The FDA has accepted the new drug application (NDA) seeking the approval of varegacestat (AL102), an investigational, oral, once-daily gamma-secretase inhibitor (GSI), for the treatment of adult patients with desmoid tumors.1
The regulatory agency assigned a Prescription Drug User Fee Act (PDUFA) target action date of April 28, 2027.
The application is supported by
"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, stated in the news release.1 “We believe varegacestat has the potential to provide an important oral treatment option, supported by robust clinical data across all key efficacy endpoints. We look forward to working closely with the FDA throughout the review.”
Immunome submitted the NDA to the FDA in April 2026 and plans to submit a marketing authorization application to the European Medicines Agency for varegacestat by the end of 2026.
The global, randomized, double-blind, placebo-controlled RINGSIDE trial enrolled adult patients with histologically confirmed desmoid tumors that had progressed within the prior 12 months per RECIST 1.1 criteria.2 Patients needed to have measurable disease and an ECOG performance status of 0 or 1; both treatment-naive and previously treated patients were eligible.
A total of 156 patients were randomly assigned 1:1 to receive varegacestat at 1.2 mg orally once daily or placebo until disease progression or death. Patients were stratified by tumor location (intra- vs extra-abdominal).
The primary end point was PFS by BICR. Statistically controlled key secondary end points were confirmed objective response rate (ORR) per RECIST 1.1 criteria and change in tumor volume at week 24, both per BICR, as well as change in patient-reported worst pain intensity at week 12 as measured by the Gounder/Desmoid Tumor Research Foundation Desmoid Symptom/Impact Scale.1,2 The trial included an ongoing open-label extension phase, and patients in either arm were permitted to cross over to open-label varegacestat upon progression. The data cutoff for the ASCO 2026 presentation was October 7, 2025.2
The confirmed ORR by BICR was 55.7% (95% CI, 44.1%-66.9%) with varegacestat vs 9.1% (95% CI, 3.7%-17.8%) with placebo (P < .0001). Responses in the varegacestat arm comprised a complete response (CR) rate of 3.8% and a partial response (PR) rate of 51.9%, with 40.5% of patients achieving stable disease and no patients experiencing progressive disease. In the placebo arm, the CR and PR rates were 1.3% and 7.8%, respectively, with 13.0% of patients experiencing progressive disease. The median time to response was 8.2 months (range, 2.6-28.0) with varegacestat vs 16.7 months (range, 8.1-30.2) with placebo, and the median duration of response was NE in both arms.
Varegacestat also produced a significant reduction in tumor volume at week 24, with a least-squares mean change from baseline of –109.6 cm3 vs 122.8 cm3 with placebo (difference, –232.4 cm3; P < .0001).2 The median best change in tumor volume was -83% (range, –100% to 55%) with varegacestat vs 11% (range, –100% to 199%) with placebo.
For patient-reported worst pain intensity at week 12, the least-squares mean change from baseline was –2.24 with varegacestat vs 0.18 with placebo (difference, –2.42; P < .0001), with a clinically meaningful difference of more than 2 points observed as early as the first assessment at week 4.
Any-grade adverse effects (AEs) occurred in all patients in the varegacestat arm vs 91% of those in the placebo arm; the rates of grade 3 or higher AEs were 57% vs 17%, respectively. The most common any-grade AEs with varegacestat were diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), cough (34%), hypophosphatemia (34%), and alopecia (33%). Serious AEs occurred in 32% of varegacestat-treated patients vs 9% of those given placebo, and AEs led to treatment discontinuation in 20% vs 7% of patients, respectively. No deaths were attributed to AEs.
Ovarian toxicity, a known class effect of GSIs, was reported in 56% of premenopausal women in the varegacestat arm vs 5% of those in the placebo arm; these events resolved in 55% of affected patients, and none led to treatment discontinuation.
