On January 5, 2021 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of targeted radiotherapies for patients with unmet needs and EpicentRx, Inc. ("EpicentRx"), a San Diego-based clinical cancer immunotherapy company reported that they have entered into a research collaboration to study Actinium’s Actimab-A targeted radiotherapy in combination with RRx-001, EpicentRx’s novel small molecule immunotherapy targeting the CD47-SIRPα axis (Press release, Actinium Pharmaceuticals, JAN 5, 2022, View Source [SID1234598257]). Under this strategic research collaboration, the two companies will work to determine the benefit of combining Actinium’s targeted radiotherapy with EpicentRx’s RRx-001, which are both clinical stage drug candidates, in acute myeloid leukemia (AML).
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CD47 is a macrophage checkpoint upregulated in certain cancers that acts as a "don’t eat me" signal on cancer cells to suppress phagocytosis and evade detection and destruction by the immune system. EpicentRx’s RRx-001, currently under investigation in a Phase 3 trial for Small Cell Lung Cancer and in other oncology and non-oncology indications, is a versatile next generation small molecule immunotherapeutic that targets the CD47-SIRPα axis and the NLRP3 inflammasome to alter the tumor microenvironment and optimize immune response. Actinium’s targeted radiotherapies have shown the ability to upregulate the cell surface "eat me" signal calreticulin, which can result in anti-tumor immune response. This collaboration will explore the mechanistic synergy of RRx-001’s CD47–SIRPα downregulation with Actinium’s targeted radiotherapy calreticulin upregulation to increase the immune detection and destruction of cancer cells and their potential to improve patient outcomes.
Actinium recently presented data (Link here) at the 36th Annual Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) in solid tumor and blood cancer models showing that combining targeted radiotherapy with the anti-CD47 antibody magrolimab resulted in an increase in the pro-phagocytic signal calreticulin and an enhanced innate anti-tumor immune response leading to improved tumor burden and survival outcomes in tumor models.
Actinium’s clinical pipeline of targeted radiotherapies, referred to as Antibody Radiation-Conjugates (ARCs), includes Iomab-B and Actimab-A. Collectively, Actinium’s ARCs have been studied in nearly 600 patients at leading comprehensive cancer centers including the pivotal Phase 3 SIERRA trial for Iomab-B, which completed patient enrollment in September 2021. Actimab-A has been studied extensively as a single agent and in combination with chemotherapy and targeted agents in approximately 150 patients with AML in Phase 1 and 2 trials. Underpinning Actinium’s clinical pipeline is its AWE technology platform, which applies Actinium’s extensive intellectual property portfolio of over 160 issued and pending patents, R&D capabilities and know-how to the development of targeted radiotherapies exploiting multiple different radioisotope payloads including the potent alpha-emitter, Actinium-225. Actinium’s R&D efforts employ a multidisciplinary approach leveraging its team’s expertise and experience in cancer cell biology, radiochemistry, radiation sciences, immunology and oncology drug development. Actinium has utilized its AWE technology platform to create a CD38 targeting ARC using the blockbuster myeloma antibody daratumumab (Darzalex) and it is also being utilized in collaboration with Astellas Pharma, to create theranostics for solid tumors.
"We are excited to begin this collaboration with EpicentRx as RRx-001 is a highly novel agent that is differentiated from other CD47-SIRPα axis targeting agents, given its multi-modal mechanism of action. As we recently demonstrated at SITC (Free SITC Whitepaper), our R&D efforts have focused on innovative approaches to developing targeted radiotherapy combinations with other therapeutic modalities. When CD47 emerged as a promising immunotherapy target, we quickly worked to explore potential synergies and we are excited that our experiments have demonstrated that targeted radiotherapies not only exert a direct cell killing effect, they also can upregulate calreticulin, a pro-phagocytic signal, resulting in an enhanced anti-tumor immune response. These efforts have also resulted in new intellectual property that we believe will be valuable as we continue our advancement in this field. This collaboration also leverages our extensive clinical experience with Actimab-A, which has produced high rates of remissions and minimal residual disease negativity in patients with AML. With potential synergy and non-overlapping mechanisms of actions, we look forward to generating data from this collaboration and advancing this potentially transformational combination together with EpicentRx", said Sandesh Seth, Chairman and CEO of Actinium.
As the flagship of EpicentRx’s CyNRGYTM platform, RRx-001 is a first-in-class investigational treatment sourced from an exclusively licensed portfolio of aerospace-derived small molecules. It is a hypoxia activated prodrug with antioxidant and anti-inflammatory properties in oxygenated healthy tissues through its inhibition of the NLRP3 inflammasome. Under hypoxic conditions, however, which is a hallmark of tumors, RRx-001 fragments, generating immunostimulatory and radiation-sensitizing activities. This hypoxia-triggered 2-stage mechanism places RRx-001 in a class of its own.
"AML’s pervasive resistance to treatment requires strategic collaborations and combinations of treatment to increase the likelihood of a good outcome. We are excited to begin this collaboration with Actinium, a company with whom we have good chemistry. As a radiosensitizer which antagonizes CD47, RRx-001 should pair well with Actinium’s ARC. This combination is a recipe for success," said Tony R. Reid, M.D., Ph.D., Chief Executive Officer of EpicentRx."