FDA Approves Zilurgisertib, an Oral ALK2 Inhibitor, for FOP

The FDA has approved zilurgisertib (Atebrioz; Mirum Pharmaceuticals, Incyte Therapeutics), a once-daily oral activin receptor-like kinase 2 (ALK2) inhibitor, to reduce the volume of total new heterotopic ossification (HO) in adults and pediatric patients aged 12 and older with fibrodysplasia ossificans progressiva (FOP), according to news releases from the FDA and Mirum Pharmaceuticals.^1,2

For pharmacists, the approval brings a third treatment option for an ultra-rare disease, along with a label that carries clinically relevant drug interactions, including a recommendation to avoid concomitant use with metformin.^1-3

FOP is a genetic disease caused by a mutation in the activin A receptor type 1 (ACVR1) gene. It causes muscle, tendons, and ligaments to gradually turn into bone, leading to limited movement, deformities, severe disability, and early death. It affects approximately 300 people in the US and 900 worldwide.^1,2

A Third Option With a Different Profile

Patients with FOP have constitutively active ALK2 signaling that drives HO; zilurgisertib inhibits both wild-type ALK2 and the pathogenic R206H variant. It joins palovarotene (Sohonos; Ipsen), an oral agent whose dose increases at the time of a flare-up, and garetosmab-grts (Pasatru; Regeneron), an intravenous infusion given every 4 weeks and approved for adults.^3-5

PROGRESS Trial Results

Approval was based on cohort 1 of the phase 2 PROGRESS trial (NCT05090891). The trial randomly assigned 63 patients (28 adults and 35 pediatric patients aged 12 years and older) to zilurgisertib 100 mg or placebo once daily for 24 weeks, followed by an open-label extension. The median age was 16 years. At week 24, the mean change in total new HO volume was −3.2 cm³ with zilurgisertib versus +24.6 cm³ with placebo, a Hodges-Lehmann estimated treatment difference of −15.8 cm³ (95% CI, −32.1 to −6.0).^1,3

The trial's primary end point, the proportion of patients who developed new HO lesions, favored zilurgisertib numerically (3.1% vs 16.7%; P = .0986) but did not reach statistical significance. According to Mirum and Incyte, no new HO lesions were observed through week 48 among the 61 patients with available scans, including those who crossed over from placebo.^1,2,6

Dosing and Interaction Considerations

The recommended dose is 100 mg (four 25-mg tablets) once daily with or without food. Tablets may be swallowed whole or crushed and mixed with 60 mL of water, orange juice, applesauce, or plain yogurt, then taken immediately. Patients should not take zilurgisertib with grapefruit, pomelo, or juices containing them.³

Zilurgisertib is a CYP3A4 substrate. The label calls for reducing the dose to 50 mg once daily with a strong CYP3A4 inhibitor and avoiding strong or moderate CYP3A4 inducers; rifampin, a prescription antibiotic and strong CYP3A4 inducer, decreased zilurgisertib’s area under the curve by 79%. Zilurgisertib also inhibits MATE1 and MATE2-K, so concomitant use with substrates such as metformin should be avoided. If unavoidable, clinicians should monitor for adverse reactions and consider reducing the substrate dose.³

Safety and Counseling Points

Zilurgisertib is contraindicated in pregnancy. Pregnancy should be ruled out before initiation, and females of reproductive potential should use effective contraception during treatment and for 1 week after the final dose. Breastfeeding is not recommended during treatment and for at least 1 week afterward. 3

Adverse reactions reported more often with zilurgisertib than placebo included:^1-3

• headache (22% vs 16%);
• arthralgia (22% vs 10%);
• upper respiratory tract infection (22% vs 10%);
• epistaxis (13% vs 0%); and
• nausea (13% vs 3%).

Patients receiving zilurgisertib also had mean increases in serum iron, hemoglobin, and transferrin saturation. These remained within the normal range and were not associated with signs of iron overload through week 100. According to the companies, no adverse events led to discontinuation or dose reduction during the placebo-controlled period.^2,3

Zilurgisertib is expected to be available in the US in October through the Mirum Access Plus patient support program, with eligible patients paying as little as $0 per month. Studies in children aged 2 to younger than 12 years are ongoing.²

REFERENCES

1. FDA approves third treatment for fibrodysplasia ossificans progressiva. News release. FDA. Released September 25, 2026. Accessed September 28, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-third-treatment-fibrodysplasia-ossificans-progressiva

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. Released September 25, 2026. Accessed September 28, 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. Atebrioz (zilurgisertib) tablets, for oral use. Prescribing information. Mirum Pharmaceuticals, Inc.; revised September 2026. Accessed September 28, 2026. https://files.mirumpharma.com/atebrioz/Atebrioz-USPI-MedGuide.pdf

4. FDA approves first treatment for fibrodysplasia ossificans progressiva. News release. FDA. Released August 17, 2023. Accessed September 28, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-fibrodysplasia-ossificans-progressiva

5. FDA approves second treatment for fibrodysplasia ossificans progressiva. News release. FDA. Released August 19, 2026. Accessed September 28, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-second-treatment-fibrodysplasia-ossificans-progressiva

6. Mirum Pharmaceuticals and Incyte announce positive pivotal phase 2 results from PROGRESS study of zilurgisertib in fibrodysplasia ossificans progressiva. News release. Mirum Pharmaceuticals, Inc. Released June 14, 2026. Accessed September 28, 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