On April 19, 2022 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 the company has entered into a clinical trial collaboration and supply agreement with Regeneron Pharmaceuticals, Inc. to evaluate nirogacestat, SpringWorks’ investigational gamma secretase inhibitor, in combination with Regeneron’s investigational bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, REGN5458, in patients with relapsed or refractory multiple myeloma (Press release, SpringWorks Therapeutics, APR 19, 2022, View Source [SID1234612496]).
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Gamma secretase inhibition helps prevent the cleavage and shedding of BCMA from the surface of myeloma cells. In preclinical models, nirogacestat has been shown to increase levels of membrane-bound BCMA and reduce levels of soluble BCMA, thereby helping to enhance the activity of BCMA-targeted therapies, including CD3 bispecific antibodies.1,2
"We are delighted to enter into our eighth BCMA clinical collaboration as we continue to advance nirogacestat as a potentially best-in-class cornerstone of BCMA-directed therapies," said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. "Our goal is to improve clinical outcomes for patients with multiple myeloma and we look forward to working with Regeneron to evaluate nirogacestat in combination with REGN5458."
Under the terms of the agreement, Regeneron is responsible for the clinical development and will assume all costs associated with the study, other than expenses related to the manufacturing and supply of nirogacestat and certain expenses related to intellectual property rights.
About Nirogacestat
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.1,2 SpringWorks is evaluating nirogacestat as a BCMA potentiator and has eight collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, four 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-directed 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.