New Drug Application Submitted for Varegacestat in Desmoid Tumors

A new drug application (NDA) has been submitted to the FDA 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 submission is supported by results from the phase 3 RINGSIDE trial (NCT04871282), in which varegacestat demonstrated an 84% reduction in the risk of disease progression or death compared with placebo (HR, 0.16; 95% CI, 0.071-0.375; P <.0001) and met all key secondary end points. Detailed RINGSIDE data will be shared in an oral presentation at the upcoming 2026 American Society of Clinical Oncology Annual Meeting.

Primary End Point and Response Data

The RINGSIDE trial met its primary end point of progression-free survival (PFS) with a highly statistically significant result. The 84% lower risk of disease progression or death relative to those receiving placebo is a clinically substantial effect size in a disease for which systemic treatment options remain limited.

The confirmed objective response rate (ORR), assessed by blinded independent central review using RECIST v1.1 criteria, was 56% with varegacestat vs 9% with placebo (P <.0001). This greater than sixfold difference in response rates reinforces the PFS benefit and provides evidence of meaningful tumor regression at the individual patient level.

In an exploratory analysis of tumor volume, varegacestat produced a median best change of −83% from baseline, compared with +11% for placebo, an absolute difference of nearly 94 percentage points, suggesting substantial and durable tumor shrinkage in the majority of treated patients.

Secondary End Points and Patient-Reported Outcomes

The trial met all key secondary end points, including statistically significant improvements vs placebo in landmark tumor volume reduction at week 24 and worst pain intensity at week 12, the latter measured using a patient-reported outcome instrument. The inclusion of pain intensity as a controlled secondary end point is particularly relevant in desmoid tumors, where chronic debilitating pain is among the most burdensome aspects of the disease for patients.

Additional secondary end points assessed in the trial included duration of response, best reduction in tumor volume, broader patient-reported outcomes, and safety and tolerability.

RINGSIDE also includes an open-label extension phase, which remains ongoing and may provide longer-term durability and safety data to support the regulatory submission.

Safety and Tolerability

Varegacestat was generally well tolerated, with a safety profile described as manageable and consistent with the GSI drug class. The most common adverse events in the treatment arm were diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). The majority of these events were grade 1 or 2 in severity. The oral once-daily administration route and manageable tolerability profile may support sustained dosing in a patient population that often requires prolonged systemic treatment.

Trial Design and Study Population

RINGSIDE is a global, randomized, double-blind, placebo-controlled phase 3 trial enrolling 156 patients with progressing desmoid tumors, representing the largest randomized study ever conducted in this population. Patients were randomly assigned to receive varegacestat 1.2 mg daily or placebo until disease progression or death. The primary end point was PFS as assessed by blinded independent central review, with statistically controlled secondary end points including confirmed ORR by RECIST v1.1, duration of response, change in tumor volume at week 24, change in pain intensity at week 12, and safety and tolerability.

Disease Background and Unmet Need

Desmoid tumors, also known as aggressive fibromatosis or desmoid-type fibromatosis, are aggressive nonmetastatic soft tissue tumors that are 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. Although desmoid tumors are not classified as malignant, they carry a substantial clinical burden: affected 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 to prevent permanent disability, yet approved targeted oral treatment options have been absent from the therapeutic landscape.

Varegacestat's mechanism, inhibition of the gamma secretase enzyme involved in Notch pathway signaling implicated in desmoid tumor growth, represents a targeted approach to a disease that has historically been managed with a combination of watchful waiting, surgery, radiation, and cytotoxic or hormonal systemic therapies, none of which are FDA-approved specifically for this indication.² If approved, varegacestat would be the second oral targeted therapy for adults with progressing desmoid tumors, after nirogacestat (Ogsiveo).

“We believe varegacestat has the potential to provide adults with progressing desmoid tumors with a meaningful new oral treatment option, and we are grateful to the patients, families, investigators and study site teams whose participation made this submission possible,” Clay B. Siegall, PhD, president and chief executive officer of Immunome, stated in the news release.¹

REFERENCES

1. Immunome announces submission of new drug application to U.S. FDA for varegacestat for the treatment of adults with desmoid tumors. News release. Immunome. April 29, 2026. Accessed April 29, 2026. https://tinyurl.com/224jy7xs

2. Federman N. Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition. NPJ Precis Oncol. 2022;6(1):62. doi:10.1038/s41698-022-00308-1