Actinium Pharmaceuticals, Inc.

Description of Our Business

Actinium Pharmaceuticals, Inc. (“Actinium”, the “Company”, or “we”) is a pioneer in the development of targeted radiotherapies intended to meaningfully improve outcomes for patients with advanced cancers including relapsed or refractory (“r/r”) disease who have failed existing therapies. We are advancing a pipeline of differentiated clinical stage product candidates focused on validated cancer targets. Our current pipeline is focused on indications in myeloid malignancies, solid tumors and conditioning for cell and gene therapies that we believe have high unmet needs that are not addressed by currently available treatment options. Our goal is to create a specialty radiopharmaceutical company with capabilities across radioisotope production, final drug product manufacturing, preclinical research and development (“R&D”) and clinical development. We are deploying our technologies and capabilities, which we believe to be industry-leading, and intellectual property with approximately 230 issued and pending patents worldwide, to develop targeted and next-generation radiotherapies.

Our Product Candidate Pipeline

We are advancing two clinical stage product candidates that are directed against validated cancer targets. Actimab-A is our lead product candidate in development and is intended to address the significant unmet medical needs of patients with myeloid malignancies including acute myeloid leukemia (“AML”) and myelodysplastic syndromes (“MDS”). We are also evaluating Actimab-A’s potential to synergize with PD-1 immune checkpoint inhibitors (“ICIs”) in solid tumor indications through the depletion of immune cells known as myeloid derived suppressor cells (“MDSCs”). Iomab-ACT is a next-generation targeted conditioning agent we are developing with the intent to improve patient access to and outcomes with cellular therapies such as CAR-T for various blood cancer indications and gene therapies for non-malignant hematologic disorders such as sickle cell disease (“SCD”). We are also developing ATNM-400, a novel preclinical, non-prostate specific-membrane antigen (“PSMA”) targeting, first-in-class radiotherapy utilizing the Actinium-225 (“Ac-225”) radioisotope payload intended for patients with prostate cancer directed against a novel radiotherapy target.

Actimab-A is being developed as a targeted radiotherapeutic to leverage the Actinium-225 (“Ac-225") isotope payload directed against CD33, a target expressed ubiquitously in patients with AML, MDS 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 myeloid malignancies, which are extremely heterogenous and radiosensitive, as a single agent or in combinations with chemotherapy, targeted agents, cellular therapy and immunotherapy. Actimab-A has been studied in over 150 patients. We plan to initiate a Phase 2/3 trial with Actimab-A in combination with the chemotherapy regimen CLAG-M in patients with r/r AML. In addition to our internal development efforts, we entered into a Cooperative Research and Development Agreement (“CRADA”) with the National Cancer Institute (“NCI”) in February 2023 for the development of Actimab-A for AML and other myeloid malignancies. The first clinical trial to be conducted under our CRADA with NCI will evaluate the triplet combination comprised of Actimab-A, Venetoclax and ASTX-727, a novel oral HMA developed by Taiho Oncology, an Otsuka Holdings company, in frontline AML patients. Venetoclax in combination with HMAs (Ven-HMA) is approved for patients with newly diagnosed AML. We believe this trial is supported by our Actimab-A + Venetoclax combination trial that showed that combination was well-tolerated and showed supportive anti-leukemic activity. Additional clinical trial concepts for Actimab-A have been submitted under the CRADA and are being reviewed. We anticipate that additional clinical trials with Actimab-A will be initiated in 2025 including under the CRADA to leverage Actimab-A’s mutation agnostic mechanism.

In March of 2025, we initiated our Actimab-A solid tumor program that will combine Actimab-A with PD-1 checkpoint inhibitors. We initiated this program to evaluate if Actimab-A can deplete CD33 expressing MDSCs and hence improve patient outcomes in combination with PD-1 ICIs such as KEYTRUDA® and OPDIVO®. The Actimab-A solid tumor program is comprised of several controlled, head-to-head clinical trials that will evaluate the combination of Actimab-A with KEYTRUDA® versus KEYTRUDA® alone, and Actimab-A with OPDIVO® versus OPDIVO® alone. The initial tumors that are being targeted are Head and Neck Squamous Cell Carcinoma (“HNSCC”) and Non-Small Cell Lung Cancer (“NSCLC”) with a separate trial for each indication.

ATNM-400 is our newest targeted radiotherapy program that we are advancing for prostate cancer. Given the biology of the antigen targeted by ATNM-400 and the precise and potent cell-killing of Ac-225, we believe ATNM-400 has the potential to address unmet needs in prostate cancer. We have generated preclinical data with ATNM-400 showing selective tumor accumulation with minimal uptake in normal tissues. Our experiments also showed dose-dependent cytotoxicity. We continue to study ATNM-400 with additional data expected from Pluvicto-resistant prostate cancer models. Pluvicto (Lu-177-PSMA-617) is a prostate-specific membrane antigen (PSMA) directed targeted radiotherapy that uses the beta-particle emitting radioisotope Lutetitium-177 (“Lu-177”) that is approved for patients with metastatic prostate cancer. ATNM-400 is differentiated from Pluvicto as it targets a different marker than PSMA that has been shown to be overexpressed in patients with prostate cancer and uses the alpha-particle emitter Ac-225, which is more potent than Lu-177 but has a shorter path length, which could result in fewer off-target effects such as xerostomia.

In addition to ATNM-400, we have active R&D efforts leveraging our in-house preclinical development and translational research capabilities that are primarily focused on supporting our ATNM-400 preclinical program, the Actimab-A and Iomab-ACT clinical programs and advancing several preclinical programs for solid tumor indications.

Iomab-ACT is our next-generation targeted conditioning agent directed against CD45, a target expressed widely across the hematopoietic system including normal nucleated immune cells such as lymphocytes that is relevant to this program and uses the Iodine-131(“I-131") radioisotope payload. We are developing Iomab-ACT for cell and gene therapies for both malignant and non-malignant hematologic indications. Iomab-ACT utilizes non-myeloablative doses of I-131, to not fully deplete the patient’s bone marrow and immune system with the goal of improving patient access and outcomes for potentially curative cell and gene therapies by replacing the need for the non-targeted, chemotherapy-based conditioning regimens that are currently used. Iomab-ACT is currently being studied in three clinical trials. These trials include Iomab-ACT with a commercial CAR-T therapy, Iomab-ACT prior to allogeneic BMT for patients with SCD, which could potentially inform a trial design with gene therapy for SCD, and Iomab-ACT with a novel investigational CD19 CAR-T therapy.

We previously advanced our targeted conditioning program Iomab-B through the Phase 3 Study of Iomab-B in Elderly Relapsed and Refractory AML (“SIERRA”) trial, a 153 patient, randomized multi-center trial conducted in the United States. and Canada. Iomab-B is comprised of the anti-CD45 monoclonal antibody apamistamab with myeloablative doses of I-131 intended to enable patient access to bone marrow transplant (“BMT”), the only potentially curative treatment option for patients with r/r AML. At this time, we are seeking a strategic partner for Iomab-B to conduct an additional clinical trial based on feedback from the U.S. Food & Drug Administration (“FDA”) and are committed to establishing the best development path forward for Iomab-B in the U.S., while keeping internal resources and strategic priorities in focus. As previously disclosed and noted above, Actinium also has a License Agreement with Immedica, granting Immedica the exclusive product rights for commercialization of Iomab-B in certain countries in the European Economic Area, Middle East and North Africa (“EUMENA”) region.

Actinium’s Approach to Targeted Radiotherapy Development

Radiation is a validated cancer therapy that has been used to treat patients for over 100 years. It is used to treat over half of all patients diagnosed with cancer today. Radiation therapy utilizes rays of energy to kill cancer cells and is commonly used in combination with other cancer treatment modalities. Radiation therapy is primarily administered from outside of the body and therefore passes through normal healthy tissue and organs that result in side effects and toxicities, which can be acute and/or chronic.

