On December 9, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium") presented new findings from its pivotal Phase 3 SIERRA trial for Iomab-B (Iodine-131 apamistamab) at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting on Sunday, December 8, 2019 in a poster presentation (Press release, Actinium Pharmaceuticals, DEC 9, 2019, View Source [SID1234552093]). Actinium is advancing the development of low dose Iodine-131 apamistamab, a CD45 targeting antibody radiation-conjugate (ARC), as an alternative to today’s standard practice of chemotherapy-based lymphodepletion regimens like fludarabine/cyclophosphamide (Flu/Cy), which have been implicated in CAR-T toxicities including cytokine release syndrome (CRS) and neurotoxicity.
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The analysis of dosimetric results with Iomab-B in the pivotal Phase 3 SIERRA trial was conducted to model a non-myeloablative dose level to be used for lymphodepletion prior to CAR-T, as well as the time frame in which an adoptive cell therapy such as CAR-T could be administered. Based on the results from 56 evaluable patients that received a dosimetric dose of Iodine-131 apamistamab, including patients initially randomized to receive Iomab-B and those that received Iomab-B upon crossover from the control arm, it was determined that a single 75 mCi dosage of Iodine-131 apamistamab would deliver approximately 200 cGy to the bone marrow, the threshold that is considered non-myeloablative. At this dose level, it expected that an adoptive cell therapy could be administered approximately six days following Iomab-ACT lymphodepletion. Actinium intends to advance its Iomab-ACT program into human proof-of-concept clinical trials in conjunction with an adoptive cell therapy. The poster can be accessed on Actinium’s investor relations page of its website HERE.
Key findings presented in the poster include:
At fractional dose levels of Iodine-131 apamistamab (median 10mCi) used for dosimetry analysis in the SIERRA trial, approximately 1/10 of the targeted lymphodepletion dose, a significant but transient reduction in lymphocytes and white blood cells was observed compared to pre-dosimetry infusion levels
85% reduction in lymphocytes was observed at the post-dosimetry infusion time point, a 67% decrease at day 1 post-dosimetric infusion, and a 43% decrease one week later just prior to the Iomab-B therapeutic infusion, demonstrating potent yet reversible lymphodepletion at this dose level
35% reduction in peripheral leukemic blasts was observed at the post-dosimetry infusion time point, suggesting a rapid anti-leukemic effect with single-agent Iodine-131 apamistamab consistent with findings from SIERRA presented at ASCO (Free ASCO Whitepaper) 2019
The levels of platelets, red blood cells, and neutrophils did not significantly change between pre-infusion and post-dosimetry infusion
Based on the analysis of the 56 treated patients, a non-myeloablative dosage of 75 mCi has been proposed as a starting dose for human clinical testing in combination with a CAR-T
Analysis of the dosimetry data establishes that the proposed 75 mCi dosage of Iodine-131 apamistamab would be sufficiently cleared in approximately 147 hours (6.1 days) to allow for CAR-T administration
Dale Ludwig, Ph.D., Actinium’s Chief Scientific Officer, said, "CAR-T, adoptive cell therapy, and gene therapy are revolutionary medical advances with great promise. However, despite the innovation in these technologies, they continue to rely on generic chemotherapies for the necessary pre-conditioning prior to their administration, which are non-targeted and toxic. We believe this restricts the true potential of these therapies by hindering their efficacy and durability while increasing toxicities such as cytokine release syndrome and neurotoxicity. With a starting clinical dose and time to clearance defined and supported by clinical results from the SIERRA trial, we look forward to our next step of advancing this program into human clinical testing with a cell therapy while continuing to introduce the Iomab-ACT program to cell and gene therapy developers."
About the Iomab-ACT program
Iomab-ACT is a lower dose of Actinium’s lead program Iomab-B, which has been studied in over 300 patients and is currently being investigated in a pivotal Phase 3 trial for targeted conditioning prior to a Bone Marrow Transplant (BMT). Iomab-ACT targets CD45, an antigen expressed on many of the cells that are relevant to CAR-T including lymphocytes, macrophages and regulatory T-cells and that have been associated with CAR-T challenges such as durability of response, cytokine release syndrome (CRS) and neurotoxicity. Actinium has generated preclinical data that targeted lymphodepletion via Iomab-ACT has the potential to improve tumor control, selectively deplete necessary cells, and be highly differentiated in terms of tolerability compared to chemotherapy-based lymphodepletion regimens, namely fludarabine/cyclophosphamide (Flu/Cy). The Iomab-ACT program may enable lymphodepletion through a single-dose outpatient administration versus Flu/Cy or other chemo-based lymphodepletion regimens that require multiple infusions in an inpatient setting over several days.