Actinium Pharma (ATNM) Reports Successful Pre-Planned Ad Hoc Interim Analysis of Phase 3 SIERRA Trial

Actinium Pharmaceuticals, Inc. (NYSE: ATNM) today announced that the independent Data Monitoring Committee (DMC) has completed the single ad hoc interim analysis of the pivotal Phase 3 SIERRA study of Iomab-B for bone marrow transplant (BMT) conditioning in patients over the age of 55 with active relapsed or refractory Acute Myeloid Leukemia (R/R AML). The SIERRA trial is a randomized, controlled study evaluating outcomes of patients receiving Iomab-B and a BMT compared to outcomes of patients on the control arm who receive physician's choice of salvage therapies, including recently approved targeting agents such as venetoclax, who may proceed to BMT if they achieve a required complete remission (CR). Based on the DMC's review of unblinded data, including the study's primary endpoint of durable Complete Remission (dCR) of at least 180 days, it was recommended that the study continue as planned to full enrollment of 150 patients. Actinium did not receive the unblinded primary and secondary endpoint efficacy data from SIERRA.

A single ad hoc analysis was exercised by Actinium in April 2020 consistent with the study's design that allowed for up to two ad hoc analyses between 70 to 110 patients. This ad hoc analysis was exercised for a number of patients representing less than two thirds of anticipated final enrollment which required a higher success threshold compared to 100% of trial enrollment. With Actinium exercising only a single analysis, there was a minimal alpha spend resulting in a p-value threshold of 0.046 for the primary endpoint evaluation at full enrollment of 150 patients. The SIERRA trial is currently over 75% enrolled. Data from the first 75% of patients showing that 100% of patients receiving a therapeutic dose of Iomab-B proceeded to transplant and achieved engraftment compared to 16% of patients on the control arm was recently highlighted in an oral presentation at the American Society of Hematology Annual Meeting. A second oral presentation evaluated safety data showing lower rates of serious adverse events categories including sepsis, febrile neutropenia, mucositis and 100-day non-relapse transplant related mortality (TRM) in patients receiving Iomab-B and BMT compared to those on the control arm.

"We are encouraged by the DMC's recommendation to continue the SIERRA trial as planned and that there continues to be no safety concerns from the Iomab-B arm. All of us at Actinium are intensely focused on completing the final portion of patient enrollment in the SIERRA trial," said Dr. Mark Berger, Actinium's Chief Medical Officer. "The recent presentations at ASH highlight Iomab-B's value proposition to universally enable older patients with active relapsed or refractory AML to proceed to a potentially curative bone marrow transplant via a well-tolerated targeted conditioning regimen, which we believe will be a paradigm shift compared to current non-targeted chemotherapy regimens that restrict patient access to BMT. While we believed there was potential for early stoppage of the trial as a result of this ad hoc analysis, we note that the hurdle rate for early stoppage, given the smaller number of patients representing less than two thirds of full enrollment, was much higher for the ad hoc than what is now required at the final analysis of 150 total patients. With the large difference in the number of patients advancing to BMT with Iomab-B and those potentially evaluable for dCR compared to the control arm through seventy-five percent of enrollment, we remain strongly optimistic about the ultimate success of SIERRA. We look forward to capitalizing on the positive momentum resulting from ASH and from our recent senior personnel additions in medical affairs and clinical development in order to complete enrollment as quickly as possible in 2021."

SIERRA Safety and Feasibility at 75% Enrollment

Detailed safety and feasibility data from 75% of patient enrollment presented at the ASH 2020 Annual Meeting highlighted that 100% (49/49) of patients receiving a therapeutic dose of Iomab-B in SIERRA have successfully proceeded to BMT and achieved engraftment, the first sign of BMT success, without delay compared to 16% (9/56) of patients in the control arm who received physician's choice of salvage therapies. The control arm includes a wide range of salvage therapies, including targeted agents like venetoclax, as there is no standard of care in this setting. Of the 84% (47/56) of patients that did not achieve complete remission on the control arm, 64% (30/47) of patients crossed over to receive Iomab-B with 100% (30/30) of those patients successfully engrafting after BMT. In total, 78% (88/113) of patients enrolled on the SIERRA trial were able to receive a BMT despite this being a patient population not typically considered for BMT. At the 100-day post BMT time point, on an ITT basis, there were 43 patients from the Iomab-B study arm potentially evaluable for the primary endpoint of (dCR) at 180 days compared to 7 patients in the control arm. By this measure, 77 percent of patients in the Iomab-B arm are potentially eligible for the dCR primary endpoint compared to 12 percent of patients in the control arm, a greater than 6-times difference, which is consistent with results at the 25% and 50% interim feasibility and safety analyses.

Detailed SIERRA Safety Analysis

It was also highlighted in an oral presentation at the ASH 2020 Annual Meeting that high amounts of radiation are able to be targeted to the bone marrow compared to non-targeted organs with Iomab-B resulting in lower rates of sepsis and sepsis related Grade ≥3 adverse events. A median of 14.9 Gy (Range: 4.6 – 32) of radiation was delivered to the marrow compared to 2.8 Gy (Range: 1.6 – 6.7) of radiation to the gastrointestinal tract. In comparing rates of adverse events in patients receiving Iomab-B and a BMT (N=47) to patients receiving salvage therapy and a BMT (N=9), lower rates of sepsis 4.3% (2/47) vs. 33% (3/9), Grade 3 – 4 febrile neutropenia 34.8% (16/47) vs. 55.6% (5/9) and Grade 3 – 4 mucositis 10.9% (5/47) vs. 33% (3/9) were observed in patients receiving Iomab-B. This is consistent with the targeted nature of Iomab-B. Unlike chemotherapy, which harms the GI tract and leads to infection with enteric bacteria, Iomab-B therapy is associated with minimal damage to the GI tract leading to lower rates of serious infections.

The SIERRA trial is the only randomized Phase 3 trial to offer BMT as an option for patients over the age of 55 with active R/R AML. BMT remains the only therapeutic option with curative potential for this patient population. Iomab-B is intended to simultaneously be a targeted induction and conditioning agent that allows patients to proceed to BMT in days after receiving Iomab-B compared to current chemotherapy-based approaches that require a patient to first achieve a complete remission before proceeding to additional conditioning and a BMT.

Sandesh Seth, Actinium's Chairman and CEO said, "With more than 75% of patients for the SIERRA trial enrolled and positive data presented at ASH earlier this month, interest in the trial has never been stronger. We were excited to report a consistent 100% engraftment rate for patients receiving a therapeutic dose of Iomab-B in SIERRA compared to 16% of patients in the control arm who received physician's choice of salvage therapies. We remain confident in the value added by Iomab-B in getting patients to BMT and look forward to the completion of the trial. In addition to the promising results from Iomab-B, we are excited by the data emerging from across our pipeline including the Actimab-A CLAG-M and Actimab-A venetoclax combination trials in fit and unfit relapsed and refractory AML. The results of these combinations demonstrate the power of targeted radiotherapy and its potentiating and synergistic effects and we are excited to be developing two promising programs for indications that are not well addressed with current standard treatment options despite several recently approved therapies. With our strong balance sheet and growing team, we are excited and confident in our ability to execute on our vision and look forward to the several milestones expected for both these programs next year."

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