With our targeted radiotherapy approach, we seek to address the limitations of external radiotherapy and achieve cellular level precision by leveraging the cancer cell targeting ability of biologic molecules with the cancer cell killing ability of radioisotopes. In doing so, we seek to improve efficacy outcomes, reduce toxicities and expand the use of radiation to cancer indications like blood cancers that cannot be addressed with externally delivered radiation. In addition, we are also testing the use of targeted radiotherapies in solid tumor cancers where there are unmet medical needs. Biological molecules have demonstrated high affinity for cancer cell identification and binding to biological markers on the surface of cells known as antigens or ligands, which are the target receptors for our targeted radiotherapies.

Actinium’s Targeted Radiotherapies

Alpha particles emitted by as the element Ac-225 are the heaviest and have the highest charge, resulting in high amounts of linear energy transfer, which is capable of producing double strand DNA breaks. However, alpha-particles travel short distances of just several microns and as a consequence do not exert radiation outside of the body. Alpha particles can be stopped by an ordinary sheet of paper. Therefore, alpha particle-based therapies do not require special shielding or that patients remain isolated following treatment. Beta particle-based therapies have a longer pathlength but have lower amounts of linear energy transfer and at certain dose levels may require isolation or special handling.

Comparison of Radioisotope Pathlength

We focus on producing drug candidates that match a specific targeting agent with the appropriate isotope for a desired indication. We employ an isotope-agnostic approach to targeted radiotherapy development. Our development efforts are centered on validated targets that are known to have high expression on cancer cells compared to normal healthy cells. We are advancing our clinical product candidates targeting CD33 and CD45 and have completed preclinical studies against other blood cancer targets such as CD38, as well as various validated solid tumors targets.

Our Strategy

We believe that the cell-killing power of linear energy transfer delivered via radiotherapeutics is unmatched by other technologies and that there are multiple indications where radiotherapeutics can succeed over other approaches. However, radiotherapeutics must be delivered on a just-in-time basis, and commercial and supply chain barriers are higher than with other types of medicines. Actinium’s strategy is to build a specialty radiotherapeutics company with the capabilities to produce radioisotopes, manufacture radiotherapies, conduct preclinical research, clinical development and supply radiotherapies to the point of care. We believe our strategy will enable us to build a successful company with the potential for high operating efficiencies.

Our strategic priorities are to:

Establish Actimab-A as a mutation agnostic, backbone therapy for myeloid malignancies including patients with AML and high-risk MDS;

Establish Actimab-A as a pan solid tumor therapy in combination with PD-1 inhibitors including KEYTRUDA® and OPDIVO® by depleting myeloid derived suppressor cells;

Determine the potential of ATNM- as a viable treatment for patients with prostate cancer;

Establish Iomab-ACT as a universal targeted conditioning agent for cell and gene therapies to improve patient access and outcomes;

Leverage our R&D capabilities and clinical development experience to further advance pipeline assets for cancer indications with high unmet needs; and

Establish in-house manufacturing infrastructure to support our planned later-stage clinical development and secure partnerships to enable the deployment of our proprietary Ac-225 cyclotron manufacturing technology.

Market Opportunity for Our Targeted Radiotherapies

We believe our clinical programs have the potential to address a significant number of patients with high unmet medical needs and therefore represent large potential market opportunities. To our knowledge, Actimab-A, Iomab-ACT and ATNM-400 are first in class targeted radiotherapies for myeloid malignancies, targeted conditioning for cell & gene therapies and multiple solid tumors, respectively, with each discrete opportunity representing a range of over 100,000 to several hundred thousand addressable patients.

Four Large & Distinct Potential Market Opportunities

Actimab-A Myeloid Malignancies Program

We are focused on developing our lead targeted radiotherapy Actimab-A for patients with AML and MDS, which are the most common myeloid malignancies in adults. AML and certain MDS can progress rapidly, especially in patients with high-risk features such as certain genetic mutations. To our knowledge, Actimab-A is the only CD33 targeted radiotherapy in development for patients with myeloid malignancies.

Myeloid malignancies are a group of cancers that affect blood-forming cells also referred to as hematopoietic cells in the bone marrow. These cells are from the myeloid lineage and include white blood cells, red blood cells and platelets. Myeloid malignancies include AML, MDS, chronic myeloid leukemia (“CML”) and myeloproliferative neoplasms (“MPNs”).

We believe Actimab-A can be used in multiple treatment settings across the myeloid patient journey. For patients with AML, we plan to develop Actimab-A for both fit and unfit patients in the frontline, relapsed or refractory and maintenance settings either as a monotherapy or in combination with other treatments. For patients with MDS, we plan to develop Actimab-A for patients who have high-risk disease and in the maintenance setting. In the United States andthe five largest countries in Western Europe (France, Germany, Italy, Spain and the United Kingdom, which we refer to as “EU5”), we estimate the patient population across our target treatment settings in these diseases to be greater than 100,000 patients annually.

U.S. and EU5 AML & MDS Addressable Patient Population

AML is increasingly defined by the presence of genetic mutations or cytogenetic abnormalities as well as prior therapy given the increased number of approved agents. AML is a mutation rich disease that is genetically heterogeneous with identifiable mutations in over 95% of all patients. The most common mutations for which there are approved therapies include fms-like tyrosine kinase 3 (“FLT3”), isocitrate dehydrogenase 1 & 2 (“IDH1”) (“IDH2”), and nucleophosmin 1 (“NPM1”) & KMT2A rearrangements.

Various treatments are currently approved or utilized for patients with AML and MDS including chemotherapies, targeted therapies, antibody drug conjugates (“ADCs”), hypomethylating agents (“HMAs”) and BMT. Since 2017, twelve therapies have been approved for patients with AML. As part of our development strategy, we have evaluated and expect to continue to evaluate Actimab-A in combination with these approved therapies and other emerging treatment options or therapeutic modalities to leverage its mutation agnostic and potentially synergistic mechanism of action. Given the ubiquitous expression of CD33, we believe Actimab-A has the potential to be a backbone therapy for myeloid malignancies.

Fewer approved treatment options exist for patients with MDS, particularly high-risk patients. Treatments currently approved or utilized for high-risk patients include chemotherapies, HMAs and IDH1 inhibitors. We intend to evaluate the potential utility of Actimab-A in MDS either as single agent or in combination with other therapies.

Given the complexity and aggressiveness of AML and High-risk MDS, these patients are often referred to and treated in comprehensive treatment centers for in-patient treatment as opposed to community, outpatient-based care. As a result, we believe the majority of AML and High-risk MDS patients largely occurs in a finite number of centers, which implies efficiencies from concentration of commercialization efforts.

Actimab-A Solid Tumor Program

We believe a large market opportunity also exists for Actimab-A in solid tumor indications by depleting MDSCs to synergize with PD-1 checkpoint inhibitors and potentially other immune checkpoint inhibitors. Several solid tumor indications have shown to have high expression of MDSCs including non-small cell lung cancer (“NSCLC”), melanoma, renal cell carcinoma (“RCC”), colorectal cancer (“CRC), triple negative breast cancer (“TNBC”), head & neck squamous cell carcinoma (“HNSCC”), pancreatic cancer, glioblastoma (“GBM”) prostate cancer and ovarian cancer. Cumulatively, over 600,000 patients are diagnosed with these cancers annually. PD-1 checkpoint inhibitors are approved in a significant number of these indications and in 2024 generated sales totaling more than $45 billion.

We are planning to conduct our initial controlled, randomized clinical trials in HNSCC and NSCLC in combination with the PD-1 checkpoint inhibitors KEYTRUDA® and OPDIVO®. These two indications represent a potential addressable patient opportunity of over 250,000 patients. We expect to continue to evaluate additional indications for potential future clinical trials assuming our initial efforts are successful.

