balance sheet sparing impact over the next several years. The NCI Cancer Therapy Evaluation Program (“CTEP”), which sponsors approximately two thirds of all combination cancer studies, will accept Letters of Intent (“LOIs”) or concepts for Phase 1, 2 or 3 studies of Actimab-A in AML and other hematological malignancies. To date, multiple Actimab-A study proposals have been submitted to the NCI, which are being mutually reviewed and considered. We expect the NCI to initiate further development of Actimab-A in combination with CLAG-M and other targeted agents to broaden the scope of its development in AML and other myeloid malignancies.

Previous wording

In June 2024, we presented the first-ever preclinical data demonstrating the combination of Actimab-A with leading menin inhibitors resulted in anti-tumor control and potent leukemia cell killing in AML models at the 2024 EHA Congress. We studied Actimab-A in combination with the leading menin inhibitors, revumenib (Syndax Pharmaceuticals, Inc.) and ziftomenib (Kura Oncology, Inc.), which are being developed for patients with KMT2A rearrangements and NMP1 mutations, which are present in approximately 10% and 30% of AML patients, respectively. Actimab-A as a single agent showed potent in vitro AML cell killing activity in both MV-4-11 and MOLM-13 KMT2A mutant cell lines, compared to the non-radio conjugated CD33 antibody lintuzumab (p<0.0001) and the combination of Actimab-A with leading menin inhibitors triggered an acute increase in AML necrosis and cell death in vivo relative to single agent therapy within 72 hours of dosing. Actimab-A enhanced AML cell death when combined with both revumenib and ziftomenib at all dose levels in difficult to treat KMT2A mutant AML. Anti-tumor effect was significantly potentiated and prolonged when combining Actimab-A with a leading menin inhibitor compared to monotherapies in xenograft leukemia models in vivo (p<0.0024 Actimab-A + menin). We have also evaluated Actimab-A in combination with FLT3 (Fms-like tyrosine kinase 3) inhibitors such as gilteritinib (Astellas Pharma, Inc.) and midostaurin (Novartis Pharmaceuticals, Inc.). FLT3 is one of the most commonly mutated genes in AML and is associated with aggressive disease with poor outcomes. Actimab-A was shown to have single-agent activity against FLT3 mutant AML cell lines, supporting its mutation-agnostic mechanism, and enhanced the anti-leukemic activity of the FLT3 inhibition in vitro.

Current wording

We continue to advance our preclinical R&D efforts to further support the mutation agnostic profile of Actimab-A in AML and other CD33 expressing hematologic malignancies as well as provide support for novel combinations to support its backbone therapy profile. In June 2024, we presented the first-ever preclinical data demonstrating the combination of Actimab-A with leading menin inhibitors resulted in anti-tumor control and potent leukemia cell killing in AML models at the 2024 European Hematology Association (“EHA”) Congress. We studied Actimab-A in combination with the leading menin inhibitors, revumenib (Syndax Pharmaceuticals, Inc.) and ziftomenib (Kura Oncology, Inc.), which are being developed for patients with KMT2A rearrangements and NMP1 mutations, which are present in approximately 10% and 30% of AML patients, respectively. Actimab-A as a single agent showed potent in vitro AML cell killing activity in both MV-4-11 and MOLM-13 KMT2A mutant cell lines, compared to the non-radio conjugated CD33 antibody lintuzumab (p<0.0001) and the combination of Actimab-A with leading menin inhibitors triggered an acute increase in AML necrosis and cell death in vivo relative to single agent therapy within 72 hours of dosing. Actimab-A enhanced AML cell death when combined with both revumenib and ziftomenib at all dose levels in difficult to treat KMT2A mutant AML. Anti-tumor effect was significantly potentiated and prolonged when combining Actimab-A with a leading menin inhibitor compared to monotherapies in xenograft leukemia models in vivo (p<0.0024 Actimab-A + menin). We have also evaluated Actimab-A in combination with FLT3 (Fms-like tyrosine kinase 3) inhibitors such as gilteritinib (Astellas Pharma, Inc.) and midostaurin (Novartis Pharmaceuticals, Inc.). FLT3 is one of the most commonly mutated genes in AML and is associated with aggressive disease with poor outcomes. Actimab-A was shown to have single-agent activity against FLT3 mutant AML cell lines, supporting its mutation-agnostic mechanism, and enhanced the anti-leukemic activity of the FLT3 inhibition in vitro.

