IMNM Varegacestat NDA Accepted: Desmoid Tumor PDUFA Apr 2027

The FDA accepted Immunome’s (IMNM) New Drug Application for varegacestat on July 8, 2026, setting a PDUFA target action date of April 28, 2027. Varegacestat is an oral, once-daily gamma-secretase inhibitor for adults with progressing desmoid tumors, a rare soft tissue tumor type with no FDA-approved therapies.

The numbers

• Ticker: IMNM
• Stock price: $22.58 (close July 25, 2026)
• Market cap: $2.56 billion
• Drug: Varegacestat (formerly AL102), an oral gamma-secretase inhibitor
• Indication: Adults with progressing desmoid tumors
• Trial: RINGSIDE Phase 3 (n=156, global, randomized, double-blind, placebo-controlled)
• PDUFA date: April 28, 2027

The RINGSIDE trial met its primary endpoint with an 84% reduction in the risk of disease progression or death versus placebo (hazard ratio 0.16, 95% CI 0.071 to 0.375, p<0.0001). The confirmed objective response rate was 56% with varegacestat versus 9% with placebo. In an exploratory analysis, the median best change in tumor volume was negative 83% with varegacestat versus positive 11% with placebo. The trial also met all key secondary endpoints, including statistically significant improvements in tumor volume reduction and worst pain intensity.

The disease

Desmoid tumors are aggressive, non-metastatic soft tissue tumors that are prone to recurrence. Approximately 1,000 to 1,650 people are diagnosed each year in the US, with 10,000 to 11,000 actively managed patients. The tumors cause debilitating pain, deformity, and in some cases life-threatening organ damage. Although not considered cancerous, they often require systemic treatment to prevent permanent disability. Current options are limited to surgery, radiation, and off-label drugs including sorafenib, methotrexate, and NSAIDs, none approved specifically for desmoid tumors.

The mechanism

Varegacestat works by inhibiting gamma-secretase, an enzyme that activates the Notch signaling pathway. In desmoid tumors, mutations in the beta-catenin gene drive aberrant Wnt signaling, and gamma-secretase inhibition disrupts the downstream signaling cascade that promotes tumor growth. The gamma-secretase inhibitor class was previously studied in Alzheimer’s disease, where it failed due to cognitive side effects from disrupting Notch signaling in the brain. In desmoid tumors, the mechanism targets the pathway driving tumor proliferation, and the safety profile is manageable for a non-malignant condition.

The most common adverse events in the RINGSIDE treatment arm were diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). Most events were grade 1 or 2.

The company

Immunome, originally focused on antibody-drug conjugates, has diversified into rare tumors with varegacestat. The company is also developing ADCs for oncology, making varegacestat one of several pipeline assets. A European Marketing Authorization Application is planned by the end of 2026.

What to watch

The risk is the safety profile. Gamma-secretase inhibitors have a history of off-target effects from Notch pathway inhibition, and the FDA will scrutinize whether the 82% diarrhea rate and other adverse events are acceptable for a non-malignant tumor type. The 275-day runway to the PDUFA date is long; watch for any FDA information requests or advisory committee scheduling in the coming months. Also watch for competitive developments: Ogsiveo (nirogacestat), SpringWorks Therapeutics’ gamma-secretase inhibitor, was approved for desmoid tumors in 2023, meaning varegacestat would not be first in class but would compete on efficacy and convenience. The 56% ORR in RINGSIDE is the highest reported in a Phase 3 desmoid tumor trial, which could differentiate it if the label is clean.

Sources: Immunome NDA acceptance press release, RINGSIDE Phase 3 results, what is a PDUFA date