Actinium Issue: On February 2023 during a Company Investor Web Conference, the company presented they met the trial endpoints (Slide 6 and the image presented in this update). On March 31, 2023, Actinium reported in the 10-K that they failed to meet the secondary endpoint of overall survival (OS). During the time between October 2022 and August 2024, Actinium continued to inform investors that a BLA would be filed, raised ~$39.8M from the Capital On Demand At-The-Market agreement with JonesTrading and B.Riley, and awarded 1.5M options awards to the board of directors at the end of 2023. Investor Relations representative left the company in October 2023. The CEO and CFO would not respond to investor inquires since March 2024. On July 1, 2024 (the end of 1H2024), there was no announcement made that the BLA had been submitted to the FDA and the Investor Presentation was taken down from the Actinium web site and replaced with "Coming Soon." On August 5, 2024, the company reported that the FDA said the SIERRA data was not adequate to support a BLA filing. Additional information obtained by Immedica (Actinium's partner) said they are planning to file a MAA in 2025; delayed from the original plan presented by Actinium that it would be filed in 2H2024.
FDA Issue: The FDA August 2024 recommendation to conduct an additional trial to determine overall survival is not ethical and does not meet the original intent to treat >55yr r/r AML patients that are ineligible to receive a bone marrow transplant. Because the new trial suggests no crossover, it is inhumane to patients and puts providers at risk for "failure to treat" the patient. The original reason for the crossover design in the SIERRA trial was to "rescue" patients and give providers a way to treat patients. This aligns with a providers ethical obligation to treat patients as well as give patients the "right to try" which meets the intent of the 2016 "Right to Try" Act. FDA AML Guidelines stated that dCR, OS, and EFS are acceptable endpoints for a BLA. Although Actinium reports they failed to meet the OS endpoint due to the crossover of patients "rescued" by Iomab-B, there is adequate data from the primary endpoint of dCR, secondary endpoint of EFS, and safety data to support Iomab-B BLA application for approval consideration. The FDA AML Guidelines state "It is common for multiple efficacy endpoints (i.e., OS, EFS, CR) to be assessed in a clinical trial for AML. The statistical analysis plan should prespecify a multiple testing strategy for important secondary endpoints that adjusts for multiplicity conditioned on demonstrating a positive outcome for the primary endpoint. Note that effects on secondary endpoints are generally not sufficient to support a marketing application in the absence of demonstration of an effect on the prespecified primary endpoint. Additionally, even if an effect on a secondary endpoint is demonstrated, it may not be acceptable for labeling if it is not an established efficacy endpoint." In the SIERRA trial, it was clear that patients that achieved the primary endpoint of dCR survived longer than the control.
References:
December 17, 2015, Actinium "agree[ed] with the FDA that the path to a BLA submission...include a single, pivotal Phase 3 clinical study if it is successful. Primary endpoint dCR and secondary endpoint OS."
August 18, 2018, Actinium decided to conduct the crossover to "rescue" patients with Iomab-B during the SIERRA trial. The crossover arm was designed in SIERRA for an equipoise that offered Iomab-B to patients failing to achieve a CR on the control arm with an intent to rescue them by taking them to transplant. Actinium made "certain protocol revisions to further expand salvage regimens in the control arm. We'll also be making it easier for patients on the Conventional Care arm who have disease progression to access Iomab-B treatment." Sandesh Seth, Actinium's Chairman and CEO added, "Iomab-B is a very compelling drug candidate that has been studied in over 500 patients in multiple hematologic malignancies including AML, myelodysplastic syndrome, lymphoma, and multiple myeloma and is intended to facilitate a potentially curative bone marrow transplant."
