SpringWorks Therapeutics has entered into a clinical collaboration and supply agreement with Janssen Biotech to evaluate SpringWorks’ investigational gamma secretase inhibitor (GSI), nirogacestat, in combination with Janssen’s bispecific antibody targeting B-cell maturation antigen (BCMA) and CD3, teclistamab, 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, which may enhance the activity of BCMA-targeted therapies, including CD3 bispecific antibodies.

“We are delighted to enter into this collaboration with Janssen to study nirogacestat in combination with teclistamab,” said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. “We now have three collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, an allogeneic CAR-T cell therapy and now a bispecific antibody. This collaboration is an important step in continuing to advance our goal of developing nirogacestat as a best-in-class BCMA potentiator.”

Under the terms of the agreement, Janssen will sponsor and conduct the Phase 1 study to evaluate the safety, tolerability and preliminary efficacy of the combination, and will assume all costs associated with the study, other than expenses related to the manufacturing of nirogacestat. SpringWorks Therapeutics will also form a joint oversight committee with Janssen. Pending discussions with regulators, the study is anticipated to commence by early 2021.

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.

Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors (June 2018) and from the European Commission for the treatment of soft tissue sarcoma (September 2019). 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 (November 2018 and August 2019).