5 minOn July 8, 2026, the biopharmaceutical company Immunome announced that the U.S. Food and Drug Administration (FDA) has officially accepted the New Drug Application (NDA) for varegacestat (AL102), an innovative oral gamma-secretase inhibitor (GSI) for the treatment of adult patients with desmoid tumors. The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of April 28, 2027. Furthermore, the company plans to submit a marketing authorization application to the European Medicines Agency (EMA) by the end of 2026.
RINGSIDE Study: More Than Just "Slowing" Progression
The NDA submission is primarily supported by landmark data from the global, randomized, double-blind, placebo-controlled Phase 3 RINGSIDE trial (NCT04871282). The study enrolled 156 adult patients with histologically confirmed desmoid tumors who had experienced disease progression within the prior 12 months.
Key clinical findings demonstrate significant superiority across all primary and secondary endpoints:
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Significant Extension of Progression-Free Survival (PFS): As assessed by Blinded Independent Central Review (BICR), varegacestat reduced the risk of disease progression or death by 84% (HR, 0.16; P < .0001). Notably, the median PFS for the placebo group was 24.87 months, whereas the median PFS for the varegacestat arm had not been reached (NE) at the time of data cutoff, demonstrating powerful tumor control.
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Overwhelming Advantage in Objective Response Rate (ORR): The confirmed ORR in the varegacestat arm was 55.7%, significantly higher than the 9.1% observed in the placebo arm (P < .0001). Encouragingly, zero patients in the varegacestat treatment arm experienced progressive disease, a result of high clinical significance in treating desmoid tumors, which are characterized by their aggressive nature.
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Dual Improvement in Tumor Volume and Pain: At the week 24 assessment, the varegacestat arm showed a mean reduction in tumor volume of 109.6 cm³ from baseline, compared to an increase of 122.8 cm³ in the placebo arm.Regarding patient-reported pain, the varegacestat group showed significant improvement from baseline by week 12,with clinically meaningful differences of more than 2 points observed as early as the first assessment at week 4.
Safety and Tolerability Profile
While demonstrating robust efficacy, varegacestat’s safety profile has been thoroughly evaluated in clinical practice as a GSI.
In the RINGSIDE trial, 100% of patients in the varegacestat arm experienced adverse events (AEs) of any grade, with a 57% incidence of grade 3 or higher AEs (compared to 17% in the placebo group). Common side effects included diarrhea (82%), fatigue (44%), rash (43%), and nausea (35%). Although approximately 20% of patients discontinued treatment due to AEs, there were no treatment-related deaths.
Regarding the well-known class effect of ovarian toxicity associated with GSIs, data showed an incidence of 56% among premenopausal women in the varegacestat arm versus 5% in the placebo arm. However, 55% of these symptoms resolved during treatment, and none led to treatment discontinuation. These results indicate that, through careful clinical management, such adverse events are controllable and reversible.
Clinical Significance: A "New Cornerstone" in Desmoid Tumor Care
Dr. Clay Siegall, President and CEO of Immunome, stated: "The FDA’s acceptance of our NDA for varegacestat is a vital milestone for Immunome and, more importantly, for patients living with desmoid tumors. Based on our robust clinical data, we believe varegacestat has the potential to fill the long-standing void for an effective oral treatment option in this disease."
With regulatory reviews underway, varegacestat is poised to become a standard-of-care regimen for desmoid tumors. For patients, compared to traditional "watch and wait" approaches or invasive procedures, varegacestat offers a more convenient, effective, and tolerable home-based oral option. This transition marks not only a victory for targeted therapy but also a significant reduction in both the physical and emotional burden of the disease.