Previous wording

We have generated preclinical data that depicts Actimab-A’s role in the tumor microenvironment to overcome immunosuppression driven by myeloid-derived suppressor cells (“MDSCs”). We believe that our findings show that Actimab-A has the potential to selectively deplete MDSCs in lung, colorectal and other cancers. Actimab-A also demonstrated statistically significant depletion of human MDSCs compared to Mylotarg®, a CD33-targeted antibody-drug conjugate (“ADC”) in colorectal cancer (p<0.01), highlighting the potent cytotoxicity and potential therapeutic benefit of radiotherapy compared to naked antibodies or ADCs.

Current wording

We have also generated preclinical data that depicts Actimab-A’s role in the tumor microenvironment to overcome immunosuppression driven by myeloid-derived suppressor cells (“MDSCs”). We believe that our findings show that Actimab-A has the potential to selectively deplete MDSCs in lung, colorectal and other cancers. Actimab-A also demonstrated statistically significant depletion of human MDSCs compared to Mylotarg®, a CD33-targeted antibody-drug conjugate (“ADC”) in colorectal cancer (p<0.01), highlighting the potent cytotoxicity and potential therapeutic benefit of radiotherapy compared to naked antibodies or ADCs.

Previous wording

The opportunity exists for better conditioning in other areas of cellular therapy, and we are working on a next generation conditioning program, Iomab-ACT, for the rapidly growing cell and gene therapy market, as well as BMT conditioning for non-malignant hematologic indications such as sickle cell disease. We are studying Iomab-ACT in collaboration with Memorial Sloan Kettering Cancer Center (“MSKCC”), for conditioning prior to CAR-T therapy for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (“B-ALL”) or DLBCL. This study funded by a NIH grant is the first study of its kind to use an ARC, with CAR-T therapy. In October 2023, we announced the extension of a NIH Small Business Technology Transfer grant to support the clinical collaboration with MSKCC. Most recently, at the 2024 Tandem Meetings, we presented results from the ongoing Phase 1 trial. No patients (0/4) developed ICANS of any grade, a major safety measure of the study, as ICANS is observed in 25% or more of patients with r/r B-ALL and DLBCL treated with various CAR T-cell products and negligible incidence of CRS. Iomab-ACT demonstrated transient depletion of peripheral blood lymphocytes and monocytes. Persistence of CAR T-cells up to 8 weeks and minimal non-hematologic toxicities have been observed to date.

Current wording

The opportunity exists for better conditioning in other areas of cellular therapy, and we are working on a next generation conditioning program, Iomab-ACT, for the rapidly growing cell and gene therapy market, as well as BMT conditioning for non-malignant hematologic indications such as sickle cell disease. We are studying Iomab-ACT in collaboration with Memorial Sloan Kettering Cancer Center (“MSKCC”), for conditioning prior to CAR-T therapy for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (“B-ALL”) or diffuse large B-cell lymphoma (“DLBCL”). This study funded by a NIH grant is the first study of its kind to use an ARC, with CAR-T therapy. In October 2023, we announced the extension of a NIH Small Business Technology Transfer grant to support the clinical collaboration with MSKCC. Most recently, at the 2024 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, we presented results from the ongoing Phase 1 trial. No patients (0/4) developed Immune Effector Cell-Associated Neurotoxicity Syndrome (“ICANS”) of any grade, a major safety measure of the study, as ICANS is observed in 25% or more of patients with r/r B-ALL and DLBCL treated with various CAR T-cell products and negligible incidence of cytokine release syndrome (“CRS”). Iomab-ACT demonstrated transient depletion of peripheral blood lymphocytes and monocytes. Persistence of CAR T-cells up to 8 weeks and minimal non-hematologic toxicities have been observed to date.

Previous wording

In May 2024, we announced FDA clearance of an IND for a new clinical trial that will study Iomab-ACT as targeted conditioning prior to patients receiving an FDA approved commercial CAR-T therapy. To our knowledge, this will be the first trial to study a targeted radiotherapy conditioning agent with a commercial CAR-T therapy. Given the robust clinical data that exists with commercial CAR-T therapies, we believe this trial may demonstrate the potential for Iomab-ACT to improve outcomes over current chemotherapy conditioning regimens, which we are seeking to replace and provide patients better access to CAR-T.

