Varegacestat Advances Toward European Approval for Desmoid Tumors Following RINGSIDE Survival Benefit
Clinical Summary:
- Regulatory Update: The European Medicines Agency (EMA) has validated the marketing authorization application for varegacestat, an investigational oral gamma-secretase inhibitor, for adults with desmoid tumors, allowing the application to proceed to regulatory review.
- Key Outcomes: The application was supported by results from the phase 3 RINGSIDE tiral, in which varegacestat significantly improved progression-free survival, reducing the risk of progression or death by 84% compared with placebo. The objective response rate was 56%, with significant improvements in patient-reported pain.
- Clinical Relevance: This regulatory milestone advances varegacestat as a potential new oral treatment option for adults with progressing desmoid tumors in the European Union. Regulatory review remains ongoing.
The European Medicines Agency (EMA) has validated the marketing authorization application (MAA) for varegacestat, an investigational oral once-daily gamma secretase inhibitor, for adults with desmoid tumors, following positive progression-free survival (PFS), objective response, and patient-reported pain results from the phase 3 RINGSIDE trial.
The validation confirms that the application is complete and allows the EMA to initiate its review under the centralized marketing authorization procedure.
In the double-blind, placebo-controlled RINGSIDE trial, 156 patients with progressing desmoid tumors were randomized to receive either 1.2 mg of once daily varegacestat or placebo until disease progression or death.
The primary end point was PFS, assessed by blinded independent central review. Key secondary end points included confirmed objective response rate (ORR) according to RECIST version 1.1, change in tumor volume at week 24, and improvement in patient-reported pain intensity at week 12.
At analysis, varegacestat significantly improved PFS compared with placebo, reducing the risk of disease progression or death by 84% (hazard ratio [HR], 0.16; P < .0001). The confirmed ORR was 56% in the varegacestat arm and 9% in the placebo arm (P < .0001).
Varegacestat also demonstrated a statistically significant improvement in worst pain intensity at week 12, with a clinically significant difference observed as early as the first assessment at week 4.
In an exploratory analysis, the median best change in tumor volume was – 83% with varegacestat compared with an 11% increase with placebo.
The safety profile of varegacestat was reported to be generally manageable and consistent with the gamma-secretase inhibitor class. The most common adverse events reported among patients receiving varegacestat included diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). Most reported adverse events (95%) were grade 1/2.
The EMA validation follows US Food and Drug Administration (FDA) acceptance of the New Drug Application for varegacestat in July 2026. The FDA assigned a Prescription Drug User Fee Act target action date of April 28, 2027.
Varegacestat remains investigational, with regulatory review ongoing in both the US and European Union.
The phase 3 RINGSIDE trial also includes an ongoing open-label extension phase to further evaluate treatment outcomes.
Source:
Immunome, Inc. Immunome announces EMA validation of marketing authorization application for varegacestat for the treatment of adults with desmoid tumors. Accessed on: November 4, 2026. https://www.businesswire.com/news/home/20261030925417/en/Immunome-Announces-EMA-Validation-of-Marketing-Authorization-Application-for-Varegacestat-for-the-Treatment-of-Adults-with-Desmoid-Tumors
