SpringWorks Therapeutics Announces Dosing of First Patient in Phase 1b/2 Trial Evaluating Nirogacestat in Combination with Elranatamab (PF-06863135) in Patients with Relapsed or Refractory Multiple Myeloma
STAMFORD, Conn., Dec. 06, 2021 (GLOBE NEWSWIRE) -- SpringWorks Therapeutics Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, today announced 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.
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.
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.
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.
About SpringWorks Therapeutics
SpringWorks is a clinical-stage biopharmaceutical company applying a precision medicine approach to acquiring, developing and commercializing life-changing medicines for patients living with severe rare diseases and cancer. SpringWorks has a differentiated targeted oncology portfolio of small molecule product candidates and is advancing 16 development programs, including two potentially registrational clinical trials in rare tumor types as well as several programs addressing highly prevalent, genetically defined cancers. SpringWorks’ strategic approach and operational excellence in clinical development have enabled it to rapidly advance its two lead product candidates into late-stage clinical trials while simultaneously entering into multiple shared-value partnerships with innovators in industry and academia to expand its portfolio and create more solutions for patients with cancer. For more information, visit http://www.springworkstx.com and follow @SpringWorksTx on Twitter and LinkedIn.
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For further information regarding the risks, uncertainties and other factors that may cause differences between SpringWorks’ expectations and actual results, you should review the “Risk Factors” in Item 1A of Part I of SpringWorks’ Quarterly Report on Form 10-Q for the quarter ended September 30, 2021, as well as discussions of potential risks, uncertainties and other important factors in SpringWorks’ subsequent filings.
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1 Karwacz et al., “BCMAxCD3 bispecific antibody PF-06863135: preclinical rationale for therapeutic combinations”, AACR 2020
2 Eastman S, Shelton C, Gupta I, Krueger J, Blackwell C, Bojczuk P. Synergistic Activity of Belantamab Mafodotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase inhibitor) in BCMA-Expressing Cancer Cell Lines. Blood. 2019;134(supplement_1):4401. doi:10.1182/blood-2019-123705.