Summary: regulatory status in the United States and the European Union

The FDA approved Atebrioz (zilurgisertib) tablets on September 25, 2026, one day before the September 26, 2026 PDUFA target action date, to reduce the volume of total new heterotopic ossification in adults and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva. The NDA had been accepted with Priority Review by May 2026 and was based on Cohort 1 of the Phase 2 PROGRESS study, whose primary endpoint did not reach statistical significance; the NDA was supported by secondary endpoints. Zilurgisertib holds FDA Fast Track and orphan drug designations, and the FDA issued a Rare Pediatric Disease Priority Review Voucher to Incyte at approval. Incyte developed zilurgisertib and licensed worldwide development and commercialization rights to Mirum Pharmaceuticals in April 2026. In the European Union, zilurgisertib received orphan designation EU/3/25/3119 on August 22, 2025, and a marketing authorization application is under review by the EMA. U.S. commercial availability is expected in October 2026.

FDA approval

“The U.S. Food and Drug Administration (FDA) has approved Atebrioz (zilurgisertib) tablets to reduce the volume of total new heterotopic ossification (bone formation outside the skeleton) in adults and pediatric patients 12 years and older with fibrodysplasia ossificans progressiva (FOP).” (opens the source at this quote in a new tab)

Field	Quoted record
Drug name	“Atebrioz”
Active ingredient	“zilurgisertib”
Approval date	“9/25/2026”
FDA-approved use on approval date	“To reduce the volume of total new heterotopic ossification in adults and pediatric patients 12 years and older with fibrodysplasia ossificans progressiva”

“Initial U.S. Approval: 2026” (opens the prescribing information at this quote)

Regulatory submission: NDA submitted by May 2026

“U.S. FDA accepted the New Drug Application (NDA) for zilurgisertib in FOP patients 12 years and older and granted Priority Review with a Prescription Drug User Fee Act (PDUFA) date of September 26, 2026.” (opens the source at this quote in a new tab)
“Results from the pivotal Phase 2 PROGRESS study in FOP formed the basis of the NDA filing for zilurgisertib; Incyte plans to present the results at an upcoming medical conference.” (opens the source at this quote in a new tab)

“The FDA has accepted for review Incyte’s NDA with a PDUFA date of September 26, 2026.” (opens the source at this quote in a new tab)

Launch: Anticipated in October 2026

“Atebrioz is expected to be commercially available in the U.S. in October, with eligible patients paying as little as $0 per month through MAP.” (opens the source at this quote in a new tab)

Primary endpoint of the pivotal study and the basis of the NDA

“In addition, while the NDA for zilurgisertib is supported by secondary endpoints, the pivotal study did not reach statistical significance on the primary endpoint.” (opens the source at this quote in a new tab)

“Atebrioz was approved based on data from Cohort 1 of the PROGRESS study evaluating zilurgisertib in adult and pediatric patients aged 12 years and older with FOP. Efficacy was established based on total new HO lesion volume.” (opens the source at this quote in a new tab)

Fast Track, Priority Review, and Orphan Drug designations

“Atebrioz received fast track, priority review and orphan drug designation for this indication.” (opens the source at this quote in a new tab)

“The FDA has granted Fast Track designation and orphan drug designation to zilurgisertib as a treatment for patients with FOP.” (opens the source at this quote in a new tab)

Breakthrough Therapy designation

No evidence found.

Rare Pediatric Disease Priority Review Voucher

“With this approval, the FDA also issued a Rare Pediatric Disease Priority Review Voucher (PRV) to Incyte. The voucher can be used for a subsequent drug application that would not otherwise qualify for a priority review.” (opens the source at this quote in a new tab)

License of worldwide rights from Incyte to Mirum Pharmaceuticals

“Atebrioz was developed by Incyte and licensed to Mirum Pharmaceuticals, Inc. for worldwide development and commercialization.” (opens the source at this quote in a new tab)

“In April 2026, the Company entered into a license agreement with Incyte Corporation, under which the Company obtained the right to develop and commercialize zilurgisertib. Zilurgisertib is an oral small molecule ALK2 inhibitor in development for the treatment of fibrodysplasia ossificans progressiva. The Company made an upfront payment of $16.0 million in April 2026. In addition, the Company is obligated to pay royalties in the mid-to-high single digit percentage range and additional regulatory milestones of up to $48.0 million, including $25.0 million upon FDA approval, and commercial milestones of up to $15.0 million.” (opens the source at this quote in a new tab)

“In April 2026, we entered into an exclusive license agreement with Mirum Pharmaceuticals, Inc. granting Mirum worldwide rights to zilurgisertib, an ALK2 inhibitor in development for fibrodysplasia ossificans progressiva. Under the terms of the agreement, we received an upfront payment and are eligible to receive a Priority Review Voucher, and additional development and regulatory milestone payments, as well as sales-based milestones and tiered royalties in the mid-to-high single digit percent range on worldwide net sales.” (opens the source at this quote in a new tab)

“Incyte will continue to lead the development of zilurgisertib through potential approval, while Mirum will assume commercialization responsibilities, if zilurgisertib is approved.” (opens the source at this quote in a new tab)

European Union orphan designation

“This medicine was designated as an orphan medicine for the treatment of fibrodysplasia ossificans progressiva in the European Union on 22 August 2025.” (opens the source at this quote in a new tab)

Designation field	Quoted record
Active substance	“zilurgisertib”
Intended use	“Treatment of fibrodysplasia ossificans progressiva”
Orphan designation status	“Positive”
EU designation number	“EU/3/25/3119”
Date of designation	“22/08/2025”
Sponsor	“Incyte Biosciences Distribution B.V.”

European Union marketing authorization application

“In the European Union, a marketing authorization application (MAA) for zilurgisertib is currently under review by the European Medicines Agency (EMA), supported by data from Cohort 1 (patients aged 12 years and older) of the PROGRESS study.” (opens the source at this quote in a new tab)

Ongoing development in children younger than 12 years

“The PROGRESS development program also continues to advance, with enrollment completed in Cohort 2 of children aged 6 to <12 years, and enrollment underway in Cohort 3 of children aged 2 to <12 years.” (opens the source at this quote in a new tab)

Compassionate use before approval

“However, individuals with FOP, ages 12 and over, living in the United States, may be able to use zilurgisertib through a new Compassionate Use Program opened by Mirum and Incyte.” (opens the source at this quote in a new tab)

Earlier development for anemia

“The oral, potent, and highly selective activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (INCB000928) is in development as a treatment for fibrodysplasia ossificans progressiva (FOP), and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma.” (opens the source at this quote in a new tab)

Manufacturer: Mirum Pharmaceuticals

“Manufactured for: Mirum Pharmaceuticals, Inc., Foster City, CA 94404” (opens the prescribing information at this quote)
“Licensed from: Incyte Corporation, Wilmington, DE 19803” (opens the prescribing information at this quote)
“ATEBRIOZ is a trademark of Incyte.” (opens the prescribing information at this quote)

“Mirum Pharmaceuticals, Inc. licensed zilurgisertib from Incyte for worldwide development and commercialization.” (opens the source at this quote in a new tab)

Brand name, generic name, and therapeutic class

“ATEBRIOZ™ (zilurgisertib) tablets, for oral use” (opens the prescribing information at this quote)
“ATEBRIOZ is an activin receptor-like kinase-2 (ALK2) inhibitor indicated to reduce the volume of total new heterotopic ossification (HO) in adults and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva (FOP).” (opens the prescribing information at this quote)

Development code

“INCB00928 (zilurgisertib)” (opens the source at this quote in a new tab)
“In May 2022, we initiated a Phase 2 trial evaluating zilurgisertib (INCB00928) in patients with fibrodysplasia ossificans progressiva” (opens the source at this quote in a new tab)

Active moiety and salt form

“ATEBRIOZ contains the active moiety zilurgisertib, an activin receptor–like kinase-2 (ALK-2) inhibitor, in the form of zilurgisertib fumarate dihydrate.” (opens the prescribing information at this quote)

Tablet strength and appearance

“ATEBRIOZ Tablets: 25 mg of zilurgisertib, film-coated, white to off-white, round, debossed with "INCY" on one side and "25" on the other side.” (opens the prescribing information at this quote)

Tablet composition and excipients

“Each tablet contains 25 mg of zilurgisertib (equivalent to 32.55 mg of zilurgisertib fumarate dihydrate) and the following inactive ingredients, colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose. The tablet coating consists of polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.” (opens the prescribing information at this quote)

Package presentation and storage

“ATEBRIOZ contains 25 mg of zilurgisertib and is available as a round, white to off-white film-coated tablet debossed on one side with "INCY" and "25" on the other side in bottles of 120 tablets with child-resistant closure (NDC 79378-029-16). Dispense in a tight container (See USP).” (opens the prescribing information at this quote)
“Store ATEBRIOZ tablets at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC and 30ºC (59ºF and 86ºF) [see USP Controlled Room Temperature].” (opens the prescribing information at this quote)

Tablet strengths used in the phase 1 studies

“Both studies used a tablet formulation of the study drug, with doses comprising 5-mg or 25-mg tablets.” (opens the source at this quote in a new tab)

Summary: announced, estimated, and comparator prices

As of 26 September 2026, Mirum Pharmaceuticals had announced no wholesale acquisition cost, list price, or average sales price for Atebrioz; the company stated that it would announce the price at the U.S. launch planned for October 2026. The only published price figure is an estimate of about $750,000 per year attributed by Reuters to a named Citizens analyst. The United Kingdom horizon-scanning briefing of July 2025 recorded the cost as not yet known. For the two other FDA-approved FOP therapies, Ipsen stated an average U.S. list price for Sohonos of $624,000 per year at its 2023 approval, and Regeneron stated an average annual U.S. list price for Pasatru of about $1.4 million, with a range of $693,000 to $2.1 million by dose and body weight. In the 2023 Canadian review, the submitted price of palovarotene was $324.22 (Canadian) per mg, corresponding to about $622,373 per year for patients younger than 14 years and $1,022,894 per year for patients aged 14 years and older.

United States wholesale acquisition cost and average sales price of zilurgisertib

“Mirum expects to launch the drug in October and plans to announce its price at the launch, CEO Chris Peetz told Reuters.” (opens the source at this quote in a new tab)

Analyst estimate of the annual price of zilurgisertib

“Citizens analyst Jonathan Wolleben estimates Atebrioz could cost about $750,000 annually and generate roughly $150 million in peak worldwide sales.” (opens the source at this quote in a new tab)

Estimated cost in the United Kingdom horizon scan

“Estimated Cost The cost of zilurgisertib is not yet known.” (opens the source at this quote in a new tab)

Comparator list price: Sohonos (palovarotene) in the United States

“Ipsen will sell the medicine under the brand name Sohonos at an average list price of $624,000 a year, though the cost will vary depending on insurance coverage, patient needs and support programs.” (opens the source at this quote in a new tab)

Comparator list price: Pasatru (garetosmab-grts) in the United States

“Pasatru will have an average annual, per-patient list price of about $1.4 million based on the enrollees in clinical studies, according to a Regeneron spokesperson. The drug is dosed at either 3 or 10 milligrams per kilogram of body weight, so the cost could total anywhere between $693,000 and $2.1 million, the spokesperson said.” (opens the source at this quote in a new tab)

Comparator price in Canada: palovarotene submitted price and annual cost

“Palovarotene is available as 1 mg, 1.5 mg, 2.5 mg, 5 mg, and 10 mg capsules at a submitted price of $324.22 per mg.” (opens the source at this quote in a new tab)

“Treatment with Sohonos is expected to cost approximately $1,022,894 per year for patients aged 14 years and older and $622,373 per year for patients younger than 14 years.” (opens the source at this quote in a new tab)

American Hospital Formulary Service classification and WHO Anatomical Therapeutic Chemical code

No evidence found.

