Zilurgisertib Cuts New Bone Formation in FOP, FDA Grants Priority Review

The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for zilurgisertib, an investigational therapy for fibrodysplasia ossificans progressiva (FOP), under Priority Review.

The regulatory milestone follows positive pivotal Phase 2 findings presented in a late-breaking session at ENDO 2026, the Endocrine Society’s annual meeting. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of September 26, 2026, positioning the therapy for a potential approval later this year.

FOP is an ultra-rare genetic disorder affecting approximately 300 patients in the United States and an estimated 900 patients worldwide. The disease causes painful flare-ups, progressive disability, severe loss of mobility, and cumulative organ and skeletal complications. Because new bone formation is irreversible, therapies that can prevent or reduce heterotopic ossification (HO) remain a major unmet need.

PROGRESS Phase 2 Results

The pivotal Cohort 1 portion of the PROGRESS study (NCT05090891) enrolled 63 patients aged 12 years and older with evidence of recent disease activity. Participants were randomized 1:1 to receive zilurgisertib 100 mg once daily (n=32) or placebo (n=31) during a 24-week double-blind treatment period, followed by an open-label extension.

At Week 24, only one patient receiving zilurgisertib developed a new HO lesion compared with five patients receiving placebo, representing an 81% reduction. The therapy also reduced the total volume of new HO lesions by 99.9% versus placebo (nominal p<0.0001), highlighting a substantial effect on disease progression.

Investigators further observed a reduction in total existing HO lesion volume among patients treated with zilurgisertib, while lesion burden increased in the placebo group (nominal p=0.004). These findings suggest the therapy may not only prevent new bone formation but also reduce overall disease burden.

The treatment effect remained durable through Week 48. No new HO lesions were detected among patients who continued zilurgisertib treatment during the open-label extension. Similarly, patients who crossed over from placebo to active treatment after Week 24 also showed no new HO lesions through Week 48. Total lesion volume continued to decline in both groups during the extension period.

Disease flare activity also improved. Annualized flare rates were nearly halved during the placebo-controlled period and remained low through Week 48, supporting sustained disease control beyond the primary analysis period.

Safety Profile

Zilurgisertib was generally well tolerated during the study. Most adverse events were mild or moderate in severity, and no treatment-related adverse events resulted in dose reductions or treatment discontinuation. Serious adverse events and Grade 3 or higher adverse events occurred infrequently in both treatment groups.

The most commonly reported adverse events among patients receiving zilurgisertib included FOP-related pain or flare-ups, headache, upper respiratory tract infection, arthralgia, epistaxis, and nausea.

Mechanism of Action

Developed by Incyte and licensed to Mirum Pharmaceuticals for global development and commercialization, zilurgisertib is an oral activin receptor-like kinase 2 (ALK2) inhibitor. The therapy inhibits abnormal ALK2 signaling, the key driver of HO, a process in which bone forms progressively within muscles, tendons, ligaments, and other soft tissues in patients with FOP.

Clinical Implications

The PROGRESS findings further support zilurgisertib as a potential disease-modifying therapy for FOP, with durable reductions in new heterotopic ossification, lesion burden, and flare activity through 48 weeks.

Steven Stein, M.D., Executive Vice President, Chief Medical Officer and Head of Late-Stage Development at Incyte, said the ENDO 2026 data strengthen the clinical evidence supporting zilurgisertib in FOP.

Joanne Quan, M.D., Chief Medical Officer at Mirum Pharmaceuticals, emphasized the continued need for additional treatment options and expressed confidence in the program’s future development.

Additional PROGRESS cohorts are evaluating zilurgisertib in younger pediatric patients, while the FDA is reviewing the NDA under Priority Review.

 Reference

Mirum Pharmaceuticals, Inc. – Mirum Pharmaceuticals and Incyte Announce Positive Pivotal Phase 2 Results from PROGRESS Study of Zilurgisertib in Fibrodysplasia Ossificans Progressiva

Mirum Pharmaceuticals and Incyte Announce Positive Pivotal Phase 2 Results from PROGRESS Study of Zilurgisertib in Fibrodysplasia Ossificans Progressiva | Incyte