October 2022, The FDA published Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment Guidance for Industry. The guidance states durable Complete Remission (dCR) is an acceptable endpoint for the treatment of AML with palliative intent and overall survival (OS) and event-free survival (EFS) are acceptable endpoints for thetreatment of AML with curative/non-curative intent. https://www.fda.gov/media/162362/download
October 31, 2022, Actinium Announces Positive Top-line Results from Pivotal Phase 3 SIERRA Trial of Iomab-B in Patients with Active Relapsed or Refractory Acute Myeloid Leukemia. Iomab-B met the primary endpoint of durable complete remission of 6-months following initial complete remission after HCT with a p-value of <0.0001
https://ir.actiniumpharma.com/press-releases/detail/428/actinium-announces-positive-top-line-results-from-pivotal
February 18, 2023, Actinium presents to investors. On slide 6, SIERRA: Positive Efficacy, Safety, and Long-Term Outcomes in R/R AML, Actinium shows that the primary and secondary endpoints were met with a "check"
Dr. Sergio Giralt, Deputy Head, Division of Hematologic Malignancies, Attending Physician, Adult BMT Service at Memorial Sloan Kettering Cancer Center, stated, "The SIERRA trial results are an exciting advancement for older patients with active r/r AML and will be practice changing in how we treat these patients. I am thrilled to see a high percentage of Iomab-B patients who achieved durable remissions reaching the critical 2-year survival mark. Significant improvement in event-free survival and overall survival, with an excellent safety profile in the SIERRA trial, demonstrate the potential of Iomab-B becoming a new standard of care for active, r/r AML."
https://d1io3yog0oux5.cloudfront.net/_19aa525aa30da9f072ecb2367dfa6e7e/actiniumpharma/db/206/1110/pdf/Actinium_SIERRA_Data_Webcast_vFINAL_02.18.2023.pptx+for+webinar.pdf
March 31, 2023, Actinium reports in 10-K, "median OS in the Iomab-B arm was similar to that in the control arm and this secondary endpoint was not met in the ITT analysis" As a result of the crossover, the overall survival data was "confounded" by those in the control arm who received Iomab-B and caused the OS secondary endpoint to not be met. An exploratory endpoint separated the Iomab-B, Iomab-B cross over, and remaining control arm overall survival data. This showed Iomab-B doubled overall survival at 1-yr. Actinium also reported "We are actively working to launch an [Early Access Program] and successfully file a BLA in the second half of 2023, and if approved, we anticipate the commercial launch for Iomab-B in 2024." https://ir.actiniumpharma.com/annual-reports/content/0001213900-23-025597/f10k2022_actiniumph.htm?TB_iframe=true&height=auto&width=auto&preload=false
August 14, 2023, Actinium reports we are actively working on launching an early access program (“EAP”) for Iomab-B. We are also working towards completing and submitting our Biologics License Application (“BLA”) for Iomab-B to the FDA by the end of 2023 and if approved, we intend to commercialize Iomab-B in the U.S. https://ir.actiniumpharma.com/quarterly-reports/content/0001213900-23-067199/f10q0623_actiniumphar.htm?TB_iframe=true&height=auto&width=auto&preload=false
November 2, 2023, "be in a position to submit a BLA filing in the first half of 2024. The Early Access Program for Iomab-B is also anticipated to start post completion of these activities." https://ir.actiniumpharma.com/quarterly-reports/content/0001213900-23-082459/f10q0923_actiniumphar.htm?TB_iframe=true&height=auto&width=auto&preload=false
March 2024, the CEO and CFO are informed of concerns that the stock is being manipulated allegedly by a third-party formerly associated with the CEO. As a result, a SEC Investigation and FBI "white collar" investigation tip are submitted regarding stock manipulation and insider trading.
April 26, 2024, "have been assigned a BLA number. We have also submitted a meeting request with the FDA to continue to discuss the clinical and non-clinical sections of our BLA package prior to submitting our BLA filing and we continue to expect to hold this meeting in the second quarter of 2024." https://ir.actiniumpharma.com/quarterly-reports/content/0001213900-24-036699/ea0203758-10q_actinium.htm?TB_iframe=true&height=auto&width=auto&preload=false
July 1, 2024, Investor Presentation is taken down and replaced with "Coming Soon". There is no information to shareholders regarding BLA filing in the first half of 2024.
August 5, 2024, "FDA determined that the Phase 3 SIERRA trial is not adequate to support a BLA filing for Iomab-B despite its statistically significant primary endpoint" and recommended a new overall survival trial without a crossover. https://ir.actiniumpharma.com/press-releases/detail/486/actinium-provides-regulatory-update-on-planned-bla-filing