Actinium Pharmaceuticals, Inc. (NYSE American: ATNM) is a biopharmaceutical company developing innovative targeted radiotherapies to deliver cancer-killing radiation with cellular level precision to treat patients with high unmet medical needs. The company's pipeline is anchored by two late-stage product candidates, Iomab-B and Actimab-A, which are focused on addressing the major unmet medical needs in relapsed or refractory acute myeloid leukemia (r/r AML), a disease with dismal prognosis and limited treatment options.
Actinium's lead product candidate, Iomab-B, is a targeted antibody-radiation conjugate (ARC) that combines the anti-CD45 monoclonal antibody apamistamab with the radioisotope iodine-131 (I-131). Iomab-B has demonstrated the ability to enable bone marrow transplant (BMT), the only potentially curative treatment option, in patients with r/r AML who are ineligible for transplant with current standard of care. In the pivotal Phase 3 SIERRA trial, Iomab-B met the primary endpoint of durable complete remission (dCR) with high statistical significance (p<0.0001) and also showed a significant improvement in overall survival (OS) compared to the control arm.
Actimab-A, the company's second late-stage product candidate, is an ARC comprised of the anti-CD33 antibody lintuzumab linked to the alpha-emitting radioisotope actinium-225 (Ac-225). Actimab-A is being developed in combination with chemotherapy regimens to treat r/r AML patients. In a Phase 1 trial, the Actimab-A + CLAG-M combination demonstrated high response rates, including complete remission, and a meaningful survival benefit in this difficult-to-treat patient population.
Actinium's pipeline also includes Iomab-ACT, a targeted conditioning program for cell and gene therapies that utilizes a lower dose of I-131 to achieve lymphodepletion prior to administration of these transformative treatments. Early clinical data has shown Iomab-ACT to be well-tolerated with minimal non-hematologic toxicities.
Business Overview
Actinium is deploying its industry-leading technology platform and intellectual property portfolio, which includes over 235 issued and pending patents worldwide, to develop a pipeline of ARCs and next-generation targeted radiotherapies. The company's focus is on addressing high unmet medical needs in hematology and oncology, with a particular emphasis on r/r AML, where its product candidates have the potential to transform patient outcomes.
Iomab-B: Enabling Bone Marrow Transplant in Unfit Patients
Iomab-B is a first-in-class ARC that has the potential to establish a new standard of care for preparing patients with r/r AML for a BMT, the only potentially curative treatment option. The SIERRA trial was a 153-patient, randomized, controlled Phase 3 study that compared outcomes of patients who received Iomab-B and a BMT to those receiving physician's choice of salvage chemotherapy.
The SIERRA trial met its primary endpoint, demonstrating a dCR rate of 22% in the Iomab-B arm compared to 0% in the control arm (p<0.0001). Importantly, Iomab-B enabled a significantly higher proportion of patients to proceed to a potentially curative BMT compared to the control arm (68% vs. 35%). Additionally, the Iomab-B arm showed a doubling of median overall survival compared to the control arm (6.4 months vs. 3.2 months).
These results highlight Iomab-B's potential to transform the treatment of r/r AML by enabling access to BMT, the only potentially curative option, for a patient population that is typically considered ineligible. Iomab-B's targeted delivery of high-dose radiation directly to the bone marrow allows for effective disease control and conditioning in a single agent, overcoming the challenges associated with the current standard of care.
Actimab-A: Combination Backbone Therapy for Relapsed/Refractory AML
Actimab-A is an ARC comprised of the anti-CD33 antibody lintuzumab linked to the alpha-emitting radioisotope Ac-225. Actimab-A is being developed in combination with chemotherapy regimens to treat r/r AML patients. In a Phase 1 trial, the Actimab-A + CLAG-M combination demonstrated a 65% overall response rate, a 52% complete remission rate, and a 75% minimal residual disease (MRD) negativity rate. Importantly, these responses translated into a meaningful survival benefit, with 1-year and 2-year overall survival rates of 53% and 32%, respectively, in this difficult-to-treat patient population.
The Actimab-A + CLAG-M combination has shown the potential to significantly improve outcomes in r/r AML patients, including those who have failed prior venetoclax-based therapy, a population with dismal prognosis. On September 6, 2023, updated data from the Actimab-A + CLAG-M combination trial was presented at the Society of Hematologic Oncology (SOHO) Annual Meeting, where 1-year overall survival for patients with prior venetoclax treatment was 46% and 48% in all patients receiving the combination.
Actinium has entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI) to further develop Actimab-A, which is expected to accelerate the program's advancement. Under the CRADA, the NCI will serve as the regulatory sponsor for any clinical trials evaluating Actimab-A, providing extensive support and resources to Actinium's development efforts.
Iomab-ACT: Targeted Conditioning for Cell and Gene Therapies
Iomab-ACT is Actinium's next-generation conditioning program designed to improve outcomes for patients receiving cell and gene therapies. Iomab-ACT utilizes a lower, non-myeloablative dose of I-131 to achieve targeted lymphodepletion prior to the administration of these transformative treatments.
Early clinical data has shown Iomab-ACT to be well-tolerated, with no patients developing the severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) that are common side effects of current lymphodepletion regimens. Iomab-ACT has also demonstrated the ability to achieve transient depletion of peripheral blood lymphocytes and monocytes, which are key contributors to these toxicities.
