Mirum reported reduced HO lesion volume with zilurgisertib in children aged 6 to under 12 years with FOP and plans an FDA submission in 2027.
Written By: Saniya Katakdhond, PharmD
Reviewed By: Pharmacally Editorial Team
Mirum Pharmaceuticals, in collaboration with Incyte, reported positive results from Cohort 2 of the Phase 2 PROGRESS study evaluating ATEBRIOZ™ (zilurgisertib) in children aged 6 to under 12 years with fibrodysplasia ossificans progressiva (FOP).
Zilurgisertib is an oral activin receptor-like kinase 2 (ALK2) inhibitor. In FOP, pathogenic variants in the ACVR1 gene cause abnormal ALK2 activation, contributing to heterotopic ossification, in which bone forms within muscles, tendons, ligaments and other soft tissues.
The findings extend the clinical evaluation of zilurgisertib to younger children following Cohort 1, which supported US Food and Drug Administration (FDA) approval in September 2026 for adults and pediatric patients aged 12 years and older. Mirum plans to submit a supplemental New Drug Application (sNDA) in the first half of 2027 to expand the approved age range.
PROGRESS Cohort 2 Study Design
Cohort 2 enrolled 25 children with FOP, with a mean baseline age of 8.3 years and a mean of 5.0 years since diagnosis. Participants were randomized to receive once-daily oral zilurgisertib 75 mg (n=12) or placebo (n=13) during a 24-week double-blind treatment period, followed by an open-label extension. All participants completed the controlled period and entered the extension.
The study assessed changes in total HO lesion volume and clinician-assessed joint mobility. Mobility was measured using the Cumulative Analogue Joint Involvement Scale (CAJIS), which ranges from 0, indicating no impairment, to 30, indicating maximum impairment.
HO Lesion Volume and Joint Mobility Results
At Week 24, mean total HO lesion volume decreased by 8.09 cm³ from baseline with zilurgisertib, compared with an increase of 9.14 cm³ with placebo. The estimated treatment difference was −14.0 cm³ in favor of zilurgisertib, with a nominal p-value of 0.003. The treatment difference was estimated using the Hodges–Lehmann method, and the p-value was calculated using a Wilcoxon rank-sum test.
No patients receiving zilurgisertib developed new HO lesions during the double-blind period, compared with one patient (7.7%) receiving placebo.
Clinician-assessed joint mobility also favored zilurgisertib. Mean CAJIS scores improved by 0.80 points with zilurgisertib and by 0.09 points with placebo. These assessments included 10 and 11 patients, respectively. The company noted that untreated patients with FOP have been reported to experience CAJIS score worsening of approximately 0.5 points annually.
Key efficacy findings
Endpoint | Zilurgisertib 75 mg once daily | Placebo |
Change in total HO lesion volume | −8.09 cm³ (n=12) | +9.14 cm³ (n=13) |
Patients with new HO lesions | 0 (0%) | 1 (7.7%) |
Change in CAJIS score | −0.80 (n=10) | −0.09 (n=11) |
The estimated HO lesion volume treatment difference was −14.0 cm³ (nominal p=0.003).
Safety and Tolerability
Zilurgisertib was generally well tolerated, with a safety profile consistent with Cohort 1. No new safety signals were identified. Most adverse events were mild or moderate, while serious adverse events and Grade 3 or higher events were infrequent and occurred less frequently with zilurgisertib than with placebo.
Adverse events occurring in more than 10% of zilurgisertib-treated patients and at a higher frequency than with placebo included arthralgia, cough, pyrexia and vomiting, each reported in three patients. Alopecia, epistaxis, falls, iron deficiency and nasopharyngitis were reported in two patients each.
No patients discontinued treatment during the double-blind period, and no growth-plate closure was reported among zilurgisertib-treated patients during this period.
Development Outlook
Mirum plans to discuss the findings with the FDA before submitting an sNDA in the first half of 2027. Cohort 3 of PROGRESS is enrolling children aged 2 to under 12 years, extending the investigation to younger patients. Longer follow-up and additional clinical data will be important to assess the durability of efficacy, functional outcomes and long-term pediatric safety.
Clinical Interpretation
The Cohort 2 findings provide evidence of zilurgisertib activity in younger children with FOP, with a reduction in total HO lesion volume relative to placebo over 24 weeks. The nominal p-value of 0.003 supports a between-group difference in the reported endpoint, while the CAJIS findings provide additional, exploratory functional context.
However, the study included only 25 patients, and CAJIS assessments were available for fewer participants than the randomized population. The absence of new HO lesions in the zilurgisertib group is encouraging but remains a descriptive finding based on a small sample. These results do not establish long-term preservation of mobility, prevention of disability or sustained disease modification. The short-controlled period also limits conclusions about long-term safety and growth.
Reference
Mirum Pharmaceuticals Announces Positive Results from Cohort 2 of the Pivotal PROGRESS Study of ATEBRIOZ™ (zilurgisertib) in Pediatric Patients Aged 6 to under 12 Years with Fibrodysplasia Ossificans Progressiva, Mirum Pharmaceuticals, Inc., and Incyte, October 26, 2026.
To Assess the Efficacy, Safety, and Tolerability of INCB000928 in Participants with Fibrodysplasia Ossificans Progressiva (Progress), ClinicalTrials.gov ID NCT05090891
About the Writer
Saniya Sanjay Katakdhond (Linkedin) is a Doctor of Pharmacy professional with hands-on experience in patient case review, clinical documentation, medical record analysis, and patient care.
Her hospital experience has strengthened her understanding of clinical conditions, treatment approaches, and multidisciplinary healthcare practices.
With ICH-GCP certification and a research-oriented approach, she brings clinical insight and attention to detail to healthcare content development.
As a healthcare writer, Saniya focuses on translating clinical knowledge and patient-care experience into clear, accurate, and evidence-informed medical content.