Pharmacologic class stated in the prescribing information

“ATEBRIOZ is an activin receptor-like kinase-2 (ALK2) inhibitor indicated to reduce the volume of total new heterotopic ossification (HO) in adults and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva (FOP).” (opens the prescribing information at this quote)

Approved indication

“ATEBRIOZ is indicated to reduce the volume of total new heterotopic ossification (HO) in adults and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva (FOP).” (opens the prescribing information at this quote)

Definition of total new heterotopic ossification volume in the label

“Efficacy was established based on the effect of ATEBRIOZ on total new HO lesion volume (assessed by whole-body computed tomography [WBCT], excluding the head) compared to placebo during the double-blind period. Total new HO lesion volume includes expansion of baseline HO lesion burden as well as any new discrete HO that developed during the 24-week” (opens the prescribing information at this quote)

Age limit of the indication

“The safety and effectiveness of ATEBRIOZ have not been established in pediatric patients younger than 12 years of age.” (opens the prescribing information at this quote)

Inhibition of wild-type and R206H-mutant ALK2

“FOP is a progressive disease caused by a monoallelic gain-of-function mutation in the activin A receptor, Type I (ACVR1) gene that codes the ALK2 Type I receptor in the bone morphogenetic protein (BMP) signaling pathway. Patients with FOP have constitutively active ALK2 signaling that causes HO. Zilurgisertib is an oral, and selective inhibitor of both wild-type ALK2 and pathogenic ALK2 (R206H mutation). Target engagement of zilurgisertib inhibits ALK2 mediated signaling and reduces endochondral bone formation.” (opens the prescribing information at this quote)

Kinase selectivity in preclinical characterization

“Here we describe the discovery and preclinical characterization of zilurgisertib, a novel small-molecule inhibitor of ALK2 kinase with high biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and excellent oral bioavailability in preclinical species.” (opens the source at this quote in a new tab)

Biochemical selectivity of zilurgisertib against related BMP and TGFβ type I receptor kinases

Kinase	IC50 (μM)	Selectivity ratio (over ALK2 FOP)
ALK2 FOP (ACVR1-R206H)	“0.019”	“−”
ALK2 wild-type (ACVR1)	“0.021”	“1.1”
ALK1 (ACVRL1)	“0.31”	“16”
ALK3 (BMPR1A)	“0.92”	“48”
ALK6 (BMPR1B)	“3.00”	“158”
ALK5 (TGFBR1)	“5.80”	“305”

“We were especially intrigued by the exquisitely high selectivity over ALK5, as the inhibition of ALK5 mediated TGFβ signaling was associated with severe adverse cardiac findings.” (opens the source at this quote in a new tab)
“The lower observed selectivity over ALK1 and ALK3 is consistent with previous reports highlighting the low differences in protein sequence homology between those BMP receptors.” (opens the source at this quote in a new tab)
“The clinical safety of inhibiting ALK1, ALK3, and ALK6 is still under investigation.” (opens the source at this quote in a new tab)

Kinome-wide selectivity screening for zilurgisertib (compound 15)

“The kinome-wide selectivity of 15 was determined by using the DiscoveRx KINOMEscan platform to measure the binding affinities for approximately 450 kinases at 1 μM, and the results are summarized in the kinome dendrogram shown in Figure 3.” (opens the source at this quote in a new tab)
“The kinases bound most strongly by 15 were ALK2 and ALK6, but ALK6 binding did not translate in any corresponding ALK6 inhibitory activity in the mobility shift assay (see Table 2). Beyond the BMP receptor kinase family, 15 interacted with only 11 kinases (20–50% of control), highlighting its supreme selectivity for ALK2 (also see the Supporting Information).” (opens the source at this quote in a new tab)

Role of ALK2 in bone and iron regulation

“Inhibition of BMP signaling by targeting ALK2 to modulate hepatic hepcidin expression and thereby regulate serum iron levels is proposed as a potential treatment for ACD” (opens the source at this quote in a new tab)

Exposure-response relationship

“The exposure-response relationship and time course of the pharmacodynamic response for the effectiveness and safety of zilurgisertib have not been fully characterized.” (opens the prescribing information at this quote)

Cardiac electrophysiology

“Clinically significant QT interval prolongation was not observed at concentrations up to 6.7 times the mean maximum concentrations achieved with the recommended daily dose of ATEBRIOZ.” (opens the prescribing information at this quote)

“As both studies indicated a dose‐dependent effect of zilurgisertib on heart rate, individualized QT correction (QTcI) was used as the primary endpoint for QTc analysis.” (opens the source at this quote in a new tab)
“No significant relationship between zilurgisertib plasma concentration and change in QTcI was identified; zilurgisertib did not have a clinically relevant effect on QTc prolongation. QT effect >10 ms could therefore be excluded within the dose range studied (up to 300 mg BID). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed.” (opens the source at this quote in a new tab)

Suppression of heterotopic ossification in a mouse model

“Zilurgisertib fully suppresses HO in a pediatric mouse model of injury-induced FOP and therefore holds great potential as a novel targeted disease-modifying therapy for FOP.” (opens the source at this quote in a new tab)
“Compound 15 (zilurgisertib) was tested at four doses administered orally bid for 6 weeks in a pediatric FOP model of injury-induced HO following postnatal induction of expression of the ALK2[R206H] human FOP mutation (Alk2(R206H); Rosa26-CreERT2 compound heterozygous mice).” (opens the source at this quote in a new tab)
“Radiographic imaging revealed dose-dependent potent suppression of heterotopic bone formation and corresponding preservation of joint mobility after the 6 week treatment period.” (opens the source at this quote in a new tab)
“The lowest tested dose of 2 mg/kg bid potently reduced HO formation and fully maintained joint mobility. Complete prevention of ankylosing heterotopic bone formation was observed at bid doses ≥5 mg/kg.” (opens the source at this quote in a new tab)

Threshold pharmacokinetic/pharmacodynamic relationship for heterotopic ossification suppression

“This consistently strong efficacy observed across all dose levels suggests an atypical pharmacokinetic/pharmacodynamic (PK/PD) relationship, in which the drug merely needs to achieve a threshold level of target engagement to trigger a durable, disease-modifying effect on heterotopic bone formation.” (opens the source at this quote in a new tab)

Hepcidin and iron effects in preclinical models

“Zilurgisertib was shown to inhibit hepcidin production in cellular assays and to improve hemoglobin levels in 2 mouse models of hepcidin-associated anemia” (opens the source at this quote in a new tab)

“The liver findings in rats are consistent with the pharmacologic effects of zilurgisertib on iron homeostasis secondary to ALK2 inhibition.” (opens the prescribing information at this quote)

Iron parameters in participants with FOP

“Compared to placebo, ATEBRIOZ-treated patients experienced mean increases in serum iron, hemoglobin, and transferrin saturation levels; the mean values for all three measures remained within the normal range.” (opens the prescribing information at this quote)

Steady-state exposure in patients with FOP

“In patients with FOP receiving zilurgisertib 100 mg once daily, the steady-state zilurgisertib AUC was 11980 nM·h (30.4%) and Cmax was 893 nM (35.4%). Following multiple doses, zilurgisertib exposure was slightly greater than dose-proportional at doses above 50 mg and steady-state was achieved by Day 5. Zilurgisertib exhibited a median accumulation ratio of 1.7-fold.” (opens the prescribing information at this quote)

Absorption

“Following a single dose of 100 mg zilurgisertib in healthy subjects, the median (minimum to maximum) time to peak zilurgisertib plasma concentration (Tmax) was 2.1 hours (2.0 to 4.0 hours).” (opens the prescribing information at this quote)

“Zilurgisertib was rapidly absorbed, with median time to maximum plasma drug concentration (Cmax) of 2.0–4.1 h post-dose. Zilurgisertib exposure was more than dose proportional after single and multiple doses over the dose range tested, suggesting non-linear pharmacokinetics.” (opens the source at this quote in a new tab)

Effect of food

“Administration of a single dose of 100 mg zilurgisertib with a high-fat, high-calorie meal (50% calories from fat) had no clinically meaningful effect on zilurgisertib pharmacokinetics.” (opens the prescribing information at this quote)

“No food effect was observed on zilurgisertib pharmacokinetics, with geometric mean ratio (90% confidence interval) Cmax and area under the plasma concentration–time curve values of 0.98 (0.91 to1.06) and 1.03 (0.97 to 1.10).” (opens the source at this quote in a new tab)

Distribution

“The protein binding of zilurgisertib was 62.6%. The in vitro blood-to-plasma ratio was 1.04. The geometric mean (%CV) apparent volume of distribution (Vz/F) of zilurgisertib was 694 L (35.4%) after a single dose of 100 mg zilurgisertib in patients with FOP.” (opens the prescribing information at this quote)

Elimination, metabolism, and excretion

“After a single dose of 100 mg zilurgisertib in patients with FOP, the apparent clearance (CL/F) of zilurgisertib was 17.6 L/h (28.7%) and the elimination half-life (t½) of zilurgisertib was 27.4 hours (23%).” (opens the prescribing information at this quote)
“Zilurgisertib is predominantly metabolized by CYP3A4 and to a minor extent by CYP2D6.” (opens the prescribing information at this quote)
“Following a single oral 400 mg dose of radiolabeled zilurgisertib, 49% of the dose was recovered in feces (10% unchanged) and 38.5% in urine (28% unchanged).” (opens the prescribing information at this quote)

“Plasma half-life values ranged from 22.8 to 31.4 h, supporting once-daily dosing.” (opens the source at this quote in a new tab)
“Renal excretion under fasted conditions was 16% and 27% of total drug clearance with single and multiple doses, respectively; therefore, it was not the predominant pathway for zilurgisertib elimination.” (opens the source at this quote in a new tab)

Effect of age, sex, race, and body weight

“No clinically significant differences in the systemic exposure of zilurgisertib were observed based on age (12 to 80 years), sex (67% males, 33% females), race (74% White, 15% Black/African American, 6.5% Asian, and 2.6% other) or body weight (25 to 135 kg).” (opens the prescribing information at this quote)

Saliva as a sampling matrix

“There was a strong correlation between zilurgisertib concentrations in saliva and plasma.” (opens the source at this quote in a new tab)

Contraindication: pregnancy

“ATEBRIOZ is contraindicated in pregnancy. ATEBRIOZ can cause fetal harm when administered to a pregnant woman” (opens the prescribing information at this quote)

