Nirogacestat

Nirogacestat, sold under the brand name Ogsiveo, is an anti-cancer medication used for the treatment of desmoid tumors. It is a selective gamma secretase inhibitor that is taken by mouth.

The most common side effects include diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.

Nirogacestat was approved for medical use in the United States in November 2023. It is the first medication approved by the US Food and Drug Administration (FDA) for the treatment of desmoid tumors. The FDA considers it to be a first-in-class medication.

Medical uses
Nirogacestat is indicated for adults with progressing desmoid tumors who require systemic treatment.

History
The effectiveness of nirogacestat was evaluated in DeFi (NCT03785964), an international, multicenter, randomized (1:1), double-blind, placebo-controlled trial in 142 adult participants with progressing desmoid tumors not amenable to surgery. Participants were randomized to receive 150 milligrams (mg) of nirogacestat or placebo orally, twice daily, until disease progression or unacceptable toxicity. The main efficacy outcome measure was progression-free survival (the length of time after the start of treatment for which a person is alive and their cancer does not grow or spread). Objective response rate (a measure of tumor shrinkage) was an additional efficacy outcome measure. The pivotal clinical trial demonstrated that nirogacestat provided clinically meaningful and statistically significant improvement in progression-free survival compared to placebo. Additionally, the objective response rate was also statistically different between the two arms with a response rate of 41% in the nirogacestat arm and 8% in the placebo arm. The progression-free survival results were also supported by an assessment of patient-reported pain favoring the nirogacestat arm.

As of 2021, nirogacestat was in phase II clinical trials for unresectable desmoid tumors. In addition, a phase III clinical trial, DeFi, was in progress for nirogacestat for adults with desmoid tumors and aggressive fibromatosis. In addition, three trials were recruiting patients that include nirogacestat with other anticancer therapies in multiple myeloma, including the UNIVERSAL study for nirogacestat with the allogeneic CAR-T therapy ALLO-715.

The FDA granted the application for nirogacestat priority review, fast track, breakthrough therapy, and orphan drug designations. The FDA granted the approval of Ogsiveo to SpringWorks Therapeutics Inc.

Legal status
Nirogacestat was granted breakthrough therapy designation by the FDA in September 2019, for adults with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.