Atebrioz

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder caused by gain-of-function variants in ACVR1 (ALK2); an estimated 97% of affected individuals carry the R206H variant. It is characterized by congenital malformations of the great toes and by progressive heterotopic ossification (HO) in specific anatomic patterns, often after episodic flare-ups. The estimated minimum prevalence is 0.88 per million in the United States (2020), and estimates in France are 1.36 per million (2012) and 1.39 per million (2020); the manufacturer states that the disease affects approximately 300 people in the United States and 900 worldwide. In an international survey, 87% of individuals initially received an incorrect diagnosis, and the mean time from symptom onset to correct diagnosis was 4.1 years.

Disability is cumulative: most patients are “confined to a wheelchair by the third decade of life” and require lifelong assistance with activities of daily living. Among 60 deaths reported in the international FOP community, the median age at death was 40 years; the estimated median lifespan was 56 years (95% CI 51 to 60), and cardiorespiratory failure from thoracic insufficiency syndrome accounted for 54% of deaths. In an international burden-of-illness survey, the mean EQ-5D-5L index score of participants aged 13 years and older was 0.24 (n = 152), and it decreased from 0.61 at the lowest level of mobility restriction to 0.05 at the highest.

In a French case-control study, mean total annual healthcare expenditure in individuals with FOP was more than 10 times that of matched controls from a societal perspective and 14 times from a payer perspective. In the international survey, U.S. respondents in the two highest levels of mobility restriction reported mean FOP-related costs of approximately 22,000 U.S. dollars, with an upper range of approximately 164,000 U.S. dollars at the highest level; family members spent a mean of 8 hours per day providing care, and 51.3% of primary caregivers reported adapting their careers.

Zilurgisertib is an oral, selective inhibitor of wild-type and R206H-mutant ALK2, taken as 100 mg once daily. The efficacy evidence comes from Cohort 1 of PROGRESS (NCT05090891), a phase 2, randomized, double-blind, placebo-controlled trial in which 63 participants aged 12 years and older (28 adults and 35 pediatric participants aged 12 to 16 years) received zilurgisertib 100 mg (n = 32) or placebo (n = 31) once daily for 24 weeks, followed by an open-label extension of zilurgisertib.

The protocol-specified primary endpoint was the proportion of participants with new HO lesions at Week 24: 1 of 32 (3.1%) with zilurgisertib and 5 of 30 (16.7%) with placebo (P = 0.0986). The manufacturer states that the pivotal study “did not reach statistical significance on the primary endpoint”. The prescribing information establishes efficacy on a different measure, total new HO volume on whole-body CT excluding the head, which includes expansion of baseline HO as well as new discrete HO. At Week 24, the mean change from baseline in total new HO volume was −3.2 cm³ (SD 19.9) with zilurgisertib and +24.6 cm³ (SD 51.9) with placebo, a Hodges-Lehmann treatment difference of −15.8 cm³ (95% CI −32.1 to −6.0). An interim congress report states that no participant had new lesions from Week 24 to Week 48 of the open-label extension.

Adverse reactions in at least 10% of zilurgisertib-treated participants through Week 24 were headache (22% vs 16% with placebo), arthralgia (22% vs 10%), upper respiratory tract infection (22% vs 10%), epistaxis (13% vs 0%), and nausea (13% vs 3%); serious treatment-emergent adverse events occurred in 2 participants (6.3%) vs 3 (9.7%), and no adverse event led to dose reduction or discontinuation of zilurgisertib. The label carries one warning, embryo-fetal toxicity: zilurgisertib is contraindicated in pregnancy, pregnancy is to be excluded before initiation, and effective contraception is advised during treatment and for one week after the final dose. Mean serum iron, hemoglobin, and transferrin saturation increased relative to placebo and remained within the normal range, and through Week 100 the increases were “not associated with signs or symptoms of iron overload”. Iron deficiency anemia was reported in 3 zilurgisertib-treated participants. Rats given zilurgisertib for 6 months developed hepatic iron accumulation and basophilic foci of cellular alteration, and long-term carcinogenicity studies have not been conducted.

At approval, no wholesale acquisition cost (WAC), list price, or average sales price (ASP) had been announced for Atebrioz; Mirum Pharmaceuticals plans to announce the price at the U.S. launch, expected in October 2026. A Citizens analyst quoted by Reuters estimated an annual cost of about $750,000. The manufacturer states that eligible patients may pay as little as $0 per month through its Mirum Access Plus program. For the two other FDA-approved FOP therapies, Ipsen set an average U.S. list price for Sohonos (palovarotene) of $624,000 per year at its 2023 approval, and Regeneron stated an average annual U.S. list price for Pasatru (garetosmab-grts) of about $1.4 million, ranging from $693,000 to $2.1 million by dose and body weight.

No budget impact model, cost-effectiveness analysis, or health technology assessment of zilurgisertib has been published, and the United Kingdom horizon-scanning briefing of July 2025 recorded its cost as not yet known. The only budget impact analysis in FOP identified for this report is the 2023 Canadian review of palovarotene. For palovarotene, the sponsor estimated a 3-year budget impact of $10,429,302 and CADTH estimated $14,336,341 (Canadian dollars), based on approximately 19 patients with FOP in Canada; CADTH's reanalysis estimated an incremental cost-effectiveness ratio of $13,055,900 per QALY gained for palovarotene and stated that a price reduction of more than 99% would be required for palovarotene to be cost-effective at $50,000 per QALY.

The FDA approved zilurgisertib on September 25, 2026, as the third treatment for FOP, to reduce the volume of total new HO in patients aged 12 years and older. The approval rests on one phase 2 trial cohort of 63 participants with a 24-week placebo-controlled period. The protocol-specified primary endpoint, the proportion of participants with new HO lesions, did not reach statistical significance, and efficacy was established on total new HO volume, a measure that includes expansion of existing lesions. Data after Week 24 come from an open-label extension in which all participants received zilurgisertib, reported as interim results through Week 48. The effect of these radiographic changes on joint function, mobility, and survival has not been reported, and a published analysis of palovarotene states that there is no consensus threshold for a clinically meaningful reduction in new HO volume.

No head-to-head trial has compared zilurgisertib with palovarotene or garetosmab-grts, and the pivotal trials differ in design and endpoint: palovarotene was studied in a single-arm trial of 97 participants against an external natural history control, and garetosmab-grts in a 56-week placebo-controlled trial of 63 adults with the number of new HO lesions as the primary endpoint. The zilurgisertib label includes pediatric patients aged 12 years and older, a group in which the garetosmab-grts label states that safety and effectiveness have not been established, and safety and effectiveness of zilurgisertib have not been established in patients younger than 12 years. Over 24 weeks, the most common adverse reactions (10% or more) were headache, arthralgia, upper respiratory tract infection, epistaxis, and nausea, and the label warning is embryo-fetal toxicity; the label states that the clinical relevance of hepatic iron accumulation and preneoplastic findings in rats, including the potential carcinogenic risk in humans, is uncertain. No U.S. price or budget impact model for zilurgisertib is available.