Current wording

In May 2024, we announced FDA clearance of an IND for a new clinical trial that will study Iomab-ACT as targeted conditioning prior to patients receiving an FDA approved commercial CAR-T therapy. To our knowledge, this will be the first trial to study a targeted radiotherapy conditioning agent with a commercial CAR-T therapy. Given the robust clinical data that exists with commercial CAR-T therapies, we believe this trial may demonstrate the potential for Iomab-ACT to improve outcomes over current chemotherapy conditioning regimens, which we are seeking to replace and provide patients better access to CAR-T. We expect to commence patient enrollment of this study in the first quarter of 2025 and generate proof of concept clinical data by year end 2025.

Previous wording

In July 2024, we announced a program for Iomab-ACT focused on providing patients with sickle cell disease broader access to cellular therapies including bone marrow transplant and gene therapies. We also announced in July 2024 the FDA clearance of an IND for an investigator led clinical trial to study Iomab-ACT as targeted conditioning prior to a BMT for patients with sickle cell disease in collaboration with Columbia University. Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need that affects approximately 100,000 people in the U.S. Patients with sickle cell disease have a mutation that causes red blood cells to develop a crescent or “sickle” shape, which restrict the flow in blood vessels and limit oxygen delivery to the body’s tissues, leading to severe pain and organ damage called vaso-occlusive events (VOEs) or vaso-occlusive crises (VOCs). The recurrence of these events or crises can lead to life-threatening disabilities and/or early death. A BMT is a potentially curative treatment option for patients with sickle cell disease, particularly in pediatric patients who have had complications such as strokes, acute chest crises or recurring pain crises due to their disease. If successful, the trial is expected to inform a clinical trial to evaluate Iomab-ACT as a targeted conditioning agent prior to gene therapy for which there are two approved agents for patients with sickle cell disease, Casgevy (Vertex Pharmaceuticals, Inc.) and Lyfgenia (Bluebird Bio, Inc.).

Current wording

In July 2024, we announced a program for Iomab-ACT focused on providing patients with sickle cell disease broader access to cellular therapies including bone marrow transplant and gene therapies. We also announced in July 2024 the FDA clearance of an IND for an investigator led clinical trial to study Iomab-ACT as targeted conditioning prior to a BMT for patients with sickle cell disease in collaboration with Columbia University. Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need that affects approximately 100,000 people in the U.S. Patients with sickle cell disease have a mutation that causes red blood cells to develop a crescent or “sickle” shape, which restrict the flow in blood vessels and limit oxygen delivery to the body’s tissues, leading to severe pain and organ damage called vaso-occlusive events (“VOEs”) or vaso-occlusive crises (“VOCs”). The recurrence of these events or crises can lead to life-threatening disabilities and/or early death. A BMT is a potentially curative treatment option for patients with sickle cell disease, particularly in pediatric patients who have had complications such as strokes, acute chest crises or recurring pain crises due to their disease. We expect patient enrollment for the Phase 1 trial to commence in the first half of 2025 with initial safety and efficacy results from the initial cohort of patients receiving Iomab-ACT prior to a BMT for their sickle cell disease beginning in 2025. If successful, the trial is expected to inform a clinical trial to evaluate Iomab-ACT as a targeted conditioning agent prior to gene therapy for which there are two approved agents for patients with sickle cell disease, Casgevy (Vertex Pharmaceuticals, Inc.) and Lyfgenia (Bluebird Bio, Inc.).

Previous wording

We currently believe that our ARCs are less likely than small molecules to face pricing pressure and negotiation from the Inflation Reduction Act of 2022 (“IRA”), given that small molecules are at risk for pricing negotiations seven years after approval compared to eleven years for biologics with negotiated prices taking effect two years after selection. Further, a drug or biological product that has an orphan drug designation, which Iomab-B and Actimab-A both have, for only one rare disease or condition will be excluded from the IRA’s price negotiations requirements until such time the biological products has designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation. In addition, regulatory barriers for a generic ARC are much higher than for small molecule radioligands such as those under development or approved, namely, Pluvicto®, Lutathera®, and Xofigo®. While generic versions of certain radiopharmaceuticals utilizing peptides, which are considered small molecules, have been submitted to the FDA via the ANDA pathway, ARCs fall under biologics. For this reason, only the biosimilar approach pertains to ARCs filed under 351(k) BLA pathway. The regulatory pathway for biosimilar is much more comprehensive than the pathway for generics, and it has not been proven that biosimilars are interchangeable with the innovator’s ARCs. In addition, we are not aware of any regulations that would require us to provide Iomab-B or Actimab-A, including their respective mAbs, apamistamab and lintuzumab, to any third party or potential competitor.

