Nirogacestat (Gamma Secretase Inhibitor)

Nirogacestat is an investigational, oral, small molecule, selective gamma secretase inhibitor with Orphan Drug and Fast Track designations in the United States for the treatment of desmoid tumors, a devastating condition for which there are currently no FDA-approved therapies.

Nirogacestat has demonstrated clinical activity and was well tolerated in patients with desmoid tumors who were studied in Phase 1 and Phase 2 studies:

  • The 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. Published results from this study demonstrated that only 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) and an additional patient achieving disease stabilization.
  • The Phase 2 study was an open-label, investigator-initiated study sponsored by National Cancer Institute (NCI) that enrolled 17 desmoid tumor patients with advanced or refractory tumors. Published results from this study demonstrated that, at the time of publication, none of the 17 patients experienced tumor progression while on treatment, with five patients achieving a reduction in tumor size of over 30% (as measured by RECIST) and the remaining 11 patients achieving disease stabilization. Patients also experienced improvements in symptom severity.
  • In both the Phase 1 and Phase 2 studies, nirogacestat was well-tolerated in desmoid tumor patients when given at a dose of 150mg twice a day, with many patients remaining on treatment for years. The most common adverse events 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.

 

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