On October 27, 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 an update from its ongoing clinical collaboration with GlaxoSmithKline (GSK) evaluating nirogacestat, SpringWorks’ investigational gamma secretase inhibitor, in combination with BLENREP (belantamab mafodotin-blmf), GSK’s antibody-drug conjugate targeting B-cell maturation agent (BCMA), in patients with relapsed or refractory multiple myeloma (Press release, SpringWorks Therapeutics, OCT 27, 2021, View Source [SID1234591999]). The nirogacestat and BLENREP combination is being evaluated as a sub-study of GSK’s ongoing DREAMM-5 platform trial.
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The first combination dose level that evaluated 0.95 mg/kg Q3W BLENREP plus nirogacestat has been expanded based on encouraging preliminary data observed in the dose exploration Phase 1 portion of the nirogacestat DREAMM-5 sub-study. The expanded Phase 2 cohort is further exploring the safety and efficacy profile compared to a 2.5 mg/kg Q3W BLENREP monotherapy control arm, which is the same as the FDA approved monotherapy dose and schedule of BLENREP. In parallel, additional dose levels and schedules of BLENREP plus nirogacestat continue to be evaluated in the Phase 1 portion of the study.
In addition, two new sub-studies will evaluate the BLENREP plus nirogacestat combination with standard-of-care multiple myeloma therapies in the DREAMM-5 trial. These two new sub-studies will explore BLENREP plus nirogacestat in combination with pomalidomide and dexamethasone and in combination with lenalidomide plus dexamethasone. Data from these sub-studies may enable future clinical trials in earlier lines of multiple myeloma.
"We continue to remain intensely focused on advancing nirogacestat as a potential best-in-class cornerstone of BCMA combination therapy for patients with multiple myeloma and are pleased with the progress that has been made with our collaborator GSK," said Saqib Islam, Chief Executive Officer of SpringWorks. "We believe in the emerging role of nirogacestat as a BCMA potentiator and we look forward to working with GSK to advance the expanded program."
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, including GSK, to evaluate nirogacestat in combination with BCMA therapies across modalities.
The platform study is being advanced pursuant to a non-exclusive global clinical trial collaboration agreement that SpringWorks and GSK entered into in June 2019 and that was amended in October 2021 to enable additional sub-studies to be conducted. Under the terms of the agreement, GSK is sponsoring and conducting the platform study to evaluate the safety, tolerability and preliminary efficacy of the combination and is assuming all development costs associated with the study other than expenses related to the manufacturing of nirogacestat and certain expenses related to intellectual property rights. SpringWorks and GSK have formed a joint development committee to help manage and oversee the clinical study.
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. 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