FDA Accepts NDA for Varegacestat in Desmoid Tumors

The FDA has accepted a new drug application (NDA) for varegacestat, an investigational oral once-daily gamma secretase inhibitor (GSI), for the treatment of adults with desmoid tumors, according to a news release.¹

The agency assigned a Prescription Drug User Fee Act (PDUFA) target action date of April 28, 2027. If approved, varegacestat would be the second oral targeted therapy for adults with progressing desmoid tumors, after nirogacestat (Ogsiveo).

The NDA acceptance is based on results from the phase 3 RINGSIDE trial (NCT04871282), which met its primary end point with a statistically significant and clinically meaningful 84% reduction in the risk of disease progression or death compared with placebo (HR, 0.16; 95% CI, 0.07-0.38; P <.0001) as assessed by blinded independent central review.²

Disease Background and Unmet Need

Desmoid tumors, also known as aggressive fibromatosis or desmoid-type fibromatosis, are aggressive nonmetastatic soft tissue tumors prone to recurrence. Approximately 1000 to 1650 people are diagnosed with desmoid tumors each year in the United States, with an estimated 10,000 to 11,000 patients actively managed at any given time.¹ Although desmoid tumors are not classified as malignant, they carry a substantial clinical burden: patients may experience debilitating chronic pain, physical deformity, and, in some cases, life-threatening organ damage depending on tumor location. These consequences frequently necessitate systemic therapy, yet until recently no targeted oral agents were FDA-approved specifically for this indication. Varegacestat inhibits the gamma secretase enzyme involved in Notch pathway signaling, which is implicated in desmoid tumor growth.

RINGSIDE Trial: Efficacy Results

The RINGSIDE trial is a global, randomized, double-blind, placebo-controlled phase 3 study enrolling 156 patients with progressing desmoid tumors. Patients were randomly assigned to receive varegacestat 1.2 mg daily or placebo until disease progression or death. Results from the trial were presented in an oral abstract session at the 2026 American Society of Clinical Oncology Annual Meeting by lead investigator Mrinal M. Gounder, MD, of Memorial Sloan Kettering Cancer Center.

The confirmed objective response rate (ORR), assessed by blinded independent central review using RECIST v1.1 criteria, was 55.7% with varegacestat vs 9.1% with placebo (P <.0001) with an earlier median time to response; the rate of progressive disease was 0% with varegacestat vs 13% with placebo. In an exploratory analysis of tumor volume, varegacestat produced a median best change of −83% from baseline compared with +11% for placebo; the difference in change of tumor volume between the arms at week 24 was -232.4 cm³ greater with varegacestat.

The trial also met all other key secondary end points, including statistically significant improvement in worst pain intensity at week 12 (difference; -2.42; standard error, 0.37; P <.0001), with a clinically significant difference observed as early as week 4. The inclusion of a patient-reported pain end point as a controlled secondary measure is particularly relevant in desmoid tumors, where chronic debilitating pain is among the most burdensome aspects of the disease. RINGSIDE includes an open-label extension phase, which remains ongoing.

Safety Profile

Varegacestat was generally well tolerated with a manageable safety profile described as consistent with the drug class. The most common adverse events (AEs) in the treatment arm were diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). The majority of events were grade 1 or 2 in severity; serious AEs were reported in 32% with varegacestat vs 9% with placebo.

The oral once-daily administration route and tolerability profile may support sustained dosing in a patient population that often requires prolonged systemic treatment. Patients had a median exposure of 20 months vs 11 months with placebo; dose reduction due to AEs was needed in 80% vs 9% and discontinuation was needed in 20% vs 7%, respectively.

Ovarian toxicity, which is a known class effect, occurred in 56% of premenopausal female patients vs 5% with placebo; it resolved in 55% of those cases and no patients discontinued treatment because of ovarian toxicity.

Regulatory and Development Context

Immunome has also indicated plans to submit a Marketing Authorization Application to the European Medicines Agency for varegacestat by the end of 2026.

“The FDA’s acceptance of our NDA for varegacestat is an important milestone for Immunome and for patients living with desmoid tumors,” said Clay Siegall, PhD, president and chief executive officer of Immunome, in the news release. “We believe varegacestat has the potential to provide an important oral treatment option, supported by robust clinical data across all key efficacy end points.”

REFERENCES

1. Immunome Announces U.S. FDA Acceptance of New Drug Application for Varegacestat for the Treatment of Adults with Desmoid Tumors. News release. Immunome. July 8, 2026. Accessed July 8, 2026. https://tinyurl.com/48mt6535

2. Gounder M, Rutkowski P, Jones RL, et al. RINGSIDE: A phase 3 randomized, placebo-controlled trial of varegacestat for treatment of progressing desmoid tumors. J Clin Oncol. 2026;44(suppl 16):11506. doi:10.1200/JCO.2026.44.16_suppl.1150