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SpringWorks Therapeutics and the Dana-Farber Cancer Institute will conduct further research into the therapeutic potential of combination therapy with nirogacestat and anti-BCMA agents for multiple myeloma.
SpringWorks Therapeutics, a clinical-stage biopharmaceutical company, has entered into a sponsored research collaboration with Dana-Farber Cancer Institute (Dana-Farber) to further evaluate the therapeutic potential of nirogacestat, an investigational oral, selective, small-molecule gamma secretase inhibitor (GSI), with anti-B-cell maturation antigen (BCMA) agents, in preclinical models to treat multiple myeloma. Under the agreement, SpringWorks will fund the work and will retain an option to exclusively license any new intellectual property that results from the collaboration, the company announced in an Aug. 30, 2021 press release.
The research will be led by Constantine Mitsiades, MD, PhD, assistant professor of Medicine at Dana-Farber and Harvard Medical School, who will serve as the Principal Investigator. The researchers will use preclinical in-vivo models from the Mitsiades Lab to simulate the multiple myeloma tumor microenvironment. They will also apply functional genomics approaches to explore determinants of response and mechanisms of resistance to a GSI + BCMA combination therapy.
Inhibition of gamma secretase prevents the cleavage and shedding of BCMA from the surface of multiple myeloma cells. Nirogacestat has been shown to increase the cell surface density of BCMA and to reduce levels of soluble BCMA in preclinical models, and thus is thought to enhance the activity of BCMA-targeted therapies. SpringWorks has entered into clinical collaborations with six industry partners to date to evaluate nirogacestat in combination with BCMA therapies across modalities.
Nirogacestat is in Phase III clinical development for treating rare and often debilitating and disfiguring soft-tissue tumors, including desmoid tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch proteins, that are believed to play a role in activating pathways that contribute to desmoid tumor growth. Gamma secretase has also been shown to directly cleave membrane-bound BCMA, which releases the BCMA extracellular domain (ECD) from the cell surface.
Membrane-bound BCMA can be preserved by inhibiting gamma secretase, which increases target density and reduces levels of soluble BCMA ECD, resulting in potential decoy receptors for BCMA-directed therapies. Nirogacestat has shown an ability to enhance the activity of BCMA-directed therapies, observed in preclinical models of multiple myeloma.
Nirogacestat has received orphan drug designation from FDA for treating desmoid tumors and from the European Commission for treating soft tissue sarcoma. FDA also granted fast track and breakthrough therapy designations for the molecule in the treatment of adult patients with progressive, unresectable, recurrent, or refractory desmoid tumors or deep fibromatosis.
“SpringWorks has demonstrated its commitment to understanding the science and advancing the clinical exploration of GSI + BCMA combination therapies,” said Mitsiades, in the company press release. “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, chief operating officer of SpringWorks, in the press release. “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.”
Source: SpringWorks Therapeutics