On August 30, 2021 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that it has entered into a sponsored research collaboration with Dana-Farber Cancer Institute (Dana-Farber) (Press release, SpringWorks Therapeutics, AUG 30, 2021, View Source [SID1234591665]). The collaboration is designed to further investigate nirogacestat, SpringWorks’ investigational gamma secretase inhibitor (GSI), with anti-B-cell maturation antigen (BCMA) agents in a variety of preclinical multiple myeloma models. Constantine Mitsiades, M.D., Ph.D., Assistant Professor of Medicine at Dana-Farber and Harvard Medical School, will serve as the Principal Investigator for the research, which will utilize preclinical in vivo models from the Mitsiades Lab to simulate the multiple myeloma tumor microenvironment. In addition, the research will also deploy functional genomics approaches to explore determinants of response and mechanisms of resistance to GSI + BCMA combination therapy.
Gamma secretase inhibition prevents the cleavage and shedding of BCMA from the surface of multiple myeloma cells. In preclinical models, nirogacestat has been shown to increase the cell surface density of BCMA and reduce levels of soluble BCMA, thereby enhancing the activity of BCMA-targeted therapies.1 To date, SpringWorks has entered into clinical collaborations with six industry partners to evaluate nirogacestat in combination with BCMA therapies across modalities.
"SpringWorks has demonstrated its commitment to understanding the science and advancing the clinical exploration of GSI + BCMA combination therapies," said Dr. Mitsiades. "I am pleased to collaborate with them towards the goal of improving clinical outcomes for patients with multiple myeloma while simultaneously enabling the advancement of the underlying science."
"We are delighted to be collaborating with the Mitsiades Lab at Dana-Farber to expand our understanding of nirogacestat’s mechanism of action when combined with BCMA therapies," said Badreddin Edris, Ph.D., Chief Operating Officer of SpringWorks. "Dr. Mitsiades and his colleagues have been at the forefront of developing cutting-edge translational models of multiple myeloma and we believe that this collaboration has the potential to yield novel insights that can help us to further refine our approach to improving outcomes for these patients."
Under the terms of the sponsored research agreement, SpringWorks will be responsible for funding the work and will retain an option to exclusively license any new intellectual property emerging from the research collaboration.
Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.
In addition, gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain, or ECD, from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has six collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, two bispecific antibodies and a monoclonal antibody. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA therapies using a variety of preclinical multiple myeloma models.
Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.