On March 20, 2019 Actinium Pharmaceuticals, Inc. (NYSE American: ATNM), reported that preclinical data from the novel combination of its CD33 ARC or Antibody Radiation-Conjugate Actimab-A (lintzumab-Ac-225) with venetoclax has been accepted for poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper), or AACR (Free AACR Whitepaper), Annual Meeting 2019 (Press release, Actinium Pharmaceuticals, MAR 20, 2019, View Source [SID1234534505]). The data to be presented builds on research by Actinium that demonstrated a synergy between Actimab-A and venetoclax, which resulted in greater cancer cell killing. This research supported the initiation of a Phase 1/2 doublet clinical trial studying Actimab-A and venetoclax and a planned Phase 1/2 triplet combination trial of Actimab-A and venetoclax with a hypomethylating agent, both for patients with relapsed or refractory AML or Acute Myeloid Leukemia. Actinium is conducting these trials with the goal of improving outcomes for patients with the addition of Actimab-A to address patients who do not respond, have suboptimal responses, no longer respond and patients who relapse after treatment with venetoclax.
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Venetoclax is a BCL-2 or B-Cell Lymphoma 2 inhibitor jointly developed and marketed by AbbVie and Genentech. BCL-2 is one of several proteins encoded by the BCL2 gene that regulates apoptosis or programmed cell death. MCL-1 is another protein encoded by the BCL2 gene that has been found to be overexpressed in relapsed or refractory AML patients, that prevents apoptosis and promotes resistance to venetoclax which does not bind to MCL-1. It has been observed that MCL-1 levels can be depleted with radiation, but only external radiation was used in these studies. Actinium believes that the targeted internalized radiation from Actimab-A can more effectively deplete MCL-1 levels thereby removing the AML cells’ resistance mechanism and rendering them more susceptible to venetoclax. Actinium has filed a patent on the combination of a targeted alpha-emitting therapeutic such as Actimab-A together with a BCL-2 inhibitor, which includes venetoclax, as a method to treat cancer. The details on Actinium’s poster are as follows:
Title: 225Ac-CD33 Radioimmunotherapy potently increases the sensitivity of resistant acute myeloid leukemia lines to the Bcl-2 inhibitor venetoclax by mediating a reduction in cellular Mcl-1 levels
Session Category: Experimental and Molecular Therapeutics
Session Title: Drug Resistance 5
Session Date and Time: Tuesday Apr 2, 2019 1:00 PM – 5:00 PM
Location: Georgia World Congress Center, Exhibit Hall B, Poster Section 10
Poster Board Number: 13
Abstract Number: 3808
Dr. Dale Ludwig, Actinium’s Chief Scientific Officer said, "We are excited to present new data from this Actimab-A ARC and venetoclax combination to further support our recently initiated clinical study and prior work. We have high confidence in the mechanistic rationale of the Actimab-A and venetoclax combination and are encouraged by the results we have seen thus far. With radiation being used in the treatment of up to 60% of cancer patients and a growing body of literature supporting the synergies of radiation therapy with other modalities, we are motivated to capitalize on numerous opportunities that can leverage our AWE or Antibody Warhead Enabling technology platform to exploit radiation’s synergistic effects. Indeed, our AWE technology platform is a tool for innovation that has the potential to expand our pipeline and facilitate collaborations and partnerships."
Actimab-A delivers the potent alpha-particle emitting radioisotope Ac-225 or Actinium-225 to cells with the CD33 antigen, which is expressed in the vast majority of patients with AML, MDS or Myelodysplastic Syndrome, and 25-35% of patients with Multiple Myeloma, or MM. Venetoclax is a BCL-2 or B-Cell Lymphoma 2 inhibitor that is jointly developed and marketed by AbbVie and Genentech that is approved for patients with AML, Chronic Lymphocytic Leukemia, and Small Lymphocytic Leukemia. Actinium has initiated a Phase 1/2 trial that is studying Actimab-A in combination with venetoclax for patients with relapsed or refractory AML and is planning a Phase 1/2 trial that is expected to study Actimab-A and venetoclax with a hypomethylating agent also for patients with relapsed or refractory AML.
Dr. Mark Berger, Actinium’s Chief Medical Officer said, "Our Actimab-A venetoclax combination trials are a strategic priority within our CD33 program that demonstrate our ability to rapidly translate research from our AWE technology platform to our clinical pipeline. Our preclinical data demonstrating a synergy between targeted radiation from Actimab-A and venetoclax, together with Actimab-A’s single agent activity and minimal extramedullary toxicities was well received by investigators, allowing us to develop two distinct clinical trials with this novel combination. As a result, we have created multiple opportunities to advance the treatment of patients with unmet needs with our ARC approach."