In April 2024, Actinium announced an Investigational New Drug (IND) application for a new clinical trial that will evaluate Iomab-ACT as targeted conditioning prior to patients receiving an FDA-approved commercial CAR-T therapy. This trial will be the first to study a targeted radiotherapy conditioning agent with a commercial cell therapy product, potentially demonstrating Iomab-ACT's ability to improve outcomes for patients receiving these transformative treatments.
Financials
For the three months ended March 31, 2024, Actinium reported no revenue and a net loss of $8.7 million, compared to no revenue and a net loss of $11.0 million in the prior-year period. The decrease in net loss was primarily due to lower research and development expenses, lower general and administrative expenses, and higher interest income.
As of March 31, 2024, the company had $84.1 million in cash and cash equivalents, compared to $76.7 million as of December 31, 2023. The increase in cash was primarily due to $14.7 million in net proceeds from the sale of common stock under the company's At-the-Market (ATM) offering program, partially offset by $7.4 million in net cash used in operating activities.
For the full year 2023, Actinium reported annual net income of -$48.8 million, annual revenue of $81,000, annual operating cash flow of -$47.3 million, and annual free cash flow of -$47.5 million.
Regulatory and Commercial Outlook
Actinium is advancing its regulatory strategy for Iomab-B, its lead product candidate. The company has conducted a successful meeting with the U.S. Food and Drug Administration (FDA) and has been assigned a Biologics License Application (BLA) number. Actinium expects to hold an additional meeting with the FDA in the second quarter of 2024 to discuss the clinical and non-clinical sections of the BLA package prior to submission.
In parallel, Actinium's commercial partner, Immedica Pharma AB, is progressing the Marketing Authorization Application (MAA) for Iomab-B in the European Union, Middle East, and North Africa (EUMENA) region. Immedica has conducted meetings with the European Medicines Agency (EMA) to review the SIERRA trial data and is now proceeding with the MAA filing.
Based on the current timeline, Actinium believes it may be able to receive regulatory approval for Iomab-B in both the U.S. and Europe in 2025. The company is committed to working to bring Iomab-B to patients globally, as there is a significant unmet need in r/r AML worldwide.
For Actimab-A, the company's collaboration with the NCI is expected to accelerate the development of this product candidate. The NCI will serve as the regulatory sponsor for any clinical trials evaluating Actimab-A, which will provide Actinium with substantial support and resources to advance the program.
Competitive Landscape and Market Opportunity
Actinium's product candidates, Iomab-B and Actimab-A, are focused on addressing the major unmet medical needs in r/r AML, a disease with a high unmet need and limited treatment options. The r/r AML segment comprises over 50% of all AML patients, and currently, less than 20% of these patients are able to access a potentially curative BMT.
Iomab-B has the potential to expand the BMT-eligible patient population from the current ~400 r/r AML patients per year in the U.S. to approximately 8,000 unfit patients who are currently not considered transplantable. In the EUMENA region, there are an estimated 7,200 BMTs performed annually for AML patients, representing a significant commercial opportunity for Iomab-B.
For Actimab-A, the addressable market is comparable to the prevalence of AML patients, which is approximately 70,000 in the U.S. and 27,500 in Europe. With its potential to improve outcomes in both newly diagnosed and r/r AML patients, Actimab-A has the opportunity to address a substantial patient population.
Beyond AML, Actinium's pipeline also includes opportunities to expand the use of Iomab-B in other hematological malignancies, such as myelodysplastic syndromes, acute lymphoblastic leukemia, Hodgkin's lymphoma, non-Hodgkin lymphoma, and multiple myeloma, where early data has demonstrated the potential to improve BMT access and outcomes.
Additionally, the rapidly growing cell and gene therapy market represents a significant opportunity for Actinium's Iomab-ACT program. The addressable patient population for cell and gene therapies is expected to nearly double and reach approximately 93,000 patients in the U.S. by 2030, and Iomab-ACT has the potential to improve the safety and efficacy of these transformative treatments.
Risks and Challenges
Actinium faces several risks and challenges common to the biopharmaceutical industry, including the inherent uncertainty of clinical development, regulatory approval, and commercialization. The company's success is highly dependent on the regulatory and commercial success of its lead product candidate, Iomab-B.
Additionally, Actinium relies on third-party manufacturers for the production of its product candidates, and any disruption in the supply chain or manufacturing capabilities could adversely impact the company's operations. The availability and cost of the radioisotopes used in Actinium's product candidates, such as I-131 and Ac-225, also represent potential risks that the company must manage.
The competitive landscape in the AML and cell/gene therapy markets is also evolving, and Actinium must continue to innovate and differentiate its product candidates to maintain a competitive advantage.
Conclusion
Actinium Pharmaceuticals is well-positioned to transform the treatment of AML with its innovative targeted radiotherapy pipeline. The positive results from the pivotal SIERRA trial for Iomab-B and the promising data for Actimab-A in combination with chemotherapy regimens demonstrate the potential of the company's ARC technology to significantly improve outcomes for patients with r/r AML, a disease with a high unmet need and limited treatment options.
With a robust intellectual property portfolio, a talented team, and a clear regulatory and commercial strategy, Actinium is poised to deliver on its mission of developing best-in-class radiotherapies that can meaningfully improve survival and access to potentially curative treatments for patients with high-risk cancers. As the company advances its pipeline and executes on its strategic priorities, Actinium represents a compelling investment opportunity in the rapidly evolving field of targeted radiotherapies.