Embryo-fetal toxicity

“Based on its mechanism of action and findings from animal reproduction studies, ATEBRIOZ can cause fetal harm when administered to a pregnant woman. Oral administration of zilurgisertib to pregnant rats during the period of organogenesis resulted in adverse outcomes, including embryofetal lethality, decreased fetal weight, and skeletal malformations at exposures ≥ 3-times the human exposure at the clinical dose of 100 mg” (opens the prescribing information at this quote)
“For females of reproductive potential, verify that the patient is not pregnant prior to initiation of treatment. Advise females of reproductive potential to use effective contraception during treatment with ATEBRIOZ and for one week after the final dose. Advise patients to discontinue ATEBRIOZ immediately if pregnancy occurs during treatment and to contact their healthcare provider” (opens the prescribing information at this quote)

Adverse reactions occurring in 10% or more of participants through Week 24

“The safety of ATEBRIOZ was evaluated in a 24-week, multicenter, randomized, double-blind, placebo-controlled trial (Study 1; NCT05090891). Sixty-three patients (28 adults and 35 pediatric patients 12 years of age and older) with FOP were randomized to ATEBRIOZ 100 mg (n = 32) or placebo (n = 31) once daily for 24 weeks.” (opens the prescribing information at this quote)

Adverse reaction	Atebrioz (N = 32), n (%)	Placebo (N = 31), n (%)
Headache	“7 (22)”	“5 (16)”
Arthralgia	“7 (22)”	“3 (10)”
Upper respiratory tract infection	“7 (22)”	“3 (10)”
Epistaxis	“4 (13)”	“0”
Nausea	“4 (13)”	“1 (3)”

Adverse reactions occurring in fewer than 10% of participants

“In patients receiving ATEBRIOZ 100 mg orally once daily through Week 24, adverse reactions occurring in < 10% of patients included gastroenteritis, gastroesophageal reflux disease, iron deficiency anemia, rash (3 patients each), and alopecia (2 patients). None of these events were reported in the placebo group.” (opens the prescribing information at this quote)

Laboratory findings: serum iron, hemoglobin, and transferrin saturation

“No significant differences in mean ferritin change from baseline was observed between ATEBRIOZ- and placebo-treated patients, including patients who took iron supplements. Based on the data through Week 100, the increases in serum iron and transferrin saturation with ATEBRIOZ were not associated with signs or symptoms of iron overload.” (opens the prescribing information at this quote)

Nonclinical hepatic findings and carcinogenic potential

“Long-term carcinogenicity studies have not been conducted with zilurgisertib. In a 6-month repeat-dose toxicity study, rats orally administered zilurgisertib developed dose-dependent basophilic foci of cellular alterations (potential preneoplastic findings) and hepatic iron accumulation in the liver (at exposures comparable to clinical exposure).” (opens the prescribing information at this quote)
“Chronic hepatic iron overload has been associated with hepatocarcinogenesis in animal models and in certain human disease states. The clinical relevance of these findings, including the potential carcinogenic risk in humans treated with zilurgisertib, is uncertain.” (opens the prescribing information at this quote)

Mutagenicity and fertility

“Zilurgisertib is not mutagenic based on the results of a bacterial mutagenicity assay. Zilurgisertib was not clastogenic in either an in vivo micronucleus assay or a comet assay in rats, and no genotoxic effects were observed in a 28-day oral toxicity study in rats.” (opens the prescribing information at this quote)
“Zilurgisertib had no effect on fertility or reproductive function in either male or female rats at doses up to 60 mg/kg/day and 200 mg/kg/day, respectively” (opens the prescribing information at this quote)

Adverse events in healthy participants in the phase 1 studies

“In total, TEAEs were reported for 28 participants (31%) during the SAD study [zilurgisertib, n = 23 (33%); placebo, n = 5 (24%)] and 32 participants (41%) during the MAD study [zilurgisertib, n = 27 (46%); placebo, n = 5 (25%)]” (opens the source at this quote in a new tab)
“No dose-limiting toxicities were observed and no deaths occurred during either study.” (opens the source at this quote in a new tab)
“Two participants withdrew from the MAD study due to TEAEs (tachycardia, n = 1; hypersensitivity, n = 1).” (opens the source at this quote in a new tab)

Pregnancy

“There are no available data on the use of ATEBRIOZ during pregnancy to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.” (opens the prescribing information at this quote)
“In animal reproduction studies, oral administration of zilurgisertib to pregnant rats during the period of organogenesis resulted in adverse outcomes, including embryofetal lethality, decreased fetal body weight, lower viability, and skeletal malformations (one or more fused sacral centra) at exposures ≥ 3-times the clinical exposure” (opens the prescribing information at this quote)

Effects on offspring bone development in rats

“Adverse developmental effects included low pup viability and malformations (bilateral retinal folds, small eye bulge, ventricular septal defect), reflex deficits (no pupillary light reflex on post-natal day 21), and lower femur width and length, abnormal tail morphology, kidney pelvic dilatation, and decreased mating index in the offspring at doses ≥ 20 mg/kg/day (at exposures equivalent to clinical exposures by AUC).” (opens the prescribing information at this quote)

Lactation

“There are no data on the presence of zilurgisertib in human milk, the effects on the breastfed infant, or the effects on milk production. During the lactation period of the pre- and post-natal development study in rats, zilurgisertib was detected in rat pup plasma. Because of the potential for serious adverse reactions, including effects on bone development, in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ATEBRIOZ and for at least one week after the final dose.” (opens the prescribing information at this quote)

Females of reproductive potential

“Verify that the patient is not pregnant prior to initiating ATEBRIOZ” (opens the prescribing information at this quote)
“Advise females of reproductive potential to use effective contraception during treatment with ATEBRIOZ and for one week after the final dose.” (opens the prescribing information at this quote)

Pediatric patients aged 12 to 16 years

“The safety and effectiveness of ATEBRIOZ to reduce the volume of total new HO have been established in pediatric patients aged 12 years and older with FOP. Use of ATEBRIOZ for this indication is supported by evidence from an adequate and well-controlled study in 35 pediatric patients aged 12 to 16 years with FOP” (opens the prescribing information at this quote)
“In pediatric patients with FOP (12 to 16 years of age), the estimated steady-state AUC and Cmax for zilurgisertib was 11478 nM·h and 883 nM, respectively. Zilurgisertib accumulated with a median ratio of 1.6 following once daily dosing.” (opens the prescribing information at this quote)

Pediatric patients younger than 12 years

“The safety and effectiveness of ATEBRIOZ have not been established in pediatric patients younger than 12 years of age.” (opens the prescribing information at this quote)

Geriatric patients

“Clinical studies of ATEBRIOZ did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.” (opens the prescribing information at this quote)

Renal impairment

“No significant difference in the exposure of zilurgisertib was observed in patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m2, MDRD) compared to healthy subjects with normal renal function. Zilurgisertib exposure (AUC0-∞) was approximately 64% higher in patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2)” (opens the prescribing information at this quote)

“Compared with matched controls, GMRs (90% CIs) for Cmax and AUC0‐∞ were as follows: mild renal impairment, 0.92 (0.64–1.34) and 0.98 (0.77–1.24); moderate, 1.22 (0.92–1.63) and 1.64 (1.28–2.10); severe, 1.00 (0.74–1.35) and 1.70 (1.33–2.16), respectively. Among participants with ESRD, values were the following: before haemodialysis, 1.17 (0.91–1.49) and 1.47 (1.15–1.88); after, 1.32 (1.00–1.75) and 1.68 (1.29–2.19), respectively.” (opens the source at this quote in a new tab)
“Our results indicate zilurgisertib dose adjustment is not required in patients with mild renal impairment or mild to moderate hepatic impairment. However, dose adjustment may be needed in those with moderate to severe renal impairment, ESRD undergoing haemodialysis, or severe hepatic impairment.” (opens the source at this quote in a new tab)

Hepatic impairment

“The zilurgisertib Cmax and AUC in patients with moderate hepatic impairment was comparable to healthy subjects with normal hepatic function. In patients with severe hepatic impairment, zilurgisertib AUC was 25% higher and Cmax was similar to that in subjects with normal hepatic function.” (opens the prescribing information at this quote)

“Among participants with hepatic impairment, values were as follows: moderate, 1.06 (0.80–1.42) and 1.13 (0.93–1.38); severe: 1.36 (1.05–1.76) and 1.25 (1.06–1.48), respectively.” (opens the source at this quote in a new tab)
“Zilurgisertib exposure was unchanged with mild renal or moderate hepatic impairment, but increased by 30%–70% with moderate or more severe renal impairment and by 25% with severe hepatic impairment.” (opens the source at this quote in a new tab)

Strong CYP3A4 inhibitors

“Reduce the ATEBRIOZ dosage to 50 mg once daily when used concomitantly with a strong CYP3A4 inhibitor” (opens the prescribing information at this quote)
“ATEBRIOZ is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase zilurgisertib exposure” (opens the prescribing information at this quote)
“Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased the geometric mean Cmax and AUC of zilurgisertib 1.28-fold and 2.13-fold, respectively” (opens the prescribing information at this quote)

“Participants in Cohort 1 (n = 18) received zilurgisertib 100 mg on Days 1 and 10 and itraconazole 200 mg once daily on Days 6-13.” (opens the source at this quote in a new tab)
“With the concomitant administration of itraconazole, the geometric mean maximum plasma drug concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) of zilurgisertib increased by 1.28- and 2.13-fold, respectively.” (opens the source at this quote in a new tab)

CYP3A4/5 estimated to account for about half of zilurgisertib clearance

“Assuming itraconazole completely inhibited CYP3A4/5 activity and had no effect on the bioavailability of zilurgisertib, CYP3A4/5 is therefore estimated to be responsible for approximately 53% of the overall clearance of zilurgisertib.” (opens the source at this quote in a new tab)
“In addition to CYP3A4/5 inhibitors, itraconazole and hydroxy-itraconazole are also P-glycoprotein (P-gp) inhibitors.” (opens the source at this quote in a new tab)

More potent strong CYP3A4 inhibitors may increase exposure more than itraconazole did

“Strong CYP enzymes are known to vary in their magnitude of inhibition.” (opens the source at this quote in a new tab)
“such as ritonavir and ketoconazole, may cause even larger increases in its exposure than the approximately 2-fold effect seen here.” (opens the source at this quote in a new tab)
“This may require even greater zilurgisertib dose reductions, and coadministration of zilurgisertib with these drugs may not be appropriate.” (opens the source at this quote in a new tab)

Mild and moderate CYP3A4 inhibitors

“No change in ATEBRIOZ dosage is needed when used concomitantly with a mild or moderate CYP3A4 inhibitor” (opens the prescribing information at this quote)
“Coadministration of zilurgisertib with moderate CYP3A4 inhibitors (ciprofloxacin, erythromycin, and fluconazole) is predicted to increase the Cmax and AUC of zilurgisertib 1.09-1.13 and 1.50-1.78-fold, respectively.” (opens the prescribing information at this quote)

Strong and moderate CYP3A4 inducers

“Avoid concomitant use of ATEBRIOZ with strong or moderate CYP3A4 inducers. Strong or moderate CYP3A4 inducers decrease zilurgisertib plasma concentrations” (opens the prescribing information at this quote)
“Coadministration of rifampin (a strong CYP3A4 inducer) decreased zilurgisertib Cmax and AUC by 56% and 79%, respectively” (opens the prescribing information at this quote)
“Concomitant use of efavirenz (a moderate CYP3A4 inducer) is predicted to decrease zilurgisertib Cmax and AUC by 25% and ~60%, respectively” (opens the prescribing information at this quote)