Current wording

We currently believe that our ARCs are less likely than small molecules to face pricing pressure and negotiation from the Inflation Reduction Act of 2022 (“IRA”), given that small molecules are at risk for pricing negotiations seven years after approval compared to eleven years for biologics with negotiated prices taking effect two years after selection. Further, a drug or biological product that has an orphan drug designation, which Iomab-B and Actimab-A both have, for only one rare disease or condition will be excluded from the IRA’s price negotiations requirements until such time the biological products has designations for more than one rare disease or condition, or if is approved for an indication that is not within that single designated rare disease or condition, unless such additional designation or such disqualifying approvals are withdrawn by the time CMS evaluates the drug for selection for negotiation. In addition, regulatory barriers for a generic ARC are much higher than for small molecule radioligands such as those under development or approved, namely, Pluvicto®, Lutathera®, and Xofigo®. While generic versions of certain radiopharmaceuticals utilizing peptides, which are considered small molecules, have been submitted to the FDA via the ANDA pathway, ARCs fall under biologics. For this reason, only the biosimilar approach pertains to ARCs filed under 351(k) BLA pathway. The regulatory pathway for biosimilar is much more comprehensive than the pathway for generics, and it has not been proven that biosimilars are interchangeable with the innovator’s ARCs. In addition, we are not aware of any regulations that would require us to provide Iomab-B or Actimab-A, including their respective monoclonal antibodies (“mAbs”), apamistamab and lintuzumab, to any third party or potential competitor.

Previous wording

We seek to expand our capabilities and technologies across therapeutic modalities, linker technologies and in vivo cancer models, and build visibility through presentations at key conferences and publications in journals of high impact. Our R&D efforts are centered on the advancement of our key ARC programs with a robust “fast-to-clinic” approach. Underpinning our development programs is our expanded patent portfolio of over 235 issued patents and pending patent applications worldwide.

Current wording

We seek to expand our capabilities and technologies across therapeutic modalities, linker technologies and in vivo cancer models, and build visibility through presentations at key conferences and publications in journals of high impact. Our R&D efforts are centered on the advancement of our key ARC programs with a robust “fast-to-clinic” approach.

Previous wording

Our proprietary technology platform is built on the core competency to produce targeted radiotherapeutics, and coupled with our know-how and IP, establishes our company in the development of isotope-agnostic, multi-targeted product candidates that have the potential to address the treatment of hard-to-treat diseases. In our clinical and preclinical programs, we have utilized multiple isotopes including Ac-225, I-131 and Lu-177 directed at multiple targets in oncology and hematology such as CD45, CD33, CD38, HER2, among others. Our targeted radiotherapies combine the cell-killing ability of radiation via a radioisotope payload with a targeting agent, such as a monoclonal antibody.

Current wording

Our proprietary technology platform is built on the core competency to produce targeted radiotherapeutics, and coupled with our know-how and intellectual property, establishes our company in the development of isotope-agnostic, multi-targeted product candidates that have the potential to address the treatment of hard-to-treat diseases. In our clinical and preclinical programs, we have utilized multiple isotopes including Ac-225, I-131 and Lu-177 directed at multiple targets in oncology and hematology such as CD45, CD33, CD38, HER2, among others. Our targeted radiotherapies combine the cell-killing ability of radiation via a radioisotope payload with a targeting agent, such as a monoclonal antibody.

Previous wording

Our extensive know-how related to this production technology is supported by five issued patents in the U.S. and 49 patents internationally and covers:

Current wording

Our extensive know-how related to this production technology is supported by five issued patents in the U.S. and 41 patents internationally and covers:

Previous wording

We have established an actively managed end-to-end supply chain that encompasses isotope sourcing through drug administration at the point of care and as a result of our approach we have reliably supplied drug to all patients enrolled in our clinical trials in the clinical trials we have conducted. We believe we have a thorough understanding and working knowledge of the intricacies required to manufacture and distribute radiotherapies. Through our clinical experience with, we have developed a wealth of proprietary knowledge to enable coordination between us and all key stakeholders including, but not limited to hematologists/oncologists, infusion center and in patient rooms, nuclear medicine and radiology, hot labs and radio-pharmacies, and radiation safety committees, among others. We have scaled up and have commercially viable manufacturing operations in place to support U.S. and international commercial sales.

