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

Mirum Pharmaceuticals, Inc. and Incyte announced pivotal Phase 2 results from Cohort 1 of the PROGRESS study evaluating zilurgisertib, an investigational oral activin receptor-like kinase 2 (ALK2) inhibitor, in adolescents and adults (=12 years of age) with fibrodysplasia ossificans progressiva (FOP). Results from Cohort 1 of the PROGRESS study demonstrated a consistent treatment effect across measures of disease activity and durability through Week 48. During the open-label extension, no new HO lesions were observed among patients who continued to receive zilurgisertib or among placebo-treated patients who crossed over to active treatment at Week 24.

Cohort 1 of the PROGRESS study evaluated zilurgisertib 100 mg once-daily in 63 adolescents and adults (=12 years of age) with FOP. Patients were randomized 1:1 to receive zilurgisertib (n=32) or placebo (n=31) during a 24-week, placebo-controlled, double-blind period, followed by an open-label extension period. Baseline demographics and disease characteristics were generally balanced between treatment groups, with a mean age of approximately 21 years and evidence of recent disease activity prior to enrollment.

A total of 61 patients had 48-week whole-body CT scan data available at the time of the open-label extension analysis. Key efficacy findings included: Fewer patients receiving zilurgisertib developed new HO lesions at Week 24, with an 81% reduction versus placebo (p=0.0986). 99.9% reduction in total volume of new HO lesions in patients receiving zilurgisertib versus placebo at Week 24.

Number (%) of patients who developed new HO lesions: Zilurgisertib (ZGB) (n=32) Week 24: 1 (3.1), Placebo (n=31) Week 24: 5 (16.7), 81% reduction vs placebo, No patients with new HO lesions observed at Week 48 (n=61). Mean (SD) total number of new HO lesions: 0.06 (0.35) ZGB, 0.23 (0.63) Placebo, Fewer new lesions vs placebo, No new lesions observed (n=61). Mean (SD) new lesion volume, cm³: 0.003 (0.02) ZGB, 6.57 (20.70) Placebo, 99.9% reduction vs placebo, No new lesions observed (n=61).

Mean (SD) change in total lesion volume, cm³: -3.24 (19.86) ZGB, 24.64 (51.94) Placebo, Reduction vs increase on placebo, Continued reduction from Week 24: -6.37 (19.43) ZGB (n=32), -5.32 (20.91) crossover (n=29). Mean (SD) new flares (annualized): 2.34 (6.06) ZGB, 4.55 (7.71) Placebo, Lower flare activity vs placebo, Low flare activity maintained: 1.01 (3.26) ZGB (n=32), 1.22 (2.54) crossover (n=30). Zilurgisertib was generally well-tolerated during the 24-week placebo-controlled period of the study.

Data showed: Most adverse events were mild or moderate in severity. No adverse events led to treatment discontinuation or dose reduction. Serious adverse events and Grade =3 adverse events occurred at low rates in both treatment groups.

The most commonly reported adverse events among patients receiving zilurgisertib were FOP flare-up or aching/pain due to FOP (25%), headache (21.9%), upper respiratory tract infection (21.9%), arthralgia (18.8%), epistaxis (12.5%), and nausea (12.5%). The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for zilurgisertib for the treatment of FOP in patients 12 years of age and older and granted Priority Review. The Prescription Drug User Fee Act (PDUFA) target action date for zilurgisertib is September 26, 2026.

Zilurgisertib is an investigational, oral, small molecule, activin receptor-like kinase 2 (ALK2) inhibitor in development for the treatment of Fibrodysplasia Ossificans Progressiva (FOP). Zilurgisertib is designed to inhibit the ALK2 receptor, which is abnormally active in most patients with FOP and leads to bone formation in soft tissues, a process known as heterotopic ossification (HO). FOP is an ultra-rare genetic disease that affects approximately 300 patients in the U.S. and 900 worldwide, with diagnosis typically occurring in early childhood.

Zilurgisertib was evaluated in the PROGRESS pivotal Phase 2 study, which formed the basis of a new drug application (NDA). The FDA has accepted the NDA for zilurgisertib in FOP under Priority Review with a Prescription Drug User Fee Act (PDUFA) date of September 26, 2026. Mirum Pharmaceuticals, Inc. licensed zilurgisertib from Incyte for worldwide development and commercialization.

PROGRESS is a global, randomized, double-blind, placebo-controlled Phase 2 study evaluating the efficacy and safety of zilurgisertib in patients with fibrodysplasia ossificans progressiva (FOP). PROGRESS Cohort 1 enrolled patients 12 years of age and older who were randomized 1:1 to receive zilurgisertib 100 mg once daily or placebo during a 24-week double-blind treatment period, followed by an open-label extension. Additional PROGRESS cohorts will evaluate the efficacy and safety of zilurgisertib in patients ages 6 to.