ATNM-400 Prostate Cancer Program

Prostate cancer is the most common cancer in men, with approximately 1 in 8 men diagnosed with prostate cancer during their lifetime. According to the American Cancer Society, an estimated 313,780 new cases of prostate cancer will be diagnosed in the United States in 2025. The global incidence of prostate cancer is approximately 1.5 million new cases annually. Approximately 20% of prostate cancer cases are more aggressive forms that progress to metastatic disease, which is associated with significantly worse survival outcomes. Radiotherapy is commonly used to treat prostate cancer, and in 2022, the PSMA-targeting radiotherapy Pluvicto was approved by the FDA and the European Medicines Agency (“EMA”) for the treatment of patients with metastatic castration-resistant prostate cancer. Pluvicto is marketed and sold by Novartis and generated sales of $1.39 billion in 2024. ATNM-400 is differentiated from Pluvicto as it targets a different marker than PSMA that has been shown to be overexpressed in patients with prostate cancer and uses the alpha-particle emitter Ac-225, which is more potent than Lu-177 but has a shorter path length, which could result in fewer off-target effects such as xerostomia.

Iomab-ACT Cell & Gene Therapy Conditioning Program

We are developing Iomab-ACT as a targeted conditioning agent to prepare patients for cellular therapies such as CAR-T or BMT and gene therapies. Our current clinical trials are focused on patients with blood cancers and non-malignant blood disorders such as SCD. The first CAR-T therapies was approved in 2017 and currently, there are 6 approved CAR-T therapies for patients with lymphomas, leukemia and multiple myeloma, which generated sales of over $4.0 billion in 2024. We estimate that there are approximately 125,000 patients diagnosed with blood cancers that can be potentially treated with CAR-T therapies, which are currently approved for r/r patients. SCD is a rare, debilitating and life-threatening blood disorder with significant unmet needs that affects approximately 100,000 people in the U.S. Patients with SCD 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. An allogeneic BMT is a potentially curative treatment option for patients with sickle cell disease, particularly in pediatric and adolescent patients who have had complications such as strokes, acute chest crises or recurring pain crises due to their disease. In addition, there are two approved gene therapies for patients with sickle cell disease, Casgevy (Vertex Pharmaceuticals, Inc. and CRISPR Therapeutics) and Lyfgenia (Bluebird Bio, Inc.).

Our Clinical Product Candidates

Actimab-A: Mutation Agnostic Mechanism of Action with Backbone Therapy Potential in Myeloid Malignancies including AML and high-risk MDS

Actimab-A*(Ac-225-lintuzumab satetraxetan)*is our lead radiotherapeutic product candidate in development for patients with myeloid malignancies. To our knowledge, Actimab-A is the only CD33 targeting radiotherapy in clinical development. We are focused on developing Actimab-A as both a monotherapy and in combination with other treatment regimens to leverage both the potential mechanistic synergies of radiation and its mutation agnostic cell killing ability. In addition to our internal development efforts, we entered into a CRADA with the NCI in February 2023 for the development of Actimab-A for AML and other myeloid malignancies.

We intend to establish Actimab-A as a backbone therapy leveraging the broad expression of CD33 in myeloid malignancies such as AML and MDS, which, like most blood cancers, are highly sensitive to radiation. AML is a highly heterogenous, mutation rich cancer with over 70 identified driver genetic mutations. However, there are only approved therapies for four mutations including FLT3, IDH1 & IDH2, and NPM1. CD33 is expressed regardless of other mutations being present The Ac-225 isotope payload that we utilize with Actimab-A emits potent alpha-particles with high linear energy that kill cells via double strand DNA breaks for which there is no known resistance or repair mechanism.

Actimab-A’s Mechanistic Synergy and Potential Combinations

Our development strategy is to exploit these properties of Actimab-A to address the unmet needs of patients with myeloid malignancies across the treatment journey including the frontline, relapsed/refractory and maintenance settings. To accomplish this, we are leveraging our clinical development experience, clinical data and preclinical work supporting Actimab-A’s mutation agnostic capabilities.

Actimab-A Clinical Development Experience

To our knowledge, Actimab-A is one of the most studied alpha-particle based targeted radiotherapies in clinical development having been studied in over 150 patients across multiple clinical trials. Actimab-A has been studied at multiple dose levels, different administration schedules and as a single agent or in combination with chemotherapy and targeted agents in patients with AML in the front line and relapsed or refractory settings with promising results to date.

Actimab-A Monotherapy Phase 2 Trial

Following multiple Phase 1 clinical trials, Actimab-A was studied in a 40-patient multi-center Phase 2 trial as a single agent in patients newly diagnosed with AML age 60 and above who were ineligible for intensive chemotherapy. At the dose level of 2.0 μCi/kg, Actimab-A produced high overall response rates (“ORR”) of 69% including Complete Remission (“CR”), Complete Remission with incomplete platelet recovery (“CRp”) and Complete Remission with incomplete blood count recovery (“CRi”). Prolonged myelosuppression was the most common adverse event and was expected as it is a known class effect of CD33 targeting therapies and given the advanced age of the patients enrolled. The Actimab-A dose was adjusted to 1.5μCi/kg, which produced an ORR of 22%. Potent anti-leukemic effect was observed at both dose levels. Of the patients treated with 1.5 μCi/kg of Actimab-A, the median age was 75 and over 50% of the patients had an antecedent hematologic disorder including MDS, chronic myelomonocytic leukemia and myelofibrosis, which can compromise a patient’s bone marrow function and ability to recover blood counts and proper function. This trial was conducted prior to the approval of many of the targeted therapies that are routinely used in the treatment of patients with AML today. As a result of the prolonged myelosuppression seen with doses of Ac-225 directed against CD33 expressing cells and the evolving AML treatment landscape, we adapted our development strategy for Actimab-A to address the emerging unmet needs of patients in the era of precision medicines for AML.

Anti-Leukemic Activity of Actimab-A Monotherapy

After completing the Phase 2 monotherapy trial, there was strong interest from trial investigators and other key opinion leaders to study Actimab-A in combination with other treatment modalities to leverage its novel mutation agnostic radiotherapy mechanism. We evaluated several clinical trial concepts and elected to pursue combination trials with Actimab-A with the salvage chemotherapy CLAG-M in patients with r/r AML and with the Bcl-2 inhibitor Venetoclax based on the potential for these combinations to address large segments of the AML patient population with high unmet needs.

Actimab-A + Venetoclax Phase 1/2 Combination Trial

Venetoclax is an oral therapy that works by attaching to and blocking the actions of the B-cell lymphoma-2 (“Bcl-2”) protein. Bcl-2 is overexpressed in several blood cancers and prevents cancer cells from undergoing normal programmed cell death or apoptosis, which can help the cancer cells overexpressing Bcl-2 live longer or increase resistance to chemotherapy. In November 2018, Venetoclax received accelerated approval from the FDA in combination with the HMA azacitidine and decitabine or low-dose cytarabine for the treatment of newly diagnosed AML in patients age 75 years or older or patients ineligible for intensive induction chemotherapy. Venetoclax was granted regular approval by the FDA in October 2020.

The Phase 1 portion of the Actimab-A + Venetoclax trial enrolled 18 patients and was conducted at five clinical trial sites. Four dose levels of Actimab-A were evaluated with the primary objective of evaluating the safety of the combination. Actimab-A + Venetoclax was well tolerated with an expected and manageable adverse event profile with no early deaths observed. Efficacy was also evaluated with reduction in bone marrow blasts up to 93% reported.

