Nirogacestat (Gamma Secretase Inhibitor)

Nirogacestat is an oral, selective, small molecule, gamma secretase inhibitor in Phase 3 development for the treatment of desmoid tumors, a devastating condition for which there are currently no FDA-approved therapies:

Nirogacestat has been generally well tolerated in over 200 patients and clinical activity was observed in the desmoid tumor patients enrolled in two previous clinical trials.

  • A Phase 1 study was conducted in 64 patients with advanced solid tumors to define the maximum tolerated dose; of these 64 patients, seven evaluable patients had a diagnosis of desmoid tumor. It was observed that one of these seven desmoid patients experienced tumor progression while on treatment, with five patients achieving a reduction in tumor size of over 30% (as measured by RECIST).
  • A Phase 2 study was an open-label, investigator-initiated study sponsored by National Cancer Institute (NCI) that enrolled 17 desmoid tumor patients. At the time of publication, 16 patients were evaluable for a response. Five patients had a confirmed partial response and 11 had stable disease. Patients also experienced improvements in symptom severity.
  • Nirogacestat was generally well tolerated in both of these studies. In the Phase 1 study the mean time on therapy was four years and approximately 59% of the Phase 2 patients remained on therapy for at least two years. One desmoid tumor patient in the combined trials discontinued treatment due to an adverse event. The most common adverse events in the Phase 2 study were diarrhea, skin disorders and hypophosphatemia.

SpringWorks is enrolling patients in a global Phase 3, double-blind, randomized, placebo-controlled clinical trial (the “DeFi” trial) to evaluate nirogacestat in adults with progressing desmoid tumors.

The FDA has granted nirogacestat Orphan Drug Designation for the treatment of desmoid tumors and Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In addition, the European Commission granted Orphan Drug Designation for nirogacestat for the treatment of soft tissue sarcoma.


How it is Designed to Work

Gamma secretase is an integral membrane protein that cleaves multiple different transmembrane protein complexes, including Notch, which is believed to play a role in activating aberrant growth pathways that contribute to desmoid tumor growth. Nirogacestat is a reversible, targeted investigational product that selectively inhibits gamma secretase.

Nirogacestat MOA


Key Publications on Desmoid Tumors


GSI Combinations in Cancer

Gamma secretase has been shown to directly cleave membrane-bound anti-B-cell maturation antigen (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 a BCMA-targeted agent. Nirogacestat’s ability to enhance the activity of a BCMA-directed therapy has been observed in preclinical models of multiple myeloma.

SpringWorks has partnered with industry leaders to evaluate nirogacestat as a potentiator to BCMA therapies. A Phase 1b clinical trial is planned, under a global clinical trial agreement with GlaxoSmithKline, to evaluate nirogacestat in combination with belantamab mafodotin, an investigational BCMA antibody-drug conjugate (ADC), in patients with relapsed or refractory multiple myeloma (r/r MM). Another Phase 1 clinical trial is planned, under a clinical trial agreement with Allogene Therapeutics, to evaluate nirogacestat in combination with ALLO-715, an investigational BCMA allogeneic CAR T cell therapy, in patients with r/r MM.


Key Publications on GSI Combinations in Cancer