Current wording

We have established an actively managed end-to-end supply chain that encompasses isotope sourcing through drug administration at the point of care and as a result of our approach, we have reliably supplied drug to all patients enrolled in our clinical trials. We believe we have a thorough understanding and working knowledge of the intricacies required to manufacture and distribute radiotherapies. Through our clinical experience with, we have developed a wealth of proprietary knowledge to enable coordination between us and all key stakeholders including, but not limited to hematologists/oncologists, infusion center and in patient rooms, nuclear medicine and radiology, hot labs and radio-pharmacies, and radiation safety committees, among others. We utilize contract development and manufacturing organizations (“CDMOs”) to manufacture our finished drug products and have selected CDMOs based on their clinical and commercial supply capabilities including significant experience in the international supply of radiotherapies. We have scaled deliberately for manufacturing flexibility and will continue to evaluate additional CDMOs.

Previous wording

As of August 2024, our patent portfolio is comprised of over 235 issued patents and pending patent applications worldwide, which we believe constitutes a valuable business asset. Our IP includes 47 patent families, including key patents that relate primarily to our radiotherapeutic candidates. Our patent portfolio includes 18 issued patents and 47 pending patent applications in the U.S., and over 170 that are issued or pending internationally. The effective lives of the issued patents in our portfolio, or patents that may issue from the pending applications in our portfolio, ranges from expirations between 2024 and 2044.

Current wording

As of November 14, 2024, our patent portfolio is comprised of over 230 issued patents and pending patent applications worldwide, which we believe constitutes a valuable business asset. Our IP includes 47 patent families, including key patents that relate primarily to our radiotherapeutic candidates. Our patent portfolio includes 20 issued patents and 48 pending patent applications in the U.S., and over 165 that are issued or pending internationally. The effective lives of the issued patents in our portfolio, or patents that may issue from the pending applications in our portfolio, ranges from expirations between 2025 and 2045.

Previous wording

For our Iomab-B product candidate, we have four issued patents in the U.S. and issued patents in Canada, Europe and Japan that relate to the composition. The basic patent terms of these patents expire in 2036 and 2037. Related patent applications are also currently pending in the U.S. and internationally. In addition, we own both U.S. and international pending patent applications that relate to the use of Iomab-B or Iomab-ACT with patent protection over Iomab-ACT aspects until 2040 for the treatment of cancers and non-malignant conditions.

Current wording

For our Iomab-B product candidate, we have four issued patents in the U.S. and issued patents in Canada, Europe and Japan that relate to its composition. The basic patent terms of these patents expire in 2036 and 2037. Related patent applications are also currently pending in the U.S. and internationally. In addition, we own both U.S. and international pending patent applications that relate to the use of Iomab-B or Iomab-ACT with currently issued U.S. patent protection into 2040 for the use of Iomab-ACT in connection with genetically modified hematopoietic stem cell therapy for the treatment of non-malignant conditions.

Previous wording

Our patents also cover key areas of our business such as manufacturing key components of our product candidate, Actimab-A, including producing Ac-225 in a cyclotron. We have expertise in utilizing the alpha emitting isotope Ac-225 including clinical experience in treating approximately 150 patients with our alpha-emitter-based therapies, “gold standard” linker technology and five issued patents in the U.S. and 49 patents internationally related to the manufacturing of Ac-225 in a cyclotron, which we believe has the potential to produce higher quantities of Ac-225 than currently utilized methods. In addition, we also own U.S. and international patents and pending patent applications that relate to the manufacturing of Actimab-A and its use in the treatment of cancers.

Current wording

Our patents also cover key areas of our business such as manufacturing key components of our product candidate, Actimab-A, including producing Ac-225 in a cyclotron. We have expertise in utilizing the alpha emitting isotope Ac-225 including clinical experience in treating approximately 150 patients with our alpha-emitter-based therapies, “gold standard” linker technology and five issued patents in the U.S. and 41 patents internationally related to the manufacturing of Ac-225 in a cyclotron, which we believe has the potential to produce higher quantities of Ac-225 than currently utilized methods. In addition, we also own U.S. and international patents and pending patent applications that relate to the manufacturing of Actimab-A and its use in the treatment of cancers.