Actimab-A + CLAG-M Phase 1b/2 Combination Trial

The Medical College of Wisconsin (“MCW”) was an active clinical trial site in the Phase 2 Actimab-A Monotherapy trial. MCW had previously conducted a study evaluating salvage chemotherapies in patients with r/r AML including the regimens MEC, CLAG and CLAG-M. The results demonstrated that CLAG-M produced superior outcomes based on rates of response and overall survival resulting in CLAG-M being the preferred salvage regimen for patients with r/r AML. Based on MCWs experience with Actimab-A and CLAG-M, the team at MCW hypothesized that combining Actimab-A with CLAG-M could improve patient outcomes compared to CLAG-M alone and lead to a clinical benefit by eliminating residual or resistant AML blasts to produce higher rates of remissions and deep remissions including measurable residual disease (“MRD”) negativity.

MCW enrolled 26 adult patients with high-risk r/r AML in the Phase 1b/2 trial of Actimab-A + CLAG-M with 23 patients evaluable for efficacy. Patients in the efficacy cohort had a median age of 62 and 91.3% of patients being intermediate risk (13%) or adverse risk (78.3%) according to the 2017 ELN cytogenetic risk classification. Additionally, 52.2% of patients had a TP53 mutation abnormality, 56.5% of patients had prior Venetoclax treatment and 56.5% of patients had a prior allogeneic BMT with patients having a median of 2 lines of prior treatment (range: 1-5). This trial evaluated four dose levels of Actimab-A in combination with CLAG-M ranging from 0.25 μCi/kg to 1.0 μCi/kg.

Patient Characteristics

The results from this trial were published in the peer-reviewed journalLeukemia in February 2025. In this publication, it was reported that Actimab-A + CLAG-M had a tolerable safety profile with manageable toxicities and demonstrated promising efficacy supporting additional trials to further evaluate the efficacy of the combination including survival outcomes. Based on the results of the study, it was determined that 0.75 μCi/kg is the recommended Phase 2 dose (“RP2D”). In addition to a safety analysis, the results of 5 patients treated in a pharmacokinetic expansion cohort at the RP2D were reported. Treatment-emergent adverse events (“TEAE”) were primarily hematologic and all grade 3/4 TEAEs were hematologic. No patients discontinued treatment due to TEAEs and no early deaths were attributed to the Actimab-A + CLAG-M. The pharmacokinetic analysis evaluated radioactivity in whole blood and results showed that Actimab-A cleared rapidly with no detectable radioactivity after a median of 24.5 hours. Importantly, no significant kidney or liver toxicity has been reported to date and no incidences of veno-occlusive disease (“VOD”) reported.

The efficacy analysis of this trial evaluated rates of CR, composite Complete Remission (“CRc”) which includes CR and Complete Remission with Incomplete Count Recovery (“CRi”) and ORR which include CR, CRi and Morphologic Leukemia-Free State (“MLFS”), as well as MRD negativity and survival outcomes. As listed in the table below, CR, CRc and ORR rates were reported for all patients as well as patients treated at the RP2D, by number of lines or prior therapy and high-risk patients including those with a TP53 mutation and prior Venetoclax treatment.

Rates of CR, CRc and ORR with Actimab-A + CLAG-M

In patients achieving a CRc, MRD negativity was assessed including in patients in various high-risk subgroups. Across all patients, the MRD negativity rate was 75% and was 100% in patients with prior Venetoclax treatment. In the ELN adverse risk patients and those with a TP53 mutation, MRD negativity was 86% and 83%, respectively. We believe these high rates of MRD negativity support the rationale for conducting this study, which was to determine if Actimab-A could deplete residual or resistant AML blasts to produce deep remissions.

MRD Negativity Rates in Evaluable Patients Achieving CRc

Long-term survival outcomes in the evaluable patients receiving Actimab-A + CLAG-M were also reported from this study from a 2-year follow-up. In the patients eligible for a BMT, 60% of patients successfully received a BMT and had a median Overall Survival (“OS”) of 24 months. In patients with one or two lines of prior salvage therapy, the median OS was 18.4 months. The median OS in patients with a TP53 mutation or prior Venetoclax treatment was 9.6 months and 7.3 months, respectively. These survival outcomes compare favorably to outcomes reported in the literature. In patients with prior Venetoclax treatment who then received intensive chemotherapy such as CLAG-M, OS has been reported to be 2.4 - 4.6 months.

Overall Survival Outcomes with Actimab-A + CLAG-M

Based on the positive findings from this trial, we plan to evaluate Actimab-A + CLAG-M will be evaluated in a pivotal Phase 2/3 trial in patients with r/r AML.

Actimab-A + CLAG-M Pivotal Phase 2/3 Trial

We have aligned with the FDA on an operationally seamless, randomized pivotal Phase 2/3 trial to compare Actimab-A + CLAG-M to CLAG-M alone in patients with r/r AML. Based on our interactions with the FDA, this trial will first complete a Phase 2 portion where the Actimab-A dose will be optimized in combination with CLAG-M. We expect the Phase 2 portion of this trial to be initiated in 2025. Once the optimized Actimab-A dose is determined, we expect the trial will seamlessly advance to the Phase 3 portion of the study, which is expected to reduce time and resources required compared to separate Phase 2 and Phase 3 studies.

Actimab-A + CLAG-M Pivotal Phase 2/3 Trial Design

The primary endpoint of the Phase 3 trial will be Overall Survival. Event-Free Survival (“EFS”) and other efficacy measures as well as safety also being evaluated. We are actively seeking potential strategic partners or collaborators to advance this trial.

Actimab-A NCI CRADA Trials

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, which we believe will be a cost-efficient approach as opposed to a Company sponsored trial and will therefore spare our balance sheet. 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.

In October 2024, the NCI announced that its myeloMATCH program was officially open to patient enrollment across the U.S. and Canda. MyeloMATCH is a portfolio of clinical trials to test precision medicine treatments for adults with AML or MDS being designed and led by four leading cancer research organizations including the Alliance for Clinical Trials in Oncology, Canadian Cancer Trials Group, ECOG-ACRIN Cancer Research Group, and SWOG Cancer Research Network in collaboration with the NCI National Clinical Trials Network (“NCTN”). Collectively, the myeloMATCH program expects to open trials at hundreds of cancer care sites across the U.S. and Canada with the goal of enrolling 5,000 or more patients over the next several years. Under our CRADA with the NCI, Actimab-A is part of the myeloMATCH program and may be included in future clinical trials.

Actimab-A, Venetoclax & ASTX-727 – Frontline AML Triplet Phase 1b Combination Trial

In March 2025, we announced the initiation of the first clinical trial to be conducted under our CRADA by NCI. The trial will evaluate the triplet combination comprised of Actimab-A, Venetoclax and ASTX-727, a novel oral HMA developed by Taiho Oncology, an Otsuka Holdings company, in frontline AML patients. Venetoclax in combination with HMAs (Ven-HMA) is approved for patients with newly diagnosed AML. We believe this trial is supported by our Actimab-A + Venetoclax combination trial that showed that combination was well-tolerated and showed supportive anti-leukemic activity. The frontline AML triplet trial is expected to enroll up to 48 patients who are newly diagnosed with AML that are age 75 and above and not eligible for intensive chemotherapy. The trial will evaluate various dose levels of Actimab-A along with dosing regimens. We expect initial clinical data to be generated from this trial in second half of 2025.

Triplet Combination Trial Design with Venetoclax, HMA & Actimab-A Backbone

Additional clinical trial concepts for Actimab-A have been submitted under the CRADA and are being reviewed. We anticipate that additional clinical trials with Actimab-A will be initiated in 2025 including under the CRADA to leverage Actimab-A’s mutation agnostic mechanism.

Broad Development Strategy for Actimab-A

Data Supporting Actimab-A’s Mutation Agnostic Profile

To leverage Actimab-A’s mutation agnostic capabilities and support its broad development, we have conducted preclinical experiments studying Actimab-A in combination with targeted agents including Bcl-2 inhibitors, FLT-3 inhibitors, IDH inhibitors and menin inhibitors for NPM1 and KMT2A AML, chemotherapies such as CLAG-M and in cell lines expressing TP53 mutations. The table below outlines the expression rates of these targets in patients with AML.

