An NDA seeking the approval of varegacestat for the treatment of adult patients with desmoid tumors has been submitted to the FDA.
A new drug application (NDA) seeking the approval of investigational, once-daily gamma secretase inhibitor varegacestat (AL102) for the treatment of adult patients with desmoid tumors has been submitted to the FDA.1
The NDA is supported by data from the phase 3 RINGSIDE trial (NCT04871282), which met its primary end point of progression-free survival (PFS) with varegacestat in patients with progressing desmoid tumors. Varegacestat led to an 84% reduction in the risk of disease progression or death vs placebo (HR, 0.16; 95% CI, 0.071-0.375; P < .0001), and the confirmed objective response rates (ORRs) per RECIST 1.1 as assessed by blinded independent central review (BICR) were 56% and 9%, respectively (P < .0001).
Data from an exploratory analysis demonstrated that the median best change in tumor volume was –83% in the investigational arm compared with 11% in the placebo arm. RINGSIDE also met all key secondary end points, with varegacestat producing significant improvements compared with placebo in landmark tumor volume reduction and worst pain intensity.
“The varegacestat NDA submission marks an important milestone for Immunome. It reflects the strength of the RINGSIDE data set and the commitment of the team advancing this program,” Clay B. Siegall, PhD, president and chief executive officer of Immunome, stated in a news release. “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.”
RINGSIDE was a global, randomized, double-blind trial that enrolled adult patients with progressing desmoid tumors.1,2 Patients were also required to have at least 1 measurable lesion amenable to volume measurements by MRI at screening and have recurrent/refractory disease after at least 1 line of therapy, including surgery, radiation, or systemic therapy.2 Of note, patients who were treatment naive could receive varegacestat if deemed appropriate by the investigator.
The study included 156 patients who were randomly assigned to receive either varegacestat at 1.2 mg daily or placebo until disease progression or death.1 This population represents the largest of its kind to be assessed in a randomized trial, according to Immunome.
The primary end point was PFS as assessed by BICR. Secondary end points included ORR per RECIST 1.1 criteria and change in tumor volume at week 24 per BICR, change in pain intensity at week 12, duration of response, best reduction in tumor volume, patient-reported outcomes, and safety and tolerability.
RINGSIDE includes an ongoing open-label extension phase.
Topline safety data from RINGSIDE demonstrated that varegacestat was generally well tolerated, with a manageable safety profile consistent with the gamma secretase inhibitor class.1 The most common any-grade adverse effects (AEs) in the investigational arm included diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). Most AEs were grade 1 or 2 in severity.
Data from RINGSIDE were selected for presentation in an oral abstract session at the 2026 American Society of Clinical Oncology Annual Meeting, according to Immunome.