Previous wording

On April 7, 2022, we entered into a license and supply agreement with Immedica Pharma AB, or Immedica, pursuant to which Immedica licensed the exclusive product rights for commercialization of Iomab-B in the European Economic Area, Middle East and North Africa (EUMENA) including Algeria, Andorra, Bahrain, Cyprus, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Monaco, Morocco, Oman, Palestine, Qatar, San Marino, Saudi Arabia, Switzerland, Syria, Tunisia, Turkey, the United Arab Emirates, the United Kingdom, the Vatican City and Yemen. Upon signing, we were entitled to an upfront payment of $35 million from Immedica, which was received in May 2022. Under the terms of the License Agreement, we are eligible to receive regulatory and commercial milestone payments and are entitled to receive royalties in the mid-20 percent range on net sales of the product in certain countries that may result from the License Agreement. We will continue to be responsible for certain clinical development activities and the manufacturing of Iomab-B and will retain commercialization rights in the U.S. and rest of the world.

Current wording

As noted above, on April 7, 2022, we entered into a License Agreement with Immedica, pursuant to which Immedica licensed the exclusive product rights for commercialization of Iomab-B in certain countries in the EUMENA region. Upon signing, we were entitled to an upfront, non-refundable payment of $35 million from Immedica, which was received in May 2022. Under the terms of the License Agreement, we are eligible to receive certain regulatory and commercial milestone payments and royalties on net sales of the product in certain countries that may result from the License Agreement. We continue to retain commercialization rights in the U.S. and rest of the world.

Previous wording

Our contract liabilities are recorded within Other revenue deferred – current liability or Long-term license revenue deferred in our condensed consolidated balance sheets depending on the short-term or long-term nature of the payments to be recognized. Our contract liabilities primarily consist of advanced payments from licensees. There was no Other revenue deferred-current liability at June 30, 2024 and December 31, 2023. Long-term license revenue deferred was $35.0 million at June 30, 2024 and December 31, 2023, resulting from the receipt from Immedica; this deferred revenue will be recognized upon European Union regulatory approval of Iomab-B.

Current wording

Our contract liabilities are recorded within Other revenue deferred – current liability or Long-term license revenue deferred in our condensed consolidated balance sheets depending on the short-term or long-term nature of the payments to be recognized. Our contract liabilities primarily consist of advanced payments from licensees. There was no Other revenue deferred-current liability at September 30, 2024 and December 31, 2023. Long-term license revenue deferred was $35 million at September 30, 2024 and December 31, 2023, resulting from the receipt from Immedica; this deferred revenue will be recognized upon the European Union’s regulatory approval of Iomab-B or provision of definitive feedback that Iomab-B will not receive approval in the European Union.

Previous wording

Research and development expenses of $8.8 million for the three months ended June 30, 2024 decreased $2.3 million from $11.1 million for the three months ended June 30, 2023. The decrease is a result of a decline in Chemistry, manufacturing and controls, or CMC, expenses of $3.5 million due to lower activity in 2024 related to Iomab-B. This decline was partially offset by increased preclinical expenses of $0.6 million, and as a result of higher headcount, increased compensation expense of $0.4 million and non-cash stock compensation expense of $0.1 million.

Current wording

Research and development expenses of $9.8 million for the three months ended September 30, 2024 decreased $1.8 million from $11.6 million for the three months ended September 30, 2023. The decrease is primarily a result of a decline in Chemistry, manufacturing and controls, or CMC, expenses of $5.5 million and lower consulting expenses of $0.5 million, both due to lower activity in 2024 related to Iomab-B. These declines were partially offset by increased preclinical expenses of $3.9 million.

Previous wording

Other income is comprised of net interest income in both reporting periods. The amount for the three months ended June 30, 2024 of $1.1 million increased from $0.5 million for the three months ended June 30, 2023 primarily due to higher average interest rates.

Current wording

Other income is comprised of net interest income in both reporting periods. The amount for the three months ended September 30, 2024 and 2023 of $1.0 million in each reporting period was virtually unchanged from the same time period in the prior year.