Actimab-A Combination Data with Menin Inhibitors

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 NPM1 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).

Enhanced Tumor Control with Actimab-A + Menin Inhibitor Revumenib

Actimab-A Combination Data with FLT3 Inhibitors

We have also evaluated Actimab-A in combination with FLT3 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. We will continue to evaluate the potential of Actimab-A in combination with FLT3 inhibitors.

Synergistic Anti-Leukemic Effect with FLT3 Inhibitors

We expect to present additional data supporting Actimab-A’s mutation agnostic capabilities and backbone potential at future scientific and medical conferences. In addition, we will continue to explore potential clinical trials under our CRADA with NCI, investigator-initiated trials or under our sponsorship.

Actimab-A Solid Tumor Program: Potential Pan Solid Tumor Therapy in Combination with PD-1 Checkpoint Inhibitors Including KEYTRUDA® and OPDIVO® by Depleting Myeloid Derived Suppressor Cells

Given the significant number of patients treated with PD-1 ICIs, there is extensive data in the medical literature on outcomes in these patients. PD-1 ICIs have significantly improved patient outcomes across several solid tumor indications, however, not all patients have robust or durable responses. Multiple therapeutic modalities have been studied in combination with PD-1 ICIs in attempt to improve patient outcomes, but few combinations have produced a sufficient enough clinical benefit to have been approved. To our knowledge, our Actimab-A solid tumor program is the only CD33 targeted radiotherapy being evaluated in combination with PD-1 ICIs. The rationale for studying Actimab-A in combination with either KEYTRUDA®or OPDIVO®is based on the premise that depleting MDSCs with Actimab-A will improve the efficacy of these drugs.

MDSCs are immune-suppressive cells that help tumors evade immune detection and promote disease progression. They are overexpressed in the tumor microenvironment in several different solid tumors and associated with poor outcomes. They work by multiple mechanisms but most relevant to PD-1 inhibitors which work by keeping T-cells active is that MDSCs prevent T-cells from recognizing and attacking cancer cells.

MDSCs Immunosuppressive Effects

Studies have shown that MDSCs are overexpressed in patients with cancers. For instance, a study by Bronte et al., in patients with NSCLC receiving ICIs evaluated the role of immune cells on patient outcomes. In this study, MDSCs were the only immune cell subtype to show a statistically significant association with tumor response. The median level of MDSCs was determined to be 1.9% with patients above that level being classified as “High-MDSC” and patients below that level being classified as “Low-MDSC”. In this study, only Low-MDSC patients had a clinical response with no responses observed in High-MDSC patients and over 80% of High-MDSC patients having progressive disease. In addition, Low-MDSC patients had a statistically significantly improvement in progression-free survival (“PFS”) of 8.39 months compared to 1.94 months in High-MDSC patients and OS of 15.15 months compared to 3.03 months in High-MDSC patients.

There is considerable preclinical scientific evidence in the literature that depleting MDSCs could be a viable strategy in improving the outcomes of PD-1 directed immunotherapy, however, there have been no viable clinical approaches that have been tried successfully to our knowledge. MDSCs are known to express the CD33 antigen which is the target of Actimab-A. Actinium has also generated published and unpublished preclinical data showing that Actimab-A can selectively deplete MDSCs in solid tumors.

Actimab-A Depletes MDSCs in In Vivo Preclinical Models

We believe there is strong scientific rationale supporting the potential for Actimab-A to deplete CD33 expressing MDSCs and hence improve patient outcomes with PD-1 ICIs such as KEYTRUDA® and OPDIVO®. Our Actimab-A solid tumor program is expected to be comprised of several controlled, head-to-head clinical trials that will evaluate the combination of Actimab-A with KEYTRUDA® versus KEYTRUDA® alone, and Actimab-A with OPDIVO® versus OPDIVO® alone. The initial tumors that are being targeted are HSNCC and NSCLC with a separate trial for each indication.

The patient population for these trials will be adults with PD-L1 expression and locally advanced metastatic HNSCC or NSCLC randomized to either Actimab-A alone or Actimab-A with a specific checkpoint inhibitor. The objective of each trial would be to evaluate the safety and tolerability as well as following endpoints including ORR, PFS and OS. Further, the following biomarker data would be collected including the pattern of depletion of CD33+ MDSCs and T-cell activity in peripheral blood. We expect to present initial proof of concept clinical data from the first of these trials in the second half of 2025 as well as provide an update on the outlook for the rest of the trials for the Actimab-A solid tumor program.

ATNM-400 Program: Potential Novel, First-in-Class Ac-225 Prostate Cancer Radiotherapy

In March 2025, we announced ATNM-400, a novel, first-in-class Ac-225-based radiotherapy intended for patients with prostate cancer. We have generated preclinical data with ATNM-400, which has been accepted for presentation at the American Association for Cancer Research (“AACR”) Annual Meeting being held April 25 – 30, 2025. The abstract accepted for presentation highlighted the following:

We continue to study ATNM-400 and expect additional data from Pluvicto-resistant prostate cancer models to be presented at AACR.

Iomab-ACT Program: Potential Universal Targeted Conditioning Agent for Cell & Gene Therapies to Improve Patient Access and Outcomes

The opportunity exists for better conditioning regimens in the area of cellular therapies beyond the non-targeted chemotherapy-based regimens that are used currently. We are working on a next generation targeted 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 SCD.

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. 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”) as outlined in the table below.

Minimal CRS and ICANS in Iomab-ACT Pilot Trial

Additionally, 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. These results prompted us to explore additional clinical trials with Iomab-ACT.

In May 2024, we announced FDA acceptance of an IND for a new Phase 1b/2 clinical trial that will study Iomab-ACT as targeted conditioning prior to patients receiving an FDA approved commercial CAR-T therapy. This is an investigator sponsored trial conducted at the University of Texas Southwestern (“UTSW”). 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. This trial will enroll up to 30 patients and we expect to commence patient enrollment of this study in the first half of 2025 and generate proof of concept clinical data by year end 2025. The primary objectives are safety, tolerability and efficacy. Second objectives will evaluate incidences of CRS and ICANS as well as the persistence and expansion of CAR-T cells, which has been associated with improved efficacy and patient outcomes. If successful, we believe this Phase 1b/2 trial could support a pivotal trial, which could be initiated as early as 2026.

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 SCD 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 and enroll up to 15 patients with initial safety and efficacy results from the initial cohort of patients receiving Iomab-ACT prior to a BMT for their SCD in the second half of 2025.If safety is demonstrated, 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.).

Iomab-ACT Clinical Trials and Objectives

We plan to continue to develop Iomab-ACT based on early promising results, ultimately with the value proposition of improving overall access and outcomes for patients who need cellular or gene therapies. We believe an opportunity exists for Iomab-ACT to potentially generate significant revenue, if it can provide one or more clinical benefits related to lower CRS, less neurotoxicity, longer duration of response or a higher overall success rate of cellular therapy due to benefits of targeted conditioning.

Iomab-B

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 met the secondary endpoint of Event-Free Survival (“EFS”) with a 78% reduction in the probability of an event (Hazard Ratio=0.22, p<0.0001 for both per protocol and ITT basis). EFS at 180 days for the Iomab-B arm was 28% compared to 0.2% for the control arm. In the SIERRA trial, an event was defined as one of the following: a patient not achieving CR/CRp or crossing over, patient not receiving BMT, a patient relapsing or death. The SIERRA trial did not, however, meet the secondary endpoint in achieving a statistically significant improvement in OS in the intent to treat (“ITT”) population.

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.