“With the concomitant administration of rifampin, there was a 2.27- and 4.76-fold reduction in the geometric mean Cmax and AUC0-inf of zilurgisertib, respectively.” (opens the source at this quote in a new tab)
“Zilurgisertib dose adjustment may be necessary with concomitant administration of strong CYP3A4 inhibitors, and coadministration of zilurgisertib with strong CYP3A4 inducers is not recommended.” (opens the source at this quote in a new tab)

Rifampin as a broad-spectrum, potent inducer represents a worst-case interaction

“Rifampin is the most potent inducer of P-gp” (opens the source at this quote in a new tab)
“Therefore, the effect of rifampin on the zilurgisertib exposure in this study represents a worst-case scenario for when zilurgisertib is coadministered with a CYP3A4/5 inducer.” (opens the source at this quote in a new tab)
“Given the significant decrease in zilurgisertib AUC (4.76-fold) when coadministered with rifampin, concomitant use of zilurgisertib and rifampin should be avoided.” (opens the source at this quote in a new tab)

CYP2D6 inhibitors

“Coadministration of paroxetine (a strong CYP2D6 inhibitor) and duloxetine is predicted to have negligible effect on zilurgisertib exposure.” (opens the prescribing information at this quote)

Transporter inhibitors

“Zilurgisertib is a substrate of P-gp, BCRP and MRP2, but P-gp, BCRP or MRP2 inhibitors are not expected to affect zilurgisertib exposure at clinically relevant concentrations. Zilurgisertib is not a substrate of key hepatic transporters OATP, OAT, or OCT families. Zilurgisertib is not a substrate for renal transporters MATE1 and MATE2-K.” (opens the prescribing information at this quote)

Grapefruit and pomelo

“Do not administer ATEBRIOZ with grapefruit, pomelo, or juices containing these fruits.” (opens the prescribing information at this quote)

MATE1 and MATE2-K substrates

“Avoid concomitant use of ATEBRIOZ with MATE1 and MATE2-K substrates (e.g., metformin). If unavoidable, monitor for adverse reactions and consider dose reduction of the substrates if appropriate, according to their approved prescribing information.” (opens the prescribing information at this quote)
“ATEBRIOZ is a MATE1 and MATE2-K inhibitor. ATEBRIOZ may increase exposure of substrates of MATE1 and MATE2-K, which may increase the risk of adverse events of MATE1 and MATE2-K substrates.” (opens the prescribing information at this quote)

Cytochrome P450 inhibition and induction in vitro

“Zilurgisertib does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4, or CYP2D6 at clinically relevant concentrations. Zilurgisertib is not an inducer of CYP1A2, CYP2B6, or CYP3A4.” (opens the prescribing information at this quote)

Other transporter inhibition in vitro

“Zilurgisertib is an inhibitor of MATE1 and MATE2-K and an inhibitor of OATP1B1, OATP1B3 and OCT2. Zilurgisertib is not an inhibitor of OAT1 or OAT3.” (opens the prescribing information at this quote)

Recommended dosage

“The recommended dosage of ATEBRIOZ is 100 mg orally once daily with or without food” (opens the prescribing information at this quote)

Pregnancy testing before treatment

“Verify that females of reproductive potential are not pregnant prior to initiating ATEBRIOZ” (opens the prescribing information at this quote)

Dosage modification with CYP3A4 inhibitors

“Reduce the ATEBRIOZ dosage to 50 mg orally once daily when used concomitantly with a strong CYP3A4 inhibitor. No change in ATEBRIOZ dosage is needed when used concomitantly with a mild or moderate CYP3A4 inhibitor” (opens the prescribing information at this quote)

Dosage modification for renal or hepatic impairment

No evidence found.

Whole or crushed tablets

“Administer ATEBRIOZ tablets whole or crushed. If crushed, mix 4 tablets (100 mg total) with four tablespoons (60 mL) of water, orange juice, apple sauce, or plain yogurt and administer immediately. Do not store the mixture for future use.” (opens the prescribing information at this quote)

Administration with or without food

“Instruct patients to take ATEBRIOZ orally once daily with or without food.” (opens the prescribing information at this quote)

“Zilurgisertib exhibited a favorable pharmacokinetic profile amenable to once-daily dosing that can be administered without regard to food.” (opens the source at this quote in a new tab)

Commercial availability, patient support program, and out-of-pocket cost

“Atebrioz will be available through Mirum Access Plus (MAP), a patient support program designed to help patients, families and healthcare providers navigate treatment access. MAP provides insurance coverage and access support, financial assistance for eligible patients, personalized patient support and educational resources for patients and caregivers. Atebrioz is expected to be commercially available in the U.S. in October, with eligible patients paying as little as $0 per month through MAP. To learn more about MAP, call 855-MRM-4YOU (1-855-676-4968).” (opens the source at this quote in a new tab)

Mirum Access Plus services for patients and prescribers

“MAP is a support program with a dedicated team that helps patients, caregivers, and their healthcare providers access medication and connect with helpful resources.” (opens the source at this quote in a new tab)
“We've built a portal that provides access to real-time information on your patient's coverage and fulfillment journey.” (opens the source at this quote in a new tab)

Specialty pharmacy distribution of the manufacturer's approved medicines

“The Company relies on a single third-party logistics provider (“3PL”) and a single specialty pharmacy for all of the Company’s sales of its approved medicines in each of the U.S. and Canada as well as a single 3PL outside of North America.” (opens the source at this quote in a new tab)

Preapproval compassionate use and continued access for trial participants

“However, individuals with FOP, ages 12 and over, living in the United States, may be able to use zilurgisertib through a new Compassionate Use Program opened by Mirum and Incyte.” (opens the source at this quote in a new tab)

“There are no planned changes to the conduct of the PROGRESS study as a result of this agreement including the open label extension period, and current study participants will not lose access to zilurgisertib.” (opens the source at this quote in a new tab)

Risk evaluation and mitigation strategy

No evidence found.

Iron supplements

“No significant differences in mean ferritin change from baseline was observed between ATEBRIOZ- and placebo-treated patients, including patients who took iron supplements.” (opens the prescribing information at this quote)

Review of concomitant medications and supplements

“Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements” (opens the prescribing information at this quote)

Concomitant use with other FOP therapies

No evidence found.

Summary: products approved or in development for fibrodysplasia ossificans progressiva

Three products are approved by the Food and Drug Administration for fibrodysplasia ossificans progressiva, and each acts at a different point in the signaling pathway driven by the gain-of-function ACVR1 (ALK2) variant. Zilurgisertib is an oral ALK2 kinase inhibitor given as 100 mg once daily to patients aged 12 years and older. Palovarotene is an oral retinoic acid receptor gamma agonist given as 5 mg daily with a 12-week 20/10 mg flare-up regimen (weight-based below age 14), labeled for females aged 8 years and older and males aged 10 years and older. Garetosmab-grts is an intravenous activin A antibody given as 10 mg/kg every 4 weeks, labeled for adults only.

The pivotal evidence differs in design and endpoint. Zilurgisertib was compared with placebo in 63 participants for 24 weeks, with total new HO volume (which includes expansion of existing lesions) of −3.2 cm³ versus +24.6 cm³ (Hodges-Lehmann difference −15.8 cm³). Palovarotene was studied in a single-arm trial of 97 participants against an external natural history control of 101 untreated participants, with annualized new HO volume of 9.4 versus 20.3 cm³/year; the trial's prespecified, square-root transformed primary analysis at this interim analysis did not show a statistically significant difference from the control, and the reported reduction rests on post hoc analyses using non-transformed volumes. Garetosmab-grts was compared with placebo in 63 adults for 56 weeks, with 90% and 94% reductions in the number of new HO lesions at 10 mg/kg and 3 mg/kg; its difference in new HO volume was not statistically significant by the prespecified test.

All three labels contraindicate use in pregnancy. Palovarotene carries a boxed warning for embryo-fetal toxicity and premature epiphyseal closure in growing pediatric patients. Garetosmab-grts carries warnings for embryo-fetal toxicity, skin and soft tissue infections, and epistaxis. Zilurgisertib carries one warning, embryo-fetal toxicity. No head-to-head trial was identified, and each label states that adverse reaction rates from one drug's trials "cannot be directly compared to rates in the clinical trials of another drug". Among investigational products, fidrisertib (another ALK2 inhibitor) did not meet its primary endpoint in the 113-participant FALKON trial, and saracatinib and andecaliximab remain in phase 2 and phase 2/3 trials.

Zilurgisertib (Atebrioz): label profile

Attribute	Quoted label text
Mechanism	“Zilurgisertib is an oral, and selective inhibitor of both wild-type ALK2 and pathogenic ALK2 (R206H mutation).”
Indication and age	“ATEBRIOZ is indicated to reduce the volume of total new heterotopic ossification (HO) in adults and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva (FOP).”
Dosage	“The recommended dosage of ATEBRIOZ is 100 mg orally once daily with or without food”
Dosage form	“ATEBRIOZ Tablets: 25 mg of zilurgisertib, film-coated”
Pivotal trial	“Sixty-three patients (28 adults and 35 pediatric patients aged 12 years of age and older) with FOP were randomized 1:1 to treatment with ATEBRIOZ 100 mg or placebo once daily for 24 weeks”
Efficacy endpoint	“Total new HO lesion volume includes expansion of baseline HO lesion burden as well as any new discrete HO”
Efficacy result	“At Week 24, the mean change (SD) from baseline in total new HO volume was −3.2 cm³ (19.9) in the zilurgisertib group and +24.6 cm³ (51.9) in the placebo group, resulting in a Hodges-Lehmann treatment difference of −15.8 cm³ (95% CI: -32.1, -6.0).”
Contraindication	“ATEBRIOZ is contraindicated in pregnancy.”
Warnings and precautions	“Embryo-Fetal Toxicity: Can cause fetal harm.”
Most common adverse reactions	“Most common adverse reactions (≥ 10%): headache, arthralgia, upper respiratory tract infection, epistaxis, and nausea.”
Pediatric patients	“The safety and effectiveness of ATEBRIOZ have not been established in pediatric patients younger than 12 years of age.”