Previous wording

Results of Operations – Six Months Ended June 30, 2024 Compared to Six Months Ended June 30, 2023

Current wording

Results of Operations –Nine Months Ended September 30, 2024 Compared to Nine Months Ended September 30, 2023

Previous wording

We recorded no commercial revenue for the six months ended June 30, 2024 and June 30, 2023.

Current wording

We recorded no commercial revenue for the nine months ended September 30, 2024 and 2023, respectively.

Previous wording

There was no other revenue recognized for the six months ended June 30, 2024 and 2023, respectively.

Current wording

There was no other revenue recognized for the nine months ended September 30, 2024 and 2023, respectively.

Previous wording

Research and development expenses of $15.5 million for the six months ended June 30, 2024 decreased $3.4 million from $18.9 million for the six months ended June 30, 2023. CMC expenses declined $4.2 million and consulting expenses declined $1.2 million due to lower CMC activity related to Iomab-B. These declines were partially offset by increased preclinical expenses of $1.0 million, and as a result of higher headcount, increased compensation expense of $0.6 million and non-cash stock compensation expense of $0.2 million.

Current wording

Research and development expenses of $25.2 million for the nine months ended September 30, 2024 decreased $5.4 million from $30.6 million for the nine months ended September 30, 2023. CMC expenses declined $9.7 million and consulting expenses declined $1.7 million due to lower CMC activity related to Iomab-B. These declines were partially offset by increased preclinical expenses of $4.9 million, and as a result of higher headcount, increased compensation expense of $0.8 million and non-cash stock compensation expense of $0.2 million.

Previous wording

General and administrative expenses of $6.6 million for the six months ended June 30, 2024 decreased by $1.7 million from $8.3 million for the six months ended June 30, 2023. Lower expenses were primarily the result of lower consulting fees and legal fees of $1.7 million, and lower compensation expense of $0.2 million due to lower headcount, partially offset by higher non-cash stock compensation expense of $0.5 million.

Current wording

General and administrative expenses of $9.4 million for the nine months ended September 30, 2024 decreased by $1.6 million from $11.0 million for the nine months ended September 30, 2023. Lower expenses were primarily the result of lower consulting fees and legal fees of $1.7 million, lower compensation expense of $0.5 million due to lower headcount, and lower office expenses of $0.5 million, partially offset by higher non-cash stock compensation expense of $1.0 million.

Previous wording

Other income is comprised of net interest income in both reporting periods. The amount for the six months ended June 30, 2024 of $2.0 million increased from $1.0 million for the six months ended June 30, 2023 due to higher average interest rates.

Current wording

Other income is comprised of net interest income in both reporting periods. The amount for the nine months ended September 30, 2024 of $3.0 million increased $0.9 million from $2.1 million for the nine months ended September 30, 2023 due to higher average interest rates.

Previous wording

Net loss of $11.4 million for the three months ended June 30, 2024 decreased by $3.8 million from $15.2 million for the three months ended June 30, 2023 due to lower research and development expenses, lower general and administrative expenses and a higher level of other income.

Current wording

Net loss of $31.6 million for the nine months ended September 30, 2024 decreased by $7.9 million from $39.5 million for the nine months ended September 30, 2023 due to lower research and development expenses, lower general and administrative expenses and a higher level of other income.

Previous wording

Net cash used in operating activities for the six months ended June 30, 2024 of $15.3 million decreased by $13.4 million from $28.7 million in the prior-year period, primarily as a result of a lower net loss of $6.2 million, and compared to the prior-year period, a reduction in prepaid expenses of $3.2 million and an increase in accounts payable and accrued expenses of $2.7 million.

Current wording

Net cash used in operating activities for the nine months ended September 30, 2024 of $27.3 million decreased by $13.5 million from $39.8 million in the prior-year period, primarily as a result of a lower net loss of $7.9 million, and compared to the prior-year period, a reduction in prepaid expenses of $1.7 million and an increase in accounts payable and accrued expenses of $1.2 million.

Previous wording

Net cash used in investing activities was $11 thousand and $0.1 million for the six months ended June 30, 2024 and 2023, respectively, due to the purchase of equipment.

Current wording

Net cash used in investing activities was $11 thousand and $153 thousand for the nine months ended September 30, 2024 and 2023, respectively, due to the purchase of equipment.

