The FDA has accepted Immunome’s NDA for varegacestat to treat adults with desmoid tumors, assigning a PDUFA date of April 28, 2027. The application is backed by positive Phase 3 RINGSIDE data showing significant improvements in progression-free survival, objective response rate, pain, and tumor reduction.
Written By: Meghana Jinka, PharmD
Reviewed By: Pharmacally Editorial Team
Immunome has reached a key regulatory milestone after the U.S. Food and Drug Administration accepted its New Drug Application for varegacestat, an investigational once-daily oral gamma secretase inhibitor (GSI), for the treatment of adults with desmoid tumors. The agency assigned a Prescription Drug User Fee Act (PDUFA) target action date of April 28, 2027.
If approved, varegacestat could become a new once-daily oral treatment option for adults with progressing desmoid tumors, a rare, locally aggressive soft tissue tumor associated with chronic pain, functional impairment, deformity, and, in severe cases, life-threatening organ damage despite its non-metastatic nature.
Phase 3 RINGSIDE Trial Met Primary and All Key Secondary Endpoints
The NDA is supported by results from the global Phase 3 RINGSIDE trial, which evaluated varegacestat in adults with progressing desmoid tumors. The study met its primary endpoint by significantly improving progression-free survival compared with placebo, reducing the risk of disease progression or death by 84% (hazard ratio 0.16; p<0.0001).
The trial also achieved all key secondary endpoints. Blinded independent central review showed an objective response rate of 56% with varegacestat compared with 9% for placebo (p<0.0001). Patients receiving varegacestat also experienced statistically significant reductions in worst pain intensity by week 12, with clinically meaningful improvement observed as early as week 4. An exploratory analysis demonstrated a median best tumor volume reduction of 83%, compared with an 11% increase in the placebo group.
Safety Profile Consistent with Gamma Secretase Inhibitor Class
Varegacestat demonstrated a safety profile consistent with the gamma secretase inhibitor class. The most frequently reported adverse events included diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). Most treatment-emergent adverse events (95%) were grade 1 or 2, indicating generally manageable toxicity.
Largest Randomized Desmoid Tumor Trial Supports NDA
The randomized, double-blind, placebo-controlled Phase 3 RINGSIDE study (NCT04871282) enrolled 156 patients, making it the largest randomized clinical trial conducted in desmoid tumors. Participants received either varegacestat 1.2 mg once daily or placebo until disease progression or death. The primary endpoint was progression-free survival assessed by blinded independent central review. Secondary endpoints included objective response rate, tumor volume changes, pain intensity, duration of response, patient-reported outcomes, safety, and tolerability. An ongoing open-label extension continues to evaluate the therapy’s long-term outcomes.
Varegacestat Targets Notch Signaling in Desmoid Tumors
Varegacestat, previously known as AL102, is an investigational oral gamma secretase inhibitor that blocks the Notch signaling pathway, which is implicated in the development and progression of desmoid tumors.
Desmoid tumors, also known as aggressive fibromatosis or desmoid-type fibromatosis, are non-metastatic but locally invasive tumors with a high risk of recurrence. Approximately 1,000 to 1,650 people are diagnosed each year in the United States, and an estimated 10,000 to 11,000 patients are actively managed. Many require systemic treatment to control disease progression, preserve physical function, and reduce long-term symptom burden.
EMA Submission Planned by End of 2026
Commenting on the regulatory milestone, Clay Siegall, Ph.D., President and Chief Executive Officer of Immunome, said the FDA’s acceptance of the NDA represents an important step for both the company and patients living with desmoid tumors. He added that the application is supported by robust efficacy data across all major clinical endpoints and that the company looks forward to working with the FDA during the review process.
In addition to the ongoing U.S. review, Immunome plans to submit a Marketing Authorization Application (MAA) for varegacestat to the European Medicines Agency (EMA) by the end of 2026, supporting the therapy’s potential expansion into European markets if approved.
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About the Writer
Meghana Jinka (LinkedIn) is a Pharm.D graduate with a strong interest in clinical pharmacy, clinical research, pharmacovigilance, and medical writing. She has developed expertise in evaluating scientific literature, interpreting clinical data, and communicating complex medical information in a clear and accessible manner. Through clinical training, patient counseling, and healthcare awareness activities, she has gained practical experience in evidence-based medicine and patient-centered care. Passionate about healthcare communication, Meghana is committed to developing accurate, engaging, and evidence-based healthcare documents that support healthcare professionals and the wider community.