Palovarotene (Sohonos): label profile

Attribute	Quoted label text
Mechanism	“Through binding to RARγ, palovarotene decreases the BMP/ALK2 downstream signaling pathway by inhibiting the phosphorylation of SMAD1/5/8, which reduces ALK2/SMAD-dependent chondrogenesis and osteocyte differentiation resulting in reduced endochondral bone formation.”
Indication and age	“SOHONOS is indicated for the reduction in volume of new heterotopic ossification in adults and pediatric patients aged 8 years and older for females and 10 years and older for males with fibrodysplasia ossificans progressiva (FOP).”
Daily dosage	“The recommended SOHONOS daily dosage for adults and pediatric patients 14 years and older is 5 mg daily.”
Flare-up dosage	“The recommended SOHONOS flare-up dosage for adults and pediatric patients 14 years and older is 20 mg daily for 4 weeks, followed by 10 mg daily for 8 weeks (for a total of 12 weeks of flare-up treatment), even if symptoms resolve earlier, then return to daily dosing of 5 mg.”
Pivotal trial	“Study PVO-1A-301 (NCT03312634, Study 301) was a single arm study in 97 subjects with FOP with R206H mutation aged 4 years and older utilizing the Natural History Study (NHS, PVO-1A-001) as an external control (n=101).”
Efficacy endpoint	“The primary efficacy endpoint was annualized volume of new heterotopic ossification (HO) as assessed by low-dose, whole body CT (WBCT) imaging (excluding head).”
Efficacy result	“The mean annualized new HO was 9.4 cm3/year in subjects receiving the chronic/flare-up SOHONOS treatment and 20.3 cm3/year in untreated subjects in the NHS based on a linear mixed effect model.”
Boxed warning	“Premature epiphyseal closure occurs in growing pediatric patients treated with SOHONOS, close monitoring is recommended”
Contraindications	“SOHONOS is contraindicated in pregnancy.”

Garetosmab-grts (Pasatru): label profile

Attribute	Quoted label text
Mechanism	“Garetosmab-grts is a human IgG4 monoclonal antibody that specifically binds to and inhibits signaling by activin A to block the activation of FOP-mutant ACVR1 and reduce the formation and progression of new heterotopic bone lesions.”
Indication and age	“PASATRU is indicated to reduce formation of new heterotopic ossification (HO) lesions and clinician-assessed flare-ups in adults with fibrodysplasia ossificans progressiva (FOP).”
Dosage	“The recommended starting dosage of PASATRU is 10 mg/kg administered as an intravenous infusion over 60 minutes once every 4 weeks.”
Pivotal trial	“The efficacy of PASATRU was evaluated in Study 1 (NCT05394116), a randomized, double-blind, parallel-group, multicenter, placebo-controlled trial in 63 adults with FOP confirmed by an ACVR1 FOP-causing mutation.”
Efficacy endpoint	“The primary efficacy endpoint was the number of new HO lesions at Week 56 assessed by low-dose, whole-body computed tomography (WBCT) imaging”
Efficacy result, new lesions	“Statistically significant reductions in the number of new HO lesions at Week 56 were observed in patients receiving PASATRU 10 mg/kg every 4 weeks or 3 mg/kg every 4 weeks compared to placebo (90% reduction or 94% reduction for PASATRU 10 mg/kg or 3 mg/kg, respectively, compared to placebo).”
Efficacy result, flare-ups	“The rate ratio (95% CI) compared to placebo was 0.12 (0.03, 0.42) for PASATRU 10 mg/kg, and 0.85 (0.26, 2.73) for PASATRU 3 mg/kg.”
Efficacy result, new HO volume	“These findings were not statistically significant based on the pre-specified Wilcoxon rank-sum test.”
Contraindication	“PASATRU is contraindicated during pregnancy.”
Warnings and precautions	“Skin and Soft Tissue Infections: Have occurred in patients treated with PASATRU.”
Pediatric patients	“The safety and effectiveness of PASATRU have not been established in pediatric patients.”

Fidrisertib: phase 2 trial did not meet its primary endpoint

“PARIS, FRANCE, 19 December 2025 – Ipsen (Euronext: IPN; ADR: IPSEY) today announced that the pivotal Phase II FALKON trial did not meet its primary endpoint of reducing new heterotopic ossification (HO) in adults and children living with fibrodysplasia ossificans progressiva (FOP) vs. placebo, as a result the study will be closed.” (opens the source at this quote in a new tab)
“Fidrisertib is an oral, highly selective and potent small molecule inhibitor of pathogenic variants of the ALK2 kinase, the underlying root cause of FOP.” (opens the source at this quote in a new tab)
“Part A is a global, multi-center, placebo-controlled, parallel-group, 3-arm trial, in which 113 patients aged 5 years of age or older with the R206H ACVR1 mutation or other FOP variants associated with progressive HO, were enrolled and randomized to receive either high dose-weight based or low dose weight-based fidrisertib or placebo. The primary endpoint is annualized change from baseline in HO volume.” (opens the source at this quote in a new tab)

Saracatinib: phase 2a trial design

“The STOPFOP team identified AZD0530 (saracatinib) as a potent inhibitor of the ALK2/ ACVR1 -kinase which is the causative gene for this rare bone disease.” (opens the source at this quote in a new tab)
“The STOPFOP trial is a phase 2a study. It is designed as a European, multicentre, 6-month double blind randomized controlled trial of AZD0530 versus placebo, followed by a 12-month trial comparing open-label extended AZD0530 treatment with natural history data as a control. Enrollment will include 20 FOP patients, aged 18–65 years, with the classic FOP mutation (ALK2 R206H).” (opens the source at this quote in a new tab)

Andecaliximab: phase 2/3 trial in pediatric and adult participants

“This study is researching an experimental drug called andecaliximab. The study will include pediatric and adult patients with fibrodysplasia ossificans progressiva (FOP).” (opens the source at this quote in a new tab)

“Reduces Activin-A release from macrophages and matrix stores; likely multimodal actions on all HO factors” (opens the source at this quote in a new tab)

Definition of fibrodysplasia ossificans progressiva

“Fibrodysplasia ossificans progressiva (FOP; MIM# 135100) is an ultra-rare, disabling, fully penetrant, autosomal dominant, genetic condition characterized by congenital malformations of the great toes and progressive, heterotopic ossification (HO) in specific anatomic patterns.” (opens the source at this quote in a new tab)
“Flare-ups that often lead to HO are episodic and may be misdiagnosed as tumors; immobility is cumulative.” (opens the source at this quote in a new tab)

Genetic cause: gain-of-function variants in ACVR1, with R206H in about 97% of cases

“A common gain-of-function, missense pathogenic variant in activin receptor IA (ACVR1, also known as ALK2), encoding a bone morphogenetic protein (BMP) type I receptor, occurs in all sporadic and familial cases with a classic presentation of FOP.” (opens the source at this quote in a new tab)
“Approximately 3% of affected individuals have different pathogenic variants in ACVR1” (opens the source at this quote in a new tab)
“However, all known individuals with FOP have gain-of-function, heterozygous, pathogenic variants in the gene encoding ACVR1.” (opens the source at this quote in a new tab)

“We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G-A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined.” (opens the source at this quote in a new tab)

Classic and variant genotypes

“All patients with classic clinical features of FOP (great toe malformations and progressive HO) have the same heterozygous mutation (c.617G>A; p.R206H) in the glycine-serine activation domain of ACVR1 (~97% of all FOP patients worldwide). Approximately 3% of FOP patients have been identified with clinical features unusual compared to classical FOP, most notably greater or lesser severity of the great toe malformations. These patients with “variant” clinical presentation of FOP have novel non-R206H activating mutations in the ACVR1 gene.” (opens the source at this quote in a new tab)

“Genotype–phenotype correlations are indicated between some ACVR1 pathogenic variants and the age of onset of HO” (opens the source at this quote in a new tab)

Inheritance, de novo occurrence, and paternal age

“All races are affected with FOP. There is no ethnic, racial, gender, or geographic predisposition. Autosomal dominant transmission with complete penetrance but variable expression is established. Inheritance can be from either mothers or fathers” (opens the source at this quote in a new tab)
“Most cases arise as a result of a spontaneous new mutation” (opens the source at this quote in a new tab)
“Fewer than ten small families with multigenerational members with FOP are known worldwide. Phenotypic heterogeneity is observed” (opens the source at this quote in a new tab)

“The vast majority of cases are due to the same alteration, R206H, and results from a spontaneous de novo mutation” (opens the source at this quote in a new tab)
“A paternal age effect has been reported” (opens the source at this quote in a new tab)

“We found this mutation in all affected members of seven families, including all five families used for linkage analysis (Fig. 1c).” (opens the source at this quote in a new tab)
“Investigation of sporadic cases of FOP with unambiguous clinical features showed the presence of the identical de novo mutation in 32 of 32 cases.” (opens the source at this quote in a new tab)
“The 617G-A nucleotide mutation was not found in any of 159 unaffected individuals (112 unrelated controls and 47 clinically unaffected family members).” (opens the source at this quote in a new tab)

Genetic and environmental determinants of phenotype

“A study of three pairs of monozygotic twins with FOP found that within each pair, congenital toe malformations were identical. However, postnatal HO varied greatly depending on life history and environmental exposure to viral illnesses and to soft tissue trauma.” (opens the source at this quote in a new tab)

Birth frequency derived from the French national prevalence estimate

“Through this method, the prevalence of FOP is estimated to be 1.36 per million inhabitants (or 1/735,000 births).” (opens the source at this quote in a new tab)

Detectability before birth and effect of paternal age on future incidence

“Another question is whether FOP prevalence may rise due to the trend toward an increased paternal age, a known risk factor for FOP as for other conditions due to single-mutation variation” (opens the source at this quote in a new tab)
“FOP is rarely detectable in utero.” (opens the source at this quote in a new tab)

Population-based annual incidence

No evidence found.

United States: minimum prevalence of 0.88 per million, 2020

“After deduplication, 373 unique patients were identified in the United States, 294 of whom who were not listed as deceased in any list.” (opens the source at this quote in a new tab)
“Based on the application of the survival probability, it is estimated that 279 of these patients were alive on the prevalence date (22 July 2020). An adjusted prevalence of 0.88 per million US residents was calculated” (opens the source at this quote in a new tab)
“This study suggests that the prevalence of FOP is higher than the often-cited value of 0.5 per million.” (opens the source at this quote in a new tab)

“Taking into account the limitations described above, we report an estimated minimum prevalence of 0.88 per million individuals (1 in 1.14 million people) living in the United States.” (opens the source at this quote in a new tab)
“In this study, 11% (n = 31) of patients were 0 to < 10 years, compared to 23% (n = 65) in the ≥ 10 to < 20 years group, and 24% (n = 67) in the ≥ 40 years group.” (opens the source at this quote in a new tab)

France: capture-recapture estimate of 1.36 per million, 2012

“Using a capture-recapture methodology to adjust the crude number of patients identified in both data sources, 89 FOP patients were identified, which results in a prevalence of 1.36 per million inhabitants (CI95% = [1.10; 1.68]).” (opens the source at this quote in a new tab)
“Previous studies in Spain and the United Kingdom estimated FOP prevalence at about one case per two million population” (opens the source at this quote in a new tab)

France: national rare disease registry estimate of 1.39 per million, 2020

“Based on the BNDMR, 94 individuals with FOP were alive on December 31, 2020. Thus, the prevalence was estimated at 1.39 per million (95% CI: 1.13-1.71).” (opens the source at this quote in a new tab)

Apparent prevalence by world region in patient organization databases

“The apparent prevalence of registered and confirmed FOP patients varied substantially from approximately 0.65 per million in North America and 0.47 per million in Western Europe to approximately 0.27 per million in Latin America, 0.05 per million in Africa, to nearly 0.04 per million in the Asia–Pacific region” (opens the source at this quote in a new tab)

Number of known individuals in the United States and worldwide

“Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, progressive genetic disease affecting approximately 300 people in the United States and 900 worldwide.” (opens the source at this quote in a new tab)

