Immunome files FDA application for desmoid drug varegacestat

Key Takeaways:

FDA accepted Immunome's NDA for varegacestat in desmoid tumors
Phase 3 RINGSIDE trial showed 84% risk reduction in progression or death
PDUFA target action date set for April 28, 2027

Immunome's varegacestat cut the risk of disease progression or death by 84% in a pivotal trial of 156 patients with desmoid tumors, positioning the oral gamma secretase inhibitor as a potential challenger to the recently approved nirogacestat in a rare disease with limited systemic options.

"The FDA's acceptance of our NDA for varegacestat is an important milestone for Immunome and for patients living with desmoid tumors," Clay Siegall, PhD, president and chief executive officer of Immunome, said in a statement. The company plans to submit a marketing authorization application to the European Medicines Agency by the end of 2026.

The RINGSIDE trial randomized patients with progressing desmoid tumors 1:1 to varegacestat 1.2 mg once daily or placebo. The drug achieved a hazard ratio for progression-free survival of 0.16 (p<0.0001), meeting its primary endpoint. The objective response rate was 56% versus 9% with placebo (p<0.0001), as assessed by blinded independent central review. Median best change in tumor volume was minus 83% in the treatment arm compared with plus 11% in the placebo arm. Varegacestat also showed statistically significant improvement in worst pain intensity at week 12, with separation observed as early as week 4.

The safety profile was consistent with the gamma secretase inhibitor class. The most common adverse events were diarrhea (82%), fatigue (44%), rash (43%), nausea (35%) and cough (34%), with 95% of events graded 1 or 2. Ovarian toxicity occurred in 67% of women of reproductive potential in the 1.2-mg cohort. Full results were presented at the 2026 American Society of Clinical Oncology annual meeting.

Desmoid tumors, also known as aggressive fibromatosis, are non-metastatic soft tissue tumors that can cause debilitating pain and organ damage. Approximately 1,000 to 1,650 people are diagnosed annually in the United States, with about 10,000 to 11,000 actively managed patients. Until recently, systemic options were limited to sorafenib, which lacks an FDA label for this indication, and off-label use of other agents.

The competitive landscape shifted in November 2023 when the FDA approved nirogacestat (Ogsiveo) from the DeFi trial, which showed a PFS hazard ratio of 0.29 versus placebo. Both nirogacestat and varegacestat are gamma secretase inhibitors, but cross-trial comparisons are complicated by differing enrollment criteria — the DeFi trial required confirmed RECIST progression at baseline, while RINGSIDE enrolled patients with progressing disease per investigator assessment. Varegacestat's 0.16 hazard ratio and 56% response rate compare favorably on the surface, though clinicians have cautioned against direct comparisons given the population differences.

Immunome, which holds a market capitalization of about $2.76 billion, now faces a roughly nine-month review window. If approved, varegacestat would enter a market where nirogacestat has established first-mover advantage but where treatment duration remains an open question — sarcoma oncologists at a recent case-based roundtable acknowledged wide variation in how long they continue therapy in responding patients, with some favoring treatment until maximal tumor reduction and others considering停药 at plateau with surveillance.

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