Previous wording

Net cash provided by financing activities was $24.7 million and $10.8 million for the six months ended June 30, 2024 and 2023, respectively, primarily from the sale of common stock.

Current wording

Net cash provided by financing activities was $29.3 million and $13.7 million for the nine months ended September 30, 2024 and 2023, respectively, primarily from the sale of common stock.

Previous wording

In August 2020, we entered into the Capital on Demand™ Sales Agreement with JonesTrading Institutional Services LLC, or JonesTrading, pursuant to which we are able to sell, from time to time, through or to JonesTrading, up to an aggregate of $200 million of our common stock. On June 28, 2022, we entered into an Amendment and Restated Capital on Demand™ Sales Agreement, or the Amended Sales Agreement, with JonesTrading and B. Riley Securities, Inc. The Amended Sales Agreement modifies the original Capital on Demand™ Sales Agreement to include B. Riley as an additional sales agent thereunder. Shares of common stock are offered pursuant to a shelf registration statement on Form S-3 (File No. 333-273911), which was declared effective February 5, 2024, including a base prospectus covering the offering, issuance and sale of up to $500 million of common stock, preferred stock, warrants, units and/or subscription rights; and a sales agreement prospectus covering the offering, issuance and sale of up to a maximum aggregate offering price of $200 million of common stock that may be issued and sold under the Amended Sales Agreement. For the six months ended June 30, 2024, we sold 2.9 million shares of common stock, resulting in gross proceeds of $25.2 million and net proceeds of $24.7 million. For the six months ended June 30, 2023, we sold 1.3 million shares of common stock, resulting in gross proceeds of $10.9 million and net proceeds of $10.6 million.

Current wording

In August 2020, we entered into the Capital on Demand™ Sales Agreement with JonesTrading Institutional Services LLC, or JonesTrading, pursuant to which we are able to sell, from time to time, through or to JonesTrading, up to an aggregate of $200 million of our common stock. On June 28, 2022, we entered into an Amendment and Restated Capital on Demand™ Sales Agreement, or the Amended Sales Agreement, with JonesTrading and B. Riley Securities, Inc. The Amended Sales Agreement modifies the original Capital on Demand™ Sales Agreement to include B. Riley as an additional sales agent thereunder. Shares of common stock are offered pursuant to a shelf registration statement on Form S-3 (File No. 333-273911), which was declared effective February 5, 2024, including a base prospectus covering the offering, issuance and sale of up to $500 million of common stock, preferred stock, warrants, units and/or subscription rights; and a sales agreement prospectus covering the offering, issuance and sale of up to a maximum aggregate offering price of $200 million of common stock that may be issued and sold under the Amended Sales Agreement. For the nine months ended September 30, 2024, we sold 3.5 million shares of common stock, resulting in gross proceeds of $29.9 million and net proceeds of $29.3 million. For the nine months ended September 30, 2023, we sold 3.0 million shares of common stock, resulting in gross proceeds of $18.9 million and net proceeds of $18.3 million.

Previous wording

In October 2021, FASB issued ASU 2021-08,Business Combinations (Topic 805),*Account for Contract Assets and Contract Liabilities from Contracts with Customers,*which provides guidance on accounting for contract assets and contract liabilities acquired in a business combination in accordance with ASC 606. To achieve this, an acquirer may assess how the acquiree applied ASC 606 to determine what to record for the acquired revenue contracts. Generally, this should result in an acquirer recognizing and measuring the acquired contract assets and contract liabilities consistent with how they were recognized and measured in the acquiree’s financial statements. The amendments of ASU 2021-08 are effective January 1, 2023, including interim periods. We will evaluate the impact of ASU 2021-08 on any future business combinations we may enter in the future.

Current wording

In October 2021, FASB issued ASU 2021-08,Business Combinations (Topic 805),*Account for Contract Assets and Contract Liabilities from Contracts with Customers,*which provides guidance on accounting for contract assets and contract liabilities acquired in a business combination in accordance with ASC 606. To achieve this, an acquirer may assess how the acquiree applied ASC 606 to determine what to record for the acquired revenue contracts. Generally, this should result in an acquirer recognizing and measuring the acquired contract assets and contract liabilities consistent with how they were recognized and measured in the acquiree’s financial statements. The amendments of ASU 2021-08 were effective January 1, 2023, including interim periods. We will evaluate the impact of ASU 2021-08 on any future business combinations we may enter in the future.