Registry coverage of the known global population

“As of December 2020, the Registry had 323 enrolled patients from 69 countries, approximately 36% of the world’s known FOP population.” (opens the source at this quote in a new tab)

Registry coverage in September 2018

“As of September 20, 2018, 299 individuals (approximately 37% of the world’s known FOP population based on IFOPA estimates) were enrolled, from 54 countries.” (opens the source at this quote in a new tab)

Onset in childhood and cumulative disability

“Most children with FOP develop episodic, painful, inflammatory soft tissue swellings called flare-ups during the first decade of life. While some flare-ups regress spontaneously, most transform soft connective tissues into mature heterotopic bone through a process of endochondral ossification.” (opens the source at this quote in a new tab)
“Most patients with FOP are confined to a wheelchair by the third decade of life and require lifelong assistance with activities of daily living. The median estimated life expectancy is 56 yr. Death often results from complications of thoracic insufficiency syndrome.” (opens the source at this quote in a new tab)

Prospective 36-month natural history study: flare-ups and new heterotopic ossification

“In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%).” (opens the source at this quote in a new tab)
“Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.” (opens the source at this quote in a new tab)

Imaged flare-ups with new heterotopic ossification at Day 84

“HO was present at the flare-up site in 71.2% of imaged flare-ups at flare-up Day 1, and 26.9% had new HO at flare-up Day 84 (Figure 1A).” (opens the source at this quote in a new tab)

Imaged flare-up frequency by age group

“A total of 52 flare-ups in 40 (35.1%) individuals were imaged (Supplement 2A). The proportion of individuals with ≥1 imaged flare-up was highest in the 2 to <8 years age group (47.1%) and lowest in the 25 to 65 years age group (25.9%).” (opens the source at this quote in a new tab)

Functional and physical function scores over 36 months

“At baseline, mean CAJIS total score was 11.8 (SD = 7.0) points and mean FOP-PFQ percentage of the worst total score was 46.3% (SD = 28.1%); small increases were observed from baseline to Month 36 (1.6 points and 7.3%, respectively; Supplement 3A and B).” (opens the source at this quote in a new tab)

One death during the 36-month natural history study

“One death occurred during the study: a 38-year-old female individual had fatal cardiac arrest not due to study procedures.” (opens the source at this quote in a new tab)

Baseline cross-sectional phenotype: HO volume and function increase with age

“Findings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm3/year.” (opens the source at this quote in a new tab)

Anatomic progression and progression without flare-ups

“Onset of FOP usually occurred first in the neck and upper back, and with the exception of the jaw, progressed from axial to appendicular regions (Figure 1).” (opens the source at this quote in a new tab)
“Most body regions were affected before the third decade of life (Figure 2c).” (opens the source at this quote in a new tab)
“Almost half of all patients (46.9%; 230/490) reported disease progression without flare-up symptoms.” (opens the source at this quote in a new tab)

Clinical staging

“Based on assessment of FOP features in seven areas, it is possible to assign five clinical stages.” (opens the source at this quote in a new tab)
“Assessments of these features assign an individual with FOP to early/mild, moderate, severe, profound, or late-stage disease.” (opens the source at this quote in a new tab)

Median lifespan and causes of death in the international FOP community

“Sixty deaths (thirty male and thirty female patients) were reported in the fibrodysplasia ossificans progressiva community during a thirty-three-year-period. For all sixty patients, the median age at the time of death was forty years (range, three to seventy-seven years).” (opens the source at this quote in a new tab)
“The median lifespan estimated from the 371 individuals in the international fibrodysplasia ossificans progressiva community who were alive and the sixty who had died was fifty-six years (95% confidence interval, fifty-one to sixty years). The most common causes of death in patients with fibrodysplasia ossificans progressiva were cardiorespiratory failure from thoracic insufficiency syndrome (54%; median age, forty-two years) and pneumonia (15%; median age, forty years).” (opens the source at this quote in a new tab)

Survival compared with matched controls in France

“Overall survival was significantly worse in individuals with FOP vs the control group (p < .0001; Figure 4). Seven deaths were reported in the 77 individuals with FOP, and 8 deaths were reported in the 769 individuals without FOP. The mean (SD) age at death for individuals with FOP and controls was 50.4 (20.9) yr and 63.1 (18.3) yr, respectively (p = .2239).” (opens the source at this quote in a new tab)

Systematic review of reported mortality

“Ten of the 32 publications reported the number of deaths within the study cohorts” (opens the source at this quote in a new tab)
“However, none of the studies calculated annual mortality rates or contextualized the number of deaths observed.” (opens the source at this quote in a new tab)
“The most frequently reported causes of death, as determined by the investigators’ medical records review, were cardiovascular or cardiorespiratory issues, pneumonia, and trauma resulting from a fall.” (opens the source at this quote in a new tab)

Constitutive and ligand-hyperresponsive ACVR1 signaling

“Protein modeling predicted destabilization of the GS domain, consistent with enhanced activation of ACVR1 signaling as the underlying pathogenesis of the ectopic chondrogenesis, osteogenesis, and joint fusion of FOP” (opens the source at this quote in a new tab)
“The GS domain is a specific binding site for FKBP12, a highly conserved inhibitory protein that prevents leaky activation of type I receptors in the absence of ligand.” (opens the source at this quote in a new tab)

Aberrant responsiveness of mutant ACVR1 to activin A

“We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation.” (opens the source at this quote in a new tab)
“When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A.” (opens the source at this quote in a new tab)

“Here, by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs), we report a third mechanism, where FOP-ACVR1 abnormally transduces BMP signaling in response to Activin-A, a molecule that normally transduces TGF-β signaling but not BMP signaling.” (opens the source at this quote in a new tab)

“recent data suggest that ACVR1[R206H] activation by activin A induces receptor clustering, homo-oligomerization, and autophosphorylation, thus triggering dysregulated BMP pathway signaling” (opens the source at this quote in a new tab)

Endochondral sequence of heterotopic bone formation

“Early pre-osseous FOP lesions consist of an intense aggregation of mononuclear inflammatory cells including lymphocytes, macrophages, and mast cells in the perivascular spaces of edematous muscle” (opens the source at this quote in a new tab)
“Following the catabolic phase of muscle cell death, a highly anabolic fibroproliferative phase (often mistaken for aggressive juvenile fibromatosis) consists, in part, of Sca1+/PDGFRα+/Tie2+/CD34- fibroadipogenic progenitor (FAP) cells that differentiate through an endochondral pathway into mature heterotopic bone” (opens the source at this quote in a new tab)

Role of inflammation and triggers

“Loss of autoinhibition of the mutant receptor results in dysregulated BMP pathway signaling and is necessary for the myriad developmental features of FOP but may not be sufficient to induce the episodic flare-ups that lead to disabling post-natal HO and that are a hallmark of the disease. Evidence from all levels of investigation in humans and animal models strongly support that the innate immune system plays a key role in inducing episodes of HO.” (opens the source at this quote in a new tab)

“depletion of mast cells or macrophages impairs injury-induced HO in Acvr1[R206H/+] mice and reduces HO volume by <50% with depletion of each cell population independently and ~75% with combined depletion of both cell populations” (opens the source at this quote in a new tab)

Hypoxia and mTOR signaling amplify BMP pathway activity

“Hypoxia-inducible factor-1α (HIF-1α) integrates the cellular response to both hypoxia and inflammation and increases the intensity and duration of BMP signaling in FOP. Inhibition of HIF-1α by genetic or pharmacologic means restores BMP signaling to normoxic levels in human FOP cells and profoundly reduces HO in a constitutively active Acvr1[Q207D/+] mouse model of FOP” (opens the source at this quote in a new tab)
“a mechanistic target of rapamycin (mTOR) signaling upstream of HIF-1α was identified as a critical pathway for hypoxia sensing in the aberrant chondrogenesis of FOP and unveiled a crucial role of the mTOR axis in FOP pathogenesis” (opens the source at this quote in a new tab)

Tissues spared from heterotopic ossification

“Several skeletal muscles including the diaphragm, intrinsic muscles of the tongue, and extra-ocular muscles are spared from HO in FOP. Cardiac muscle and smooth muscle are also notably spared from HO” (opens the source at this quote in a new tab)

ACVR1 as a therapeutic target

“The discovery of the genetic variants in ACVR1 that cause FOP established a critical milestone in understanding FOP, revealed a highly conserved therapeutic target in the BMP signaling pathway, and propelled the development of novel inhibitors of ACVR1-mediated BMP pathway signaling.” (opens the source at this quote in a new tab)

Guideline: clinical diagnosis with required genetic confirmation

“The diagnosis of FOP is clinical (malformed great toes and progressive HO) but requires genetic confirmation of a pathogenic ACVR1 gene variant.” (opens the source at this quote in a new tab)
“If FOP is suspected, all elective procedures such as surgeries, biopsies, and IM immunizations should be deferred until a definitive diagnosis is confirmed.” (opens the source at this quote in a new tab)

Early clinical signs that prompt genetic testing

“Definitive genetic testing of FOP by DNA sequence analysis of the ACVR1 locus can confirm a diagnosis of FOP prior to the appearance of HO” (opens the source at this quote in a new tab)
“Clinicians should be aware of the early diagnostic signs of FOP - congenital malformation of the great toes and episodic soft tissue swelling even before the appearance of HO. This awareness should prompt genetic consultation and testing and the institution of assiduous precautions to prevent injury and iatrogenic harm.” (opens the source at this quote in a new tab)
“The clinical diagnosis of FOP can be made by simple clinical evaluation that associates rapidly appearing soft tissue lesions with malformations of the great toes.” (opens the source at this quote in a new tab)

“Individuals will often present in their first decade of life with great toe malformations and lumps/swellings on the scalp, head, neck and/or back” (opens the source at this quote in a new tab)
“FOP is the only condition with this combination of symptoms.” (opens the source at this quote in a new tab)

International survey: misdiagnosis in 87% and diagnostic delay of 4.1 years

“Incorrect diagnoses were given initially to 87% of individuals with FOP.” (opens the source at this quote in a new tab)
“The most common incorrect diagnosis was cancer (32%). The mean period from the onset of symptoms to correct diagnosis was 4.1 years, and the median number of physicians consulted before the correct diagnosis of FOP was 6. For 67% of patients, unnecessary invasive procedures (biopsies) were performed; 68% received inappropriate therapies. Forty-nine percent of all patients reported permanent loss of mobility resulting from invasive medical interventions that caused posttraumatic ossification.” (opens the source at this quote in a new tab)

FOP Registry: time to diagnosis and number of providers consulted

“Data from the FOP Registry (as of December 2020) show that on average, individuals with FOP receive a correct diagnosis around 1.5 years following symptom onset, with over 50% of individuals initially misdiagnosed” (opens the source at this quote in a new tab)
“According to recent FOP Registry data, individuals with FOP receive a correct diagnosis after seeing an average of 3.3 HCPs” (opens the source at this quote in a new tab)

“According to the FOP Registry, 53.5% of patients had received a misdiagnosis prior to correct diagnosis.” (opens the source at this quote in a new tab)

