On December 6, 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 the first patient has been dosed in a Phase 1b/2 trial evaluating nirogacestat, SpringWorks’ investigational gamma secretase inhibitor (GSI), in combination with elranatamab (PF-06863135) Pfizer’s investigational B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody, in patients with relapsed or refractory multiple myeloma (Press release, SpringWorks Therapeutics, DEC 6, 2021, View Source [SID1234596493]).
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Gamma secretase inhibition prevents the cleavage and shedding of BCMA from the surface of 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, including CD3 bispecific antibodies.1,2
"We are very pleased to be dosing patients in this study, which is one of six collaborations evaluating the combination of nirogacestat with a BCMA-targeted therapy as part of our broader effort to explore our gamma secretase inhibitor’s role as a potential cornerstone of BCMA combination therapy," said Saqib Islam, Chief Executive Officer of SpringWorks. "Our goal is to improve treatment options for patients with multiple myeloma and we look forward to generating data with our collaborators to determine if adding nirogacestat can potentiate the activity of BCMA-directed therapies for these patients."
The Phase 1b/2 trial, which is one sub-study of Pfizer’s umbrella MagnetisMM-4 trial (NCT05090566), is an open-label study evaluating the safety, tolerability and preliminary efficacy of elranatamab in combination with nirogacestat in patients with relapsed or refractory multiple myeloma. The trial is being advanced pursuant to a clinical trial collaboration agreement between SpringWorks and Pfizer. Under the terms of the agreement, Pfizer is sponsoring and conducting the Phase 1b/2 study and is assuming all costs other than expenses related to the manufacturing of nirogacestat and certain expenses related to intellectual property rights. The companies have formed a joint development committee to manage the clinical study.
About Elranatamab
Elranatamab is an investigational B-cell maturation antigen (BCMA) CD3-targeted bispecific antibody being investigated in relapsed or refractory multiple myeloma. Binding affinity to BCMA and CD3 has been optimized, to potentially elicit more potent T-cell-mediated anti-myeloma activity. Elranatamab is being investigated as a subcutaneous administration, which is intended to allow higher doses than intravenous administration without increasing adverse events.
Elranatamab has been granted Orphan Drug Designations by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of multiple myeloma. The U.S. FDA and EMA have also granted elranatamab Fast Track Designation for the treatment of patients with multiple myeloma who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and the PRIME scheme for the treatment of multiple myeloma, respectively.
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. 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. 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.