Zilurgisertib reduces HO volume in children aged 6 to 11 with FOP

Children aged 6 to 11 years with fibrodysplasia ossificans progressiva (FOP) who received the oral activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (Atebrioz; Mirum Pharmaceuticals) had a reduction in total heterotopic ossification (HO) volume over 24 weeks, while placebo recipients continued to accumulate heterotopic bone, according to topline results from Cohort 2 of the phase 2 PROGRESS study.¹ No zilurgisertib-treated patient developed a new HO lesion.¹

The data build on PROGRESS Cohort 1, which supported the FDA's September 2026 approval of zilurgisertib for patients aged 12 years and older.² Mirum plans to submit a supplemental new drug application in the first half of 2027 for children aged 6 to younger than 12 years.¹ Frederick S. Kaplan, MD, Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine at the University of Pennsylvania Perelman School of Medicine, noted in the company's announcement that "childhood is a critical window in FOP," and that such results raise the possibility of slowing progression before the disease's most serious consequences develop.¹

PROGRESS Cohort 2 design and zilurgisertib efficacy in pediatric FOP

Cohort 2 randomly assigned 25 children 1:1 to zilurgisertib 75 mg once daily (n = 12) or placebo (n = 13) for 24 weeks of double-blind treatment, followed by an open-label extension planned to run an additional 292 weeks.¹,³ Mean baseline age was 8.3 years, and all patients completed the double-blind period.¹

At week 24, mean (SD) total HO volume decreased by 8.09 (15.58) cm³ with zilurgisertib and increased by 9.14 (11.66) cm³ with placebo (Hodges-Lehmann treatment difference, −14.0 cm³; nominal P = .003).¹ One placebo recipient (7.7%) developed a new HO lesion.¹ Cumulative Analogue Joint Involvement Scale (CAJIS) scores, which range from 0 to 30 with higher scores indicating greater impairment, improved by a mean of 0.80 points with zilurgisertib vs 0.09 points with placebo among evaluable patients (n = 10 and n = 11); no P value was reported.¹

Safety of zilurgisertib in children aged 6 to 11 years

Mirum reported no new safety signals relative to Cohort 1, no discontinuations, and no growth plate closure among zilurgisertib-treated children.¹ Most adverse events were mild or moderate, and serious and grade 3 or higher events were less frequent with zilurgisertib than placebo.¹ Arthralgia, cough, pyrexia, and vomiting each occurred in 3 zilurgisertib recipients, more often than with placebo.¹

FOP disease burden and ALK2 inhibition with zilurgisertib

FOP is an ultra-rare genetic disorder affecting approximately 300 people in the US and 900 worldwide; pathogenic ACVR1 variants cause abnormal ALK2 activation that drives bone formation in muscles, tendons, and ligaments.¹ In a natural history cohort of 114 individuals, HO volume rose with age by an estimated 25.6 cm³ per year and correlated with functional impairment.⁴

In Cohort 1, 63 patients aged 12 years and older received 100 mg daily; at week 24, total new HO volume decreased by 3.2 cm³ with zilurgisertib vs an increase of 24.6 cm³ with placebo.¹,² Zilurgisertib is contraindicated in pregnancy.¹

Interpreting pediatric PROGRESS data for zilurgisertib in FOP

The direction of effect mirrors Cohort 1, and the absence of new lesions is notable in an age group in which HO typically accumulates. Still, the cohort was small, the wide SDs suggest substantial between-patient variability, and the P value is nominal. Natural history data suggest CAJIS worsens by roughly 0.5 points per year, and investigators have cautioned that the scale may not capture meaningful progression over 1 to 2 years, so a sub-1-point change at 24 weeks should be interpreted carefully.⁴

References

1. Mirum Pharmaceuticals announces positive results from Cohort 2 of the pivotal PROGRESS study of Atebrioz (zilurgisertib) in pediatric patients aged 6 to <12 years with fibrodysplasia ossificans progressiva. News release. Mirum Pharmaceuticals, Inc. October 26, 2026. Accessed October 26, 2026. https://www.businesswire.com/news/home/20261026062788/en/

2. Mirum Pharmaceuticals and Incyte announce U.S. FDA approval of Atebrioz (zilurgisertib) for adult and pediatric patients with fibrodysplasia ossificans progressiva. News release. Mirum Pharmaceuticals, Inc. September 2026. Accessed October 26, 2026. https://ir.mirumpharma.com/news/news-details/2026/Mirum-Pharmaceuticals-and-Incyte-Announce-U-S--FDA-Approval-of-Atebrioz-zilurgisertib-for-Adult-and-Pediatric-Patients-with-Fibrodysplasia-Ossificans-Progressiva/default.aspx

3. To assess the efficacy, safety, and tolerability of INCB000928 in participants with fibrodysplasia ossificans progressiva. ClinicalTrials.gov identifier: NCT05090891. Accessed October 26, 2026. https://clinicaltrials.gov/study/NCT05090891

4. Pignolo RJ, Baujat G, Brown MA, et al. Natural history of fibrodysplasia ossificans progressiva: cross-sectional analysis of annotated baseline phenotypes. Orphanet J Rare Dis. 2019;14(1):98. doi:10.1186/s13023-019-1068-7