Initial evaluation and diagnosing provider in the IFOPA registry

“Most patients consulted a pediatrician (27.4%) or an orthopaedic physician (12%) for their initial diagnostic evaluation, and most often received their correct diagnosis from a geneticist (18.1%) [data not shown].” (opens the source at this quote in a new tab)

China: misdiagnosis in 78.8% and iatrogenic harm in 62.7%

“Up to 78.8% of patients would have been misdiagnosed at least once, with tumors (40.9%) being the most common misdiagnosed condition. 62.7% of patients received iatrogenic harm, with surgeries (26.9%), biopsies (25.4%), and punctures (17.9%) being the most common iatrogenic injuries experienced.” (opens the source at this quote in a new tab)
“Only 23.9% of patients received a correct diagnosis at their initial hospital visit (Table S1).” (opens the source at this quote in a new tab)

Age at diagnosis

“Mean age at FOP diagnosis was 6.9 years (range: birth to 63 years); the median age was 5 years.” (opens the source at this quote in a new tab)

“Mean age at diagnosis was 10 years, and above 18 years for 14.9% of the patients.” (opens the source at this quote in a new tab)

“Based on the age group at index date, the mean (SD) age at diagnosis was 2.43 (2.34) yr for individuals aged <10 yr at index date, 4.64 (4.59) years for individuals aged 10-20 yr, 5.91 (4.90) years for individuals aged 20-30 yr, and 9.29 (8.29) yr for individuals aged ≥30 yr (p = .0189 for the difference between age at diagnosis for age groups).” (opens the source at this quote in a new tab)

Age at symptom onset and age at diagnosis in the IFOPA registry

Measure	Age at symptom onset (years)	Age at diagnosis (years)
n	“209”	“208”
Mean (SD)	“5.3 (6.13)”	“7.2 (7.18)”
Median	“3.0”	“5.0”
Minimum, maximum	“0.1, 45”	“0.1, 48.0”

Pediatric cohort: biopsy before referral and scalp nodules as an early sign

“Four patients underwent biopsy prior to referral to our institution. One was coincidentally associated with Ewing sarcoma.” (opens the source at this quote in a new tab)
“Scalp nodules could be a transient finding with spontaneous regression and were an early manifestation in 2.” (opens the source at this quote in a new tab)

Newborn screening

“Therefore, the routine screening of newborns to diagnose FOP, either clinically or genetically, is unlikely to become more widespread in the near future.” (opens the source at this quote in a new tab)

Congenital skeletal malformations: great toes and other anomalies

“Individuals with FOP appear normal at birth except for characteristic malformations of the great toes that are present in all classically affected individuals” (opens the source at this quote in a new tab)
“Other skeletal anomalies associated with FOP include short malformed thumbs with interphalangeal joint fusion, clinodactyly, malformation of the temporomandibular joints, variable and often asymmetric fusions of the costovertebral and costotransverse joints, short broad femoral necks, and osteochondromas, most notably of the proximal medial tibias and femurs, but variably present throughout the normotopic skeleton” (opens the source at this quote in a new tab)

Flare-ups: presenting symptoms, frequency, and triggers

“Major symptoms experienced during a flare-up included swelling (93.1%; 429/461), pain (86.3%; 398/461), decreased movement (78.5%; 362/461), stiffness (72.9%; 336/461), and warmth (15%; 313/461) [Figure 3a].” (opens the source at this quote in a new tab)
“About 71% (341/460) reported at least one flare-up in the previous 12 months. Overall, patients reported an average of 1.9 ± 0.1 flare-ups in the preceding 12 months (median 1.0; range of 0 to 7)” (opens the source at this quote in a new tab)
“Intramuscular immunization was the cause of a flare-up in 25.1% (115/459), which led to bone formation in 84.3% (97/115) of these patients. As many as 61% of all flare-ups occurred spontaneously.” (opens the source at this quote in a new tab)

Heterotopic ossification: anatomic pattern

“FOP HO progresses in characteristic anatomic and temporal patterns with age, typically first occurring in the dorsal, axial, cranial, and proximal regions of the body and later in the ventral, appendicular, caudal, and distal regions.” (opens the source at this quote in a new tab)
“Ribbons, sheets, and plates of heterotopic bone replace skeletal muscles and connective tissues through a process of endochondral ossification that leads to an armament-like encasement of bone and permanent immobility.” (opens the source at this quote in a new tab)

Joint immobility and loss of function after flare-ups

“Among all responders, 96.4% (479/685) reported at least one body region with partial or limited movement.” (opens the source at this quote in a new tab)
“Almost half of survey participants reported that their last flare-up resulted in at least a 50% reduction of mobility around a joint, with 15% reporting a complete loss of movement.” (opens the source at this quote in a new tab)

Pain: during and outside flare-ups

“We observed that although moderate to severe pain (≥4, 0 to 10 pain scale) was commonly associated with flare‐ups (56% to 67%), surprisingly, 30% to 55% of patients experienced similar pain levels during non–flare‐up states.” (opens the source at this quote in a new tab)

“Chronic pain syndromes are common in FOP and may be related to neuropathies (eg, entrapment, nerve damage, allodynia), musculoskeletal origin (eg, back pain, myofascial pain), inflammation, or mechanical/compressive causes (eg, from expanding HO, especially late in the course of a flare-up).” (opens the source at this quote in a new tab)

Respiratory: restrictive chest wall disease and thoracic insufficiency

“Severe restrictive chest wall disease and decrease in pulmonary function due to developmental arthropathy of the costo-vertebral joints and heterotopic ossification of the chest wall develops early” (opens the source at this quote in a new tab)
“Pneumonia or right-sided heart failure may complicate rigid fixation of the chest wall.” (opens the source at this quote in a new tab)

“Restrictive pulmonary function, identified by TLC or suspected by FVC, was found in all, but one, patients.” (opens the source at this quote in a new tab)
“In conclusion, restrictive pulmonary function was found in the majority of patients already at an early age.” (opens the source at this quote in a new tab)

Hearing: conductive hearing impairment

“Conductive hearing impairment is common in FOP through various mechanisms. Fibrodysplasia ossificans progressiva patients should be screened in childhood by audiometry for hearing impairment.” (opens the source at this quote in a new tab)

“In the literature, prevalence is reported between 30.8% and 42%” (opens the source at this quote in a new tab)
“All the patients developed at least a mild hearing loss.” (opens the source at this quote in a new tab)

Jaw ankylosis and nutrition

“Severe weight loss may result following ankylosis of the jaw.” (opens the source at this quote in a new tab)

“In cases of ankylosis of the jaw, a dietician should be consulted to ensure adequate nutrition.” (opens the source at this quote in a new tab)

Spinal deformity

“Spinal deformity is common in FOP and can occur independently of flare-ups.” (opens the source at this quote in a new tab)

“92.5% of total patients had complications, with the highest proportion of complications being spinal deformities (80.6%).” (opens the source at this quote in a new tab)

Renal: kidney stones

“There is a 3-fold greater risk of kidney stones in FOP.” (opens the source at this quote in a new tab)

Neurological: headache and neurological symptoms

“Patients with FOP have reported a higher incidence of neurological symptoms, including pain both during and after an FOP flare-up.” (opens the source at this quote in a new tab)
“Some individuals with FOP report chronic headaches.” (opens the source at this quote in a new tab)

Psychological: anxiety, depression, and irritability

“In those patients reporting pain levels of ≥4, 45% to 74% of patients report experiencing anxiety, depression, or irritability, with 36% to 48% reporting emotional problems during no to mild pain states.” (opens the source at this quote in a new tab)

Gastrointestinal: nausea and vomiting

“Many patients with FOP report frequent nausea and vomiting. The cause and significance of this is unknown.” (opens the source at this quote in a new tab)

System-based symptom burden in the IFOPA registry

“Auditory complaints were the most common and included hearing loss and earaches/drainage. Sleep problems, especially poor sleep quality, and increased sleep latency, were the next most common complaints. Among pulmonary issues reported, difficulty breathing, cough, and respiratory infection were the most prominent conditions. Dermatologic complaints included rash and ulcers. Abdominal pain was the most prevalent gastrointestinal complaint, followed by reflux symptoms and nausea. The most prevalent neurological symptoms were headaches, paresthesias, and neuropathic pain. Flank pain and nephrolithiasis were the most frequent renal/urologic concerns. Menstrual abnormalities were the most common endocrine problem and heart palpitations the most common cardiac issue.” (opens the source at this quote in a new tab)

Comorbidities by organ system in a systematic review

“In our SLR, data on FOP comorbidity were extracted from 27 of the included studies, encompassing 73 distinct diseases and disorders. The three organ systems most affected by the conditions studied were, in order of severity, the cardiovascular (40–70%), skeletal (50–65%), and respiratory (20–42%) (Table 2).” (opens the source at this quote in a new tab)
“Falls and fractures were prevalent, affecting roughly 50% of the 260 patients with FOP collectively included in three of the eight studies reviewed” (opens the source at this quote in a new tab)

Comorbidities compared with matched controls in France

“Almost one-quarter (22.9%; n = 16) of individuals with FOP had a CCI score ≥ 1 compared with 3% (n = 21) of controls (Table 3). Notable long-term comorbidities occurred significantly more frequently among individuals with FOP compared with the control group and included neurological and muscular disorders (21.4% vs 0.9%; p < .0001), malignant tumors (4.3% vs 0.9%; p = .0407), inherited metabolic diseases (4.3% vs 0%; p = .0007), systemic disease (2.9% vs 0.1%; p = .0231), and ankylosing spondylitis (2.9% vs 0%; p = .0082; Table 3).” (opens the source at this quote in a new tab)

Disability severity by age

“According to these definitions, approximately half of all individuals with FOP (55.7%; n = 39/70) had a high severity of disability, whereas 37.1% (n = 26/70) had no identified severity between 2008 and 2019.” (opens the source at this quote in a new tab)

“FOP patients generally exhibited higher levels of disability, with 98.5% of them being disabled due to FOP and 64.2% holding disability certifications related to physical impairments.” (opens the source at this quote in a new tab)

Developmental arthropathy and degenerative joint disease

“Thus, the effects of the ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. Associated degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life.” (opens the source at this quote in a new tab)

Hospitalization in the 12 months before registry enrollment

“in the 12 months prior to enrollment in the FOP Registry (a global disease registry operated by the International FOP Association [IFOPA] containing the largest and most detailed collection of clinical and medical information on people living with FOP), 27% of individuals had been hospitalized, with the most common reasons for admission being pain management (8.4%), fall/injury/accident/fracture (7.9%), and respiratory infection (4.4%)” (opens the source at this quote in a new tab)

Hospitalizations in a 10-year Swiss six-disease cohort

“Of the 2875 hospitalizations, 1146 were attributed to XLH, 925 to OI, 437 to FD, 219 to ACH, 87 to PHP, and 62 to FOP (Figure 1).” (opens the source at this quote in a new tab)
“Adult hospitalizations predominated in individuals with XLH (95.2%) and FOP (90.3%), while pediatric hospitalizations were common in individuals with ACH (52.1%) and OI (41.1%). Female sex was more prevalent in hospitalizations of individuals with ACH (63%) and FOP (61%), and similarly distributed in the other studied rare bone disease groups and the general population (48%-57%).” (opens the source at this quote in a new tab)

