FDA approves zilurgisertib for fibrodysplasia ossificans progressiva in patients aged 12 years and older

Adolescents and adults with fibrodysplasia ossificans progressiva (FOP) now have a once-daily oral therapy that acts directly on the receptor driving the disease. On September 25, 2026, the FDA approved zilurgisertib (Atebrioz; Mirum Pharmaceuticals/Incyte), an activin receptor-like kinase 2 (ALK2) inhibitor, to reduce the volume of total new heterotopic ossification (HO) in patients aged 12 years and older with FOP.¹ The recommended dose is 100 mg orally once daily.¹

The decision follows the August 2026 approval of garetosmab-grts (Pasatru) for adults, making zilurgisertib the third FDA-approved FOP therapy and the second option available to adolescents.³˒⁴ "Having another treatment option is meaningful in a progressive disease like FOP, particularly for adolescents who may be earlier in the course of their disease," said Robert Pignolo, MD, PhD, Robert and Arlene Kogod Professor of Geriatric Medicine at Mayo Clinic College of Medicine and lead investigator for the PROGRESS study.¹

PROGRESS phase 2 trial design and zilurgisertib efficacy in FOP

Cohort 1 of the randomized, double-blind, placebo-controlled phase 2 PROGRESS study assigned 63 patients aged 12 years and older 1:1 to zilurgisertib 100 mg daily (n = 32) or placebo (n = 31) for 24 weeks, followed by an open-label extension.² Mean age at baseline was approximately 21 years.²

The FDA based efficacy on total new HO volume, which captures both expansion of existing lesions and new discrete lesions during the 24-week double-blind period.¹ At week 24, mean total HO volume decreased by 3.2 cm³ with zilurgisertib and increased by 24.6 cm³ with placebo (nominal P = .004).¹˒²

The prespecified primary end point told a less decisive story. One patient (3.1%) receiving zilurgisertib vs 5 (16.7%) receiving placebo developed new HO lesions on whole-body CT, an 81% relative reduction that did not reach statistical significance (P = .0986).² Mean new lesion volume was 0.003 cm³ vs 6.57 cm³ (nominal P < .001), and annualized new flares averaged 2.34 vs 4.55.² Through week 48, no new HO lesions were detected among 61 patients with CT data, including those who crossed over from placebo.²

The most common adverse reactions were headache, arthralgia, upper respiratory tract infection, epistaxis, and nausea; most events were mild or moderate, and none led to discontinuation or dose reduction.¹ FOP flare-up or FOP-related pain was reported in 25% of zilurgisertib-treated patients.² The label carries an embryo-fetal toxicity warning, and patients of reproductive potential should use effective contraception.¹

FOP disease burden and heterotopic ossification treatment options

FOP affects approximately 300 people in the US and 900 worldwide, with symptoms typically emerging in early childhood.¹ Pathogenic ACVR1 variants cause aberrant ALK2 activation, driving bone formation in muscles, tendons, and ligaments; as HO accumulates, it progressively restricts movement and function.¹

Palovarotene (Sohonos), a retinoic acid receptor gamma agonist, was approved in 2023 for females aged 8 years and older and males aged 10 years and older, using a daily regimen that is escalated during flare-ups.³ Garetosmab is administered by intravenous infusion every 4 weeks and is indicated only for adults.⁴ Zilurgisertib adds a fixed-dose oral option that targets ALK2 directly in patients aged 12 years and older.¹

References

1. Mirum Pharmaceuticals, Incyte. Mirum Pharmaceuticals and Incyte announce U.S. FDA approval of Atebrioz (zilurgisertib) for adult and pediatric patients with fibrodysplasia ossificans progressiva. News release. Business Wire. September 25, 2026. Accessed September 25, 2026. https://www.businesswire.com/news/home/20260925436454/en/

2. Mirum Pharmaceuticals, Incyte. Mirum Pharmaceuticals and Incyte announce positive pivotal phase 2 results from PROGRESS study of zilurgisertib in fibrodysplasia ossificans progressiva. News release. June 14, 2026. Accessed September 25, 2026. https://ir.mirumpharma.com/news/news-details/2026/Mirum-Pharmaceuticals-and-Incyte-Announce-Positive-Pivotal-Phase-2-Results-from-PROGRESS-Study-of-Zilurgisertib-in-Fibrodysplasia-Ossificans-Progressiva/default.aspx

3. US Food and Drug Administration. FDA approves first treatment for fibrodysplasia ossificans progressiva. Published August 16, 2023. Accessed September 25, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-fibrodysplasia-ossificans-progressiva

4. US Food and Drug Administration. FDA approves second treatment for fibrodysplasia ossificans progressiva. Published August 19, 2026. Accessed September 25, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-second-treatment-fibrodysplasia-ossificans-progressiva