Actinium continued interactions with the FDA in the third quarter of 2024 to further discuss the specifics of the additional head-to-head clinical trial required by the FDA, including the patient population, which the FDA had suggested could include all adult AML patients. In the fourth quarter of 2024, Actinium conducted a further meeting with the FDA. Based on this meeting, Actinium believes it has aligned with the FDA on the patient population for a head-to-head Phase 3 clinical trial to further evaluate allogeneic BMT using Iomab-B plus a reduced intensity conditioning regimen of Flu/TBI versus allogeneic BMT using reduced intensity conditioning comprised of cyclophosphamide plus Flu/TBI in all adult patients aged 18 and above with active AML with blasts counts greater than 5% and less than 20%. This is a broader patient population than the patients enrolled on the SIERRA trial, which only enrolled patients aged 55 and above. Further, the FDA now requires that an additional dose optimization trial demonstrating safety and efficacy be completed to calculate the dose of Iomab-B based on absorbed dose by the bone marrow, rather than the maximum tolerable dose of 24 Gy of radiation to the liver as was done in the SIERRA trial based on several interactions we had with the FDA before starting the SIERRA trial. We are actively seeking a strategic partner for Iomab-B in the U.S. to advance the head-to-head clinical trial or other clinical development activity for Iomab-B.

On April 7, 2022, we entered into a License Agreement with Immedica Pharma AB (“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 $35.0 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. Immedica is responsible for regulatory submissions in the EUMENA region, and we continue to retain commercialization rights in the U.S. and rest of the world.

R&D and Platform Technology

Our R&D capabilities have the potential to yield differentiated, high-value targeted radiotherapy programs that demonstrate our experience across multiple validated cancer targets and isotopes and cover broad areas of focus leveraging our clinical development experience across hematology, targeted conditioning, solid tumors, and next generation radiotherapies. We have internal R&D capabilities with our research laboratory capable of executing in vitro and in vivo experiments and translational research. We are working on several preclinical programs which include novel approaches to validated cancer targets, as well as novel targets that we believe show immense potential for radiotherapeutic approaches. Preclinical pharmacology studies with our targeted radiotherapeutics, such as HER2, CD33 and CD38, have shown strong improvement in tumor growth inhibition in various preclinical tumor models.

We currently believe that our targeted radiotherapies, which utilize biologic molecules, are less likely than small molecules to face pricing pressure and negotiation from 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 our Actimab-A and Iomab-B programs 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 generic large molecule biologic based targeted radiotherapies are much higher than for small molecule radioligands such as those under development or approved, namely, Pluvicto®, Lutathera®, and Xofigo®. Generic versions of certain radiopharmaceuticals utilizing peptides, which are considered small molecules, have been submitted to the FDA via the ANDA pathway. To our knowledge, only the biosimilar approach pertains to large molecule biologic-based radiotherapies filed under 351(k) BLA pathway. The regulatory pathway for a biosimilar is much more comprehensive than the pathway for generics, and it has not been proven that biosimilars are interchangeable with the innovator’s large molecule biologic targeted radiotherapy. In addition, we are not aware of any regulations that would require us to provide Actimab-A or Iomab-ACT, including their respective mAbs, lintuzumab and apamistamab, to any third party or potential competitor. Despite the above, we are aware that one or more of the policies or regulations that afford our pipeline candidates market protections may change in the future and that one or more of pour product candidates may be disadvantaged by such change.

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 key programs with a robust “fast-to-clinic” approach. Underpinning our development programs is our expanded patent portfolio of approximately 230 issued patents and pending patent applications worldwide.

Our Proprietary Ac-225 Cyclotron Manufacturing Technology

With our in-depth, long-term experience in clinical development of Ac-225 based radiopharmaceuticals, we have developed an end-to-end technology solution for producing Ac-225 that has demonstrated radiochemical and radionuclidic purity identical to current gold standard methods. This patented technology has been used to produce Ac-225 in a cyclotron that is essentially identical to that derived from a Th-229 generator and has the potential to be a lower-cost, commercially scalable higher-yielding approach. Importantly, the Ac-225 material produced by our proprietary method contains no long-lived contaminants and less than 0.001% Actinium-227 (“Ac-227”). Using the cyclotron-produced Ac-225 technology may allow for large commercial scale production with estimated cost of goods sold including capital expenditures and operational costs for a single cyclotron facility to be several times less expensive than the price of currently available Ac-225 material.

Demonstrated Radiochemical Equivalence

Blue: Actinium’s cyclotron-produced Ac-225**

Red**: Ac-225 from a Th-229 generator

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:

With our Ac-2225 based Actimab-A and ATNM-400 programs and the rapidly increasing number of Ac-225 based programs in development, we believe that we are well positioned to leverage this technology to produce Ac-225 to address the growing clinical and potential commercial demand.

Manufacturing and Supply Chain

Actinium has established significant manufacturing and supply chain expertise having delivered over 500 doses for 18 clinical trials at 45 large cancer hospitals and have never missed a dose.

We believe this experience provides us with insights that are highly relevant to the unique manufacturing and distribution requirements of radiotherapeutics. Due to the short half-life of radioisotopes, our finished drug products are shipped “hot” and must be administered within days. Actinium has established core competencies in the process of manufacturing radiotherapeutics, coordinating with the hospital’s care team, and delivering “just-in-time” doses.

We plan to establish our own manufacturing capabilities and intend to commence the build-out of a facility in the second quarter of 2025. We believe that having in-house manufacturing will provide enhanced control, flexibility and scalability to serve our current and planned clinical trials and R&D efforts as well as potential future activity.

Isotope supply is critical for the manufacturing of radiotherapeutics, and we have engaged several sources for the procurement of alpha (e.g., Ac-225) and beta (e.g., I-131 and Lu-177) emitters. We also have multiple isotope supply agreements and qualified vendors in place to supply isotopes for our active and planned clinical trials. In March 2025, we announced that we entered into Ac-225 supply agreement with Eckert & Ziegler, a leading specialist in isotope-related components for nuclear medicine and radiation therapy, to support our comprehensive development including U.S. and international clinical trials.

Actinium has commercial agreements with Contract Development and Manufacturing Organizations (“CDMOs”) with significant experience in mAb and final radio-labeled drug products. Our finished drug product CDMOs are located in the U.S. and have experience in the international supply of radiotherapies. We have scaled deliberately for manufacturing flexibility and are currently qualifying additional CDMOs to ensure readily available drug product upon FDA approval and the ability to ramp up rapidly to meet commercial demand.** **

We have established an actively managed end-to-end supply chain that encompasses isotope sourcing through drug administration at the point of care to execute our clinical trials. Our end-to-end supply chain did not miss a patient dose in our international, 24-site SIERRA Phase 3 clinical trial including 40 additional patients that crossed over from the control arm to receive Iomab-B. We believe we have a thorough understanding and working knowledge of the intricacies required to manufacture and distribute radiotherapies. Through our clinical experience with Iomab-B and Actimab-A, we have developed a wealth of proprietary knowledge to enable coordination between Actinium 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.

Intellectual Property

Our proprietary technology platform is supported by IP, know-how and trade secrets that cover the generation, development, methods of use and manufacture of targeted radiotherapies and their select components. Our IP covers various methods of use in multiple diseases, including indication, dose and scheduling, radionuclide warhead, and therapeutic combinations.

As of March 2025, our patent portfolio is comprised of approximately 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 15 issued patents and 52 pending patent applications in the U.S., and 166 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 2043.

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 in the treatment of cancers and non-malignant conditions.

Our patents also cover key areas of our business such as manufacturing key components of our product candidate, Actimab-A, including 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 5 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.

Competition

The biopharmaceutical industry is extremely competitive and rapidly evolving, particularly in the fields of oncology, hematology and cell and gene therapy. Our competition is likely to come from larger pharmaceutical companies, biotechnology companies, academia, and other public and private entities that focus on three broad areas relevant to our pipeline candidates – hematology/oncology agents, conditioning agents and radiopharmaceuticals. In addition, in markets where we are going after a target, companies with research programs and capabilities in our disease area focus may also be competing with our programs and pipeline. Additionally, our competition may have more resources than we do and more experience in drug development.

