STAMFORD, Conn.--(BUSINESS WIRE)--SpringWorks Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, today announced that the company has entered into a clinical trial collaboration agreement with GlaxoSmithKline to evaluate SpringWorks Therapeutics’ investigational gamma secretase inhibitor (GSI), nirogacestat, in combination with GlaxoSmithKline’s investigational anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC), belantamab mafodotin (formerly GSK2857916), in patients with relapsed or refractory multiple myeloma.
Gamma secretase is an enzyme that cleaves multiple transmembrane proteins, including BCMA. As evidenced in publications and preclinical experiments, treatment with a GSI, including nirogacestat, can increase BCMA cell surface expression levels on multiple myeloma cells1, potentially improving the activity of BCMA-targeted therapies, including BCMA ADCs.
“While significant advances have been made in treating multiple myeloma over the past decade, a significant unmet need remains for patients who have relapsed or are refractory to available treatments,” said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. “We are delighted to enter into this agreement with GlaxoSmithKline, who also invested in our recent Series B financing, and we look forward to exploring the potential benefit of nirogacestat and belantamab mafodotin for multiple myeloma patients. With this collaboration, we are pleased to further expand on our strategy in building our targeted oncology portfolio with another industry leader.”
Under the terms of the agreement, GlaxoSmithKline will sponsor and conduct the adaptive Phase 1b study to evaluate the safety, tolerability and preliminary efficacy of the combination, and will assume all development costs associated with the study. GlaxoSmithKline and SpringWorks Therapeutics will also form a joint development committee to manage the clinical study.
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 June 2018, the FDA granted Orphan Drug designation for nirogacestat for the treatment of desmoid tumors, and in November 2018, the FDA granted Fast Track designation for nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.
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.2 Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma.
About belantamab mafodotin (GSK2857916)
Belantamab mafodotin is an investigational anti-B-cell maturation antigen (BCMA) antibody-drug conjugate in Phase 2 clinical development for patients with relapsed/refractory multiple myeloma and other advanced hematologic malignancies expressing BCMA.
In 2017, belantamab mafodotin was awarded Breakthrough Therapy designation from the U.S. Food and Drug Administration and PRIME designation from the European Medicines Agency; these designations are intended to facilitate development of investigational medicines that have shown clinical promise for conditions where there is significant unmet need.
About SpringWorks Therapeutics
At SpringWorks Therapeutics, a clinical-stage biopharmaceutical company, we are driven to develop life-changing medicines for patients with severe rare diseases and cancer. Since our launch in 2017, we have worked to identify and advance promising science, beginning with our licensed clinical therapies from Pfizer Inc. We pioneer efficient pathways for drug development, leveraging shared-value partnerships with patient advocacy groups, innovators in industry and academia, and investors so that together, we can unlock the potential of science and bring new therapies to underserved patients. Nirogacestat, our gamma secretase inhibitor for the treatment of desmoid tumors is currently in a Phase 3 clinical trial, and SpringWorks Therapeutics expects to initiate a Phase 2b study of mirdametinib, our MEK 1/2 inhibitor for neurofibromatosis type 1 patients with plexiform neurofibromas, in the third quarter of 2019. Mirdametinib also holds promise as the backbone for combination therapies to treat metastatic solid tumors. At SpringWorks, we ignite the power of promising science to unleash new possibilities for patients. For more information, please visit www.springworkstx.com.
1 Laurent S, Hoffmann F, Kuhn P, Cheng Q, Chu Y, Schmidt-Supprian M, Hauck S, Schuh E, Krumbholz M, Rubsamen H, Wanngren J, Khademi M, Olsson T, Alexander T, Hiepe F, Pfister H, Weber F, Jenne D, Wekerle H, Hohlfeld R, Lichtenthaler S, & Meinl E, Gamma-secretase directly sheds the survival receptor BCMA from plasma cells, Nature Communications (2015).
2 Chen H, Li M, Xu N, Ng N, Sanchez E, Soof CM, Patil S, Udd K, Bujarski S, Cao J, Hekmati T, Ghermezi M, Zhou M, Wang EY, Tanenbaum EJ, Zahab B, Schlossberg R, Yashar MA, Wang CS, Tang GY, Spektor TM, Berenson JR, Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells, Leukemia Research (2019), https://doi.org/10.1016/j.leukres.2019.04.008