Comorbidity burden and lifelong hospitalization pattern in fibrodysplasia ossificans progressiva

“Individuals with FD and ACH showed comorbidity patterns broadly comparable to the general population. Estimates for PHP and FOP were variable due to small sample sizes, with a possible trend toward a higher comorbidity burden.” (opens the source at this quote in a new tab)
“Hospitalizations in PHP and FOP occurred throughout the lifespan, reflecting lifelong healthcare need, although clear trends were limited by small sample sizes.” (opens the source at this quote in a new tab)

EQ-5D-5L and PROMIS Global Health in an international burden of illness survey

“Mean (SD) EQ-5D-5L index score for patients (≥13 years; n = 152) was 0.24 (0.36). Patients with greater restrictions in joint mobility had worse QoL, with mean (SD) EQ-5D-5L index score decreasing from 0.61 (0.26; n = 20) for patients with PRMA total scores in Level 1 to 0.05 (0.26; n = 62) for those in Level 4 (Figure 3).” (opens the source at this quote in a new tab)
“Mean (SD) PROMIS (pediatric) global total T-score for patients aged 5–14 years was 42.3 (9.9; n = 50).” (opens the source at this quote in a new tab)
“Mean (SD) PROMIS global physical and mental health T-scores for patients (≥15 years) were 37.6 (9.0; n = 140) and 44.9 (9.5; n = 137), respectively.” (opens the source at this quote in a new tab)

PROMIS Global Health Scale scores by age in the IFOPA registry

“The mean total scores for age groups 0– < 9 years, 9–15 years, and > 15 years were 25.4, 26.6, and 32, respectively.” (opens the source at this quote in a new tab)
“There is a strong, statistically significant association between the total PROMIS Global Health score and the number of anatomic sites subjectively reported as being affected by HO.” (opens the source at this quote in a new tab)

FOP-PFQ physical function by age

“There was a clear trend for worsening mobility and joint function with age; 55.3% of patients aged ≥25 years had PRMA total scores in Level 4, compared with no patients aged <8 years (Figure 2(a)), and mean (SD) FOP-PFQ score increased from 29.6 (25.1) for patients aged <8 years (n = 25) to 76.1 (26.7) for patients aged ≥25 years (n = 104; Supplementary Figure S1).” (opens the source at this quote in a new tab)

Validation of the FOP Physical Function Questionnaire

“Factor analysis confirmed a two-factor solution: Mobility and Upper Extremity.” (opens the source at this quote in a new tab)
“The FOP-PFQ was demonstrated to be a reliable, valid measure that may be responsive to change in individuals with FOP, although some results were inconclusive for pediatric versions.” (opens the source at this quote in a new tab)

Development and factor structure of the FOP-PFQ

“Development of the adult and pediatric versions of the FOP-PFQ involved a literature review, two iterative phases of qualitative work with participants, and clinical expert review.” (opens the source at this quote in a new tab)
“The comprehensiveness, relevance, and understandability of the adult measure was evaluated throughout and resulted in the final 28-item questionnaire.” (opens the source at this quote in a new tab)
“Initial exploratory factor analysis models based on retention of factors with eigenvalues of ≥1 suggested a two-factor solution (Factor 1: Upper Extremity function; Factor 2: Mobility function), which was confirmed by follow-up models that pre-specified two factors.” (opens the source at this quote in a new tab)

Reliability of the FOP-PFQ

“The FOP-PFQ yielded high alphas and ICCs at Baseline and Month 12.” (opens the source at this quote in a new tab)
“This indicates that FOP-PFQ scores were stable over the 1–3-week interval between questionnaires for individuals with no flare-ups.” (opens the source at this quote in a new tab)

Convergent and known-groups validity of the FOP-PFQ

“Adult and pediatric FOP-PFQ scores were worse for individuals with worse physical function and correlated with other measures of physical function, supporting convergent validity (Table 3).” (opens the source at this quote in a new tab)
“FOP-PFQ scores were significantly worse in groups of individuals with more severe disease, supporting known-groups validity, suggesting the instrument performs effectively as a measure of severity and potentially disease progression over time.” (opens the source at this quote in a new tab)

Correlation of HO volume with physical function

“There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52).” (opens the source at this quote in a new tab)

Pain severity and quality of life in the FOP Registry (PROMIS-based)

“Furthermore, independent of the flare‐up status, the severity of pain in FOP patients was found to be significantly anti‐correlated with emotional health, physical health, and overall quality‐of‐life.” (opens the source at this quote in a new tab)

EQ-5D health utility by age in China

“The average health utility values of patients < 8 and 8–15 years were 0.700 ± 0.163, 0.618 ± 0.202 measured by EQ-5D-Y. The utility values of patients ≥ 16 years were 0.221 ± 0.336 measured by EQ-5D-5L, significantly lower than the younger patients (Table 3).” (opens the source at this quote in a new tab)

SF-36 in a Mexican cohort

“Eight patients, mean age 30.2 years, were included. The physical dimension was the most affected, with an average of 25.5 points.” (opens the source at this quote in a new tab)

France: annual healthcare expenditure 10 to 14 times higher than matched controls

“Mean total annual healthcare expenditure was more than 10 times greater in individuals with FOP than those without FOP from a societal perspective (largely driven by outpatient costs) and 14 times greater from a payer perspective.” (opens the source at this quote in a new tab)
“Consultations with general practitioners and non-physician healthcare providers, hospitalizations, and use of medical devices and treatments were significantly greater in individuals with vs without FOP (p < .05 for all).” (opens the source at this quote in a new tab)

France: costs by disability severity and age

“Mean total expenditures for individuals with no identified severity were €3152 compared with €11 820 for individuals with high disability severity level (p = .0002)” (opens the source at this quote in a new tab)
“Outpatient costs were the only societal cost category to increase significantly with age (<10 yr, €1399; >30 yr, €7438; p = .0133).” (opens the source at this quote in a new tab)
“Total societal costs were largely driven by outpatient costs, of which medical devices were the most expensive component (mean annual cost: €1761).” (opens the source at this quote in a new tab)

China: annual cost per patient of USD 10,820, mostly indirect

“The average total annual cost was $10,820 ± 10,894, of which indirect and direct non-medical costs accounted for 75.2% ($8,134 ± 7,978) and 21.6% ($2,332 ± 7,374), respectively (Fig. 2).” (opens the source at this quote in a new tab)
“In the past year, up to 61.2% of patients had neither outpatient nor inpatient visits due to FOP. Only 14.9% of patients had hospital admissions, with an annual average of 1.8 ± 1.6 hospitalizations per patient.” (opens the source at this quote in a new tab)

United States: out-of-pocket cost of care by mobility level

“Additionally, while costs appear to plateau for patients with PRMA total scores in Levels 3 and 4, at a mean of approximately 22,000 U.S. dollars, the range of costs becomes progressively wider with each PRMA level; patients with PRMA total scores in Level 4 reported an upper range of approximately 164,000 U.S. dollars for costs related to FOP.” (opens the source at this quote in a new tab)
“Living adaptations related to mobility, daily activities, and/or pay for assistance constituted the greatest overall costs for U.S. patients compared with the other four categories of living adaptations assessed (Supplementary Table S9).” (opens the source at this quote in a new tab)

Healthcare services and assistive devices used

“The healthcare services most commonly consulted by patients with FOP in the 12 months prior to survey completion were general practitioners (GP; 78.3%) and dentists/orthodontists (59.5%), with healthcare service utilization varying by the patient’s PRMA level (Figure 5(a)).” (opens the source at this quote in a new tab)
“Overall, financial costs limited or prevented nearly half (47.7%) of patients with FOP from traveling (Supplementary Table S8).” (opens the source at this quote in a new tab)

In-hospital outcomes among FOP hospitalizations compared with matched controls in Switzerland

Outcome	FOP hospitalizations	Matched comparators	Relative risk or change (95% CI)
Length of hospital stay, days, median (IQR)	“5.5 (3-13)”	“3 (2-5.75)”	“2.04 (1.58, 2.62)”
ICU admission, n (%)	“10 (16.1)”	“19 (6.1)”	“2.63 (1.29, 5.38)”
In-hospital mortality, n (%)	“1 (1.6)”	“5 (1.6)”	“1.00 (0.12, 8.41)”
30-day readmission, n (%)	“9 (14.5)”	“18 (5.8)”	“2.50 (1.18, 5.30)”

Caregiver time, burden, and career effects

“Family members spent eight hours per day (mean) helping to provide care or assistance to their relative with FOP (Supplementary Table S7).” (opens the source at this quote in a new tab)
“Close to half (45.1%) of primary caregivers (n = 153) reported a ZBI total score between 21 and 40, indicating a mild to moderate impact on their health and/or psychological wellbeing (Supplementary Table S6).” (opens the source at this quote in a new tab)
“Over one-third of family members (38.9%) and over half of primary caregivers (51.3%) reported needing to adapt their career to look after their relative with FOP.” (opens the source at this quote in a new tab)
“When asked whether FOP had impacted career decisions, 82.8% of patients aged ≥18 years (n = 142) reported ‘yes.’” (opens the source at this quote in a new tab)

Work days missed by primary caregivers

“Primary caregivers reported missing a mean (SD) of 30.6 (87.8) days of work in the 12 months prior to completing the survey due to caring for a family member with PRMA total scores in Level 1. Mean (SD) number of work days missed was similar if the related patient had PRMA total scores in Level 3 (35.4 [91.4]) and lower for Level 2 (7.1 [13.0]) and Level 4 (3.1 [6.2]).” (opens the source at this quote in a new tab)

Emotional impact on family members

“Learning of their relative’s FOP diagnosis was very/extremely difficult for 79.2% of family members, and 85.4% of family members reported that the occurrence of flare-ups in their relative with FOP was very/extremely stressful (Supplementary Table S7).” (opens the source at this quote in a new tab)

Caregiver productivity loss in children and adolescents in China

“For patients aged < 8 years and 8–15 years, the main cost components arose from productivity loss in indirect costs incurred by caregivers totaling $7,409 ± 6,406 (52.4%) and $6,806 ± 8,367 (79.5%), respectively.” (opens the source at this quote in a new tab)
“In patients aged < 8 and 8–15 years, 50% and 23.5% were suspended or absent from school respectively. Additionally, 40.6% of those aged ≥ 16 years were unemployed due to FOP.” (opens the source at this quote in a new tab)
“Moreover, a substantial 95.5% of patients relied on caregivers for caregiving.” (opens the source at this quote in a new tab)

School accommodations for children

“Children with disabilities may be entitled to Individual Educational Programs (IEPs) to help students succeed in school. Use school aides to protect and assist children.” (opens the source at this quote in a new tab)

Cost and availability of ACVR1 genetic testing as a barrier

“The ability to provide a clinical diagnosis of FOP is particularly valuable for individuals living in regions where genetic testing is either not available or cost prohibitive. However, where available, genetic testing can also be beneficial, particularly for individuals with an atypical genetic mutation or for those who have great toe malformations without HO” (opens the source at this quote in a new tab)
“However, there are also important ethical considerations over screening for a disease with no approved treatment, concerns over the risk of misdiagnosis based on clinical observation in newborns, and regulatory/cost-