In myeloid malignancies, specifically AML, there are a significant number of programs in preclinical and clinical development. In addition, there are 12 approved products including small molecules and targeted therapies. However, to our knowledge, our Actimab-A program is the only Ac-225 based targeted radiotherapy in clinical development for AML and myeloid malignancies. In addition, Actimab-A is potentially synergistic with a majority of the approved AML therapies. AML assets primarily consist of agents targeting specific AML mutations, immunotherapies, or cell cycle modulators, which largely address finite segments of the population and do not have the broad potential for utilization like Actimab-A. Early clinical and preclinical stage assets consist of more cell therapy and immune cell engagers, and the potential success of these modalities in AML remain uncertain. Our strategy is to develop Actimab-A in combination with other products, and agents in the development pipeline have the potential for synergies in combination with Actimab-A.

In conditioning, agents currently used for myeloablation prior to a BMT, lymphodepletion prior to CAR-T and other adoptive cell therapies and reduced intensity conditioning for gene therapy are largely generic, non-targeted chemotherapeutic agents. Jasper Therapeutics and Magenta Therapeutics ceased development of their antibody and antibody-drug conjugate or ADC conditioning programs for BMT in malignant diseases. Certain companies such as Vertex Pharmaceuticals (“Vertex”), Gilead Sciences (“Gilead”) and Allogene Therapeutics (“Allogene") have or continue to explore non-chemotherapy conditioning with ADCs and antibodies for their in-house, proprietary cellular therapy programs. For example, Vertex in-licensed ADC technology from ImmunoGen Inc. (acquisition by AbbVie announced in November 2023) and had a collaboration with Molecular Templates, Inc. (ceased operations in 2024) to develop targeted conditioning agents, which was subsequently terminated. Allogene is using its own proprietary anti-CD52 monoclonal antibody for use as a lymphodepletion agent in conjunction with CAR-T therapies. Telix Pharmaceuticals has announced plans for a conditioning program based on a CD66 radiotherapeutic approach in systemic amyloid light-chain amyloidosis (“SALA”) via an early-stage investigator-sponsored trial. Molecular Partners is developing a switch-DARPin targeting cKIT×CD16a×CD47 as a conditioning regiment in AML, but this asset is in early preclinical studies. Without exception, all these companies have either preclinical or early-stage programs that are, for the most part, solely focused on their proprietary programs.

Several companies are focused on developing radiotherapies for solid tumors, with a majority of radiotherapy programs focused on PSMA or prostate-specific membrane antigen in prostate cancer, neuroendocrine tumors or fibroblast activation protein (“FAP”). Companies with radiotherapeutics in development include, but not limited to: Abdera Therapeutics, Aktis Oncology, Alpha-9 Theranostics, Ariceum Therapeutics, ARTbio, Bayer AG, Clarity Pharmaceuticals, Cellectar Biosciences, Convergent Therapeutics, CuraSight, Curium Pharma, Full-Life Technologies, Fusion Pharmaceuticals, Inc., Johnson & Johnson, Lantheus Holdings, Inc., Mariana Oncology (acquired by Novartis AG in May 2024) ), Molecular Partners, Monopar Therapeutics, Novartis AG, Orano Med, Perspective Therapeutics, Point Biopharma, Inc. (acquired by Lilly in December 2023), RadioMedix, Inc., Radiopharm Theranostics, Radionetics Oncology, Ratio Therapeutics, RayzeBio, Inc. (acquired by Bristol Myers Squibb in February 2024), Q BioMed, Inc., Scintomics, Telix, and Y-mAbs Therapeutics, Inc. None of these or other companies that we are aware of appears to be pursuing a development program directed against our biological target.

Government Regulation

Regulatory Compliance

Our research and development activities are all subject to stringent regulation, primarily by the FDA in the U.S. under the Federal Food, Drug, and Cosmetic Act (the “FDCA”) and its implementing regulations, and the Public Health Service Act (“PHSA”) and its implementing regulations, and by comparable authorities under similar laws and regulations in other countries. This includes research and development, testing, and oversight of suppliers and contract manufacturers involved in the production of our product candidates we are developing, as well as the design, manufacturing, safety, efficacy, handling, labeling, storage, record-keeping, advertising, promotion and marketing. If, for any reason, we do not comply with applicable requirements, such noncompliance can result in adverse consequences, including delays in approval of, or even the refusal to approve product licenses or other applications, the suspension or termination of clinical investigations, the revocation of approvals previously granted, as well as fines, criminal prosecution, recall or seizure of products, injunctions against shipping products and suspension of production and/or refusals of government contracts.

FDA Review Process and Product Approval

Our product candidates are regulated as biologics and must be approved by the FDA before they may be marketed in the U.S. This process generally involves the following:

Clinical trials generally are conducted in three sequential phases, although they may overlap or be combined.

The results of the preclinical and clinical testing, along with information regarding the manufacturing of the product and proposed product labeling, are evaluated and, if determined appropriate, submitted to the FDA through a BLA. Once the BLA submission has been accepted for filing, the FDA’s standard goal is to review applications within ten months of the filing date or, if the application relates to a drug that treats a serious condition and would provide a significant improvement in safety or effectiveness qualifying for Priority Review, six months from the filing date. The review process is often significantly extended by FDA requests for additional information or clarification.

The FDA offers certain programs, such as Breakthrough Designation (“BTD”) and Fast Track designation, designed to expedite the development and review of applications for products intended for the treatment of a serious or life-threatening disease or condition. For BTD, preliminary clinical evidence of the product indicates that it may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. The FDA may initiate review of sections of a BLA before the application is complete, and the product may be eligible for accelerated approval. However, receipt of BTD or Fast Track designation does not ensure that a product will be developed or approved on an expedited basis, or at all.

The FDA reviews the BLA to determine, among other things, whether the proposed product is safe, pure and potent, which includes determining whether it is effective for its intended use, and whether the product is being manufactured in accordance with cGMP, to assure and preserve the product’s identity, strength, quality, potency and purity. The FDA may refer an application to an advisory committee for review, evaluation and recommendation as to whether the application should be approved, and applications for new molecular entities and original BLAs are generally discussed at advisory committee meetings unless the FDA determines that this type of consultation is not needed under the circumstances.

After the FDA evaluates the BLA and conducts inspections of manufacturing facilities, it may issue an approval letter or a complete response letter (“CRL”). An approval letter authorizes commercial marketing of the biologic with specific prescribing information for specific indications. A CRL indicates that the review cycle of the application is complete, but the FDA cannot grant approval. A CRL may require additional inspections, and/or other significant, expensive and time-consuming requirements related to clinical trials, preclinical studies or manufacturing. The FDA could approve the BLA with a Risk Evaluation and Mitigation Strategy (“REMS”) to mitigate risks, which could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling, development of adequate controls and specifications, or a commitment to conduct one or more post-market studies or clinical trials. Such post-market testing may include Phase 4 clinical trials and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

Post-Approval Requirements

Any products manufactured or distributed by us or on our behalf pursuant to FDA approvals are subject to continuing regulation by the FDA and certain state agencies, including requirements for record-keeping, reporting of adverse experiences with the biologic, submitting biological product deviation reports to notify the FDA of unanticipated changes in distributed products, establishment registration, compliance with cGMP standards, and certain state licensing requirements.

Additionally, any significant change in the approved product or in how it is manufactured, including changes in formulation or the site of manufacture, generally require prior FDA approval. The packaging and labeling of all products developed by us are also subject to FDA approval and ongoing regulation. Noncompliance with any regulatory requirements can result in, among other things, issuance of warning letters, civil and criminal penalties, seizures, and injunctive action. Accordingly, manufacturers must continue to maintain compliance with cGMP and other aspects of regulatory compliance. The commercial distribution of prescription drugs is subject to the Drug Supply Chain Security Act (“DSCSA”), which regulates the distribution of the products at the federal level and sets certain standards for federal or state registration and compliance of entities in the supply chain.

