Mirum Pharmaceuticals announced new data from the pivotal Phase II PROGRESS study showing that zilurgisertib, an oral ALK2 inhibitor licensed from Incyte, substantially suppressed heterotopic ossification (HO) in patients with fibrodysplasia ossificans progressiva (FOP) over 24 weeks, with benefits that persisted and deepened through a 48-week open-label extension. The results come as Mirum advances the candidate toward a potential US approval, with the FDA having accepted a New Drug Application for Priority Review and set a PDUFA date of September 26, 2026. If approved, zilurgisertib could become the first approved oral therapy for FOP in the US.
FOP is among the most severe rare genetic disorders known, affecting approximately 300 patients in the US and 900 worldwide. Caused by gain-of-function mutations in the ALK2 receptor, the disease drives progressive bone formation in soft tissue, locking patients into increasingly restricted movement over decades. There is no approved disease-modifying therapy, and management has historically been limited to supportive care and avoidance of triggers.
Trial data
The PROGRESS Cohort 1 study is a randomized, double-blind, placebo-controlled Phase II trial enrolling 63 adolescents and adults aged 12 and older, randomized 1:1 to zilurgisertib 100 mg once daily or placebo for 24 weeks, followed by an open-label extension in which placebo patients crossed over to active treatment.
The primary endpoint—proportion of patients developing new heterotopic ossification lesions at Week 24—showed an 81% reduction with zilurgisertib versus placebo (3.1% vs. 16.7%), though this did not achieve nominal statistical significance (p=0.0986), likely reflecting the small sample size inherent to an ultra-rare disease population. The volume endpoint told a clearer story: new HO lesion volume was reduced by 99.9% compared with placebo (nominal p<0.0001), and total existing HO lesion volume decreased in the zilurgisertib group while increasing in placebo patients (nominal p=0.004). Flare activity was also lower in treated patients.
The extension data are clinically notable. Among all 61 patients with 48-week CT data available—including those who crossed over from placebo—no new HO lesions were observed, and total lesion volume continued to decline. The crossover cohort's response after switching to active treatment suggests the suppression of new bone formation is attributable to the drug rather than natural disease fluctuation.
Zilurgisertib was generally well-tolerated. No treatment discontinuations or dose reductions occurred due to adverse events. The most common adverse events included FOP flare-up or pain (25%), headache (21.9%), and upper respiratory tract infection (21.9%).