The DSCSA preempts certain previously enacted state laws and the pedigree requirements of the Prescription Drug Marketing Act (“PDMA”). Trading partners within the drug supply chain must now ensure certain product tracing requirements are met, and are required to exchange transaction information, transaction history, and transaction statements. Product identifier information (an aspect of the product tracing scheme) is also now required. The DSCSA requirements, development of standards, and the system for product tracing have been and will continue to be phased in over a period of years through 2023. In addition to new legislation, FDA regulations, guidance documents, and policies are often revised or reinterpreted by the agency in ways that may significantly affect our business and our product candidates.

Orphan Drug Act

We have received Orphan Drug designation for Iomab-B and Actimab-A for patients with AML. Under the Orphan Drug Act, FDA may grant Orphan Drug designation to drugs intended to treat a rare disease or condition, which is generally defined as a disease or condition that affects fewer than 200,000 individuals in the U.S. Orphan Drug designation must be requested before submitting a BLA. In the U.S., Orphan Drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages, and user-fee waivers. Orphan Drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process. The first BLA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA Orphan Drug designation is entitled to a seven-year exclusive marketing period in the U.S. for that product, for that indication. During the seven-year exclusivity period, FDA may not approve any other applications to market the same drug for the same orphan indication, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or where the manufacturer of the approved product cannot assure sufficient quantities. As a result, there can be no assurance that our competitors will not receive approval of drugs or biologics that have a different active ingredient for treatment of the diseases for which our products and product candidates are targeted.

Pediatric Information

Under the Pediatric Research Equity Act (“PREA”), certain BLAs must contain data to assess the safety and efficacy of the drug or biologic for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The Food and Drug Administration Safety and Innovation Act (“FDASIA”), amended the FDCA to require that a sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan (“PSP”) within 60 days of an end of Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 study. The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver. The FDA may grant deferrals for submission of pediatric data or full or partial waivers. A sponsor can submit amendments to an initial PSP if changes to the pediatric plan need to be considered based on preclinical data collected, early phase clinical trials as well as other clinical development programs.

Foreign Regulation

In addition to regulations in the U.S., we are subject to foreign regulations governing clinical trials and commercial sales and distribution of our product candidates, and products being marketed outside of the U.S. We must obtain approval by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of our products in those countries. The approval process varies from country to country, and the time may be longer or shorter than required by the FDA for BLA licensure. The requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from country to country. As in the U.S., we are subject to post-approval regulatory requirements.

Other Regulatory Considerations

We are also subject to regulation under the Occupational Safety and Health Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act, The Clean Air Act, and other current and potential future federal, state, or local regulations. Our research and development activities involve the controlled use of hazardous materials, chemicals, biological materials and various radioactive compounds. We believe that our procedures comply with the standards prescribed by state and federal regulations; however, the risk of injury or accidental contamination cannot be completely eliminated. We may also be subject to healthcare regulation and enforcement by the federal government and the states and foreign governments where we may market our products and product candidates, if approved. These laws and regulations include, without limitation, state and federal anti-kickback, fraud and abuse, false claims, data privacy and security, aggregate spend reporting, and product price advertising.

The federal Anti-Kickback Statute, which prohibits, among other things, persons and entities including pharmaceutical manufacturers from knowingly and willfully soliciting, receiving, offering or paying remuneration, directly or indirectly, overtly or covertly, in case or in kind, to induce or reward, or in return for, or either the referral of an individual for, or the purchase, lease or order or recommendation of an item or service reimbursable, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs. The failure to meet all of the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the federal Anti-Kickback Statute. Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all of its facts and circumstances.

In addition, Patient Protection and Affordable Care Act of 2010, as amended (“ACA”) codified as law that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act (“FCA”). The FCA prohibits individuals or entities from, among other things, knowingly presenting or causing the presentation of a claims for payment to, or approval by, the federal government that are false, fictitious or fraudulent, or knowingly making, using or causing to be made or used, a false record or statement material to a false or fraudulent claim to avoid, decrease or conceal an obligation to pay money to the federal government. Our activities relating to the reporting of wholesaler or estimated retail prices for products we may commercialize in the future, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state and third-party reimbursement for products we may commercialize in the future, and the sale and marketing of products we may commercialize in the future, will be subject to scrutiny under the FCA. State statutes and regulations equivalent or substantially similar to the federal laws may extend to items and services reimbursed by commercial insurers and/or by patients directly. State law equivalents to the Anti-Kickback Statute and False Claims Act may not have adopted exceptions and safe harbors available at the federal level and therefore, may implicate a broader range of activities.

The Federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”) imposes criminal and civil liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud or obtain, by any means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third-party payors, and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. The federal physician payment transparency requirements, sometimes referred to as the “Physician Payments Sunshine Act,” created under the ACA, and its implementing regulations, which requires applicable manufacturers of covered drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the State Children’s Health Insurance Program (with certain exceptions) to annually report to the Department of Health and Human Services (“HHS”), information related to certain payments or other transfers of value made or distributed to physicians and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Under recent legislation, the Sunshine Act will extend to payments and transfers of value to physician assistants, nurse practitioners, and other mid-level healthcare providers. The Centers for Medicare and Medicaid Services (“CMS”) has the potential to impose penalties for violations of the Sunshine Act, depending on the circumstances, and payments reported under the Sunshine Act also have the potential to draw scrutiny on payments to and relationships with physicians and teaching hospitals, which may have implications under the Anti-Kickback Statute and other healthcare laws.

We may also be subject to data privacy and security regulation by both the federal government and the state governments in which we conduct our business. HIPAA, as amended by the Health Information Technology and Clinical Health Act of 2009 (“HITECH”) and their respective implementing regulations, imposes, among other things, obligations, including mandatory contractual terms with respect to safeguarding the privacy, security and transmission of individually identifiable health information held by certain healthcare providers, health plans and healthcare clearinghouses, known as covered entities, and business associates. The HHS Office of Civil Rights (“OCR”) has increased its focus on compliance and continues to train state attorneys general for enforcement purposes. Even where HIPAA does not apply, according to the U.S. Federal Trade Commission (“FTC”), failing to take appropriate steps to keep consumers’ personal information secure constitutes unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act (“FTCA”), 15 U.S. Code §45(a). Medical data is considered sensitive data that merits stronger safeguards. There are numerous other laws and legislative and regulatory initiatives at the federal and state levels addressing privacy and security concerns, and some state privacy laws apply in broader circumstances than HIPAA.

We are subject to the U.S. Foreign Corrupt Practices Act (“FCPA”), which prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity. Our present and future business has been and will continue to be subject to various other laws and regulations.

Human Capital

As of March 28, 2025, we had 37 full-time employees, 22 of whom have Ph.D. or M.D. degrees and 22 of whom are engaged in research and development and clinical development activities. We believe that we have been successful to date in attracting skilled and experienced personnel despite the competitive hiring marketing in the industry. Our employees are not covered by a collective bargaining agreement, and we believe that our relationship with our employees is excellent. We continue to engage external consultants on an as-needed basis to temporarily supplement existing staff.

Corporate Information

We were incorporated under the laws of the State of Delaware in 2013. Our principal executive offices are located at 100 Park Avenue, New York, NY 10017, and our telephone number is (646) 677-3870. Our website address is www.actiniumpharma.com. The information contained on our website or that can be accessed through our website is not considered part of this report.

We make available free of charge through our website our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, and any such amendments to those reports as soon as reasonably practicable after we electronically file such material with or furnish such material to the Securities and Exchange Commission (“SEC”). The SEC maintains a website at http://www.sec.gov that contains reports, proxy and information statements and other information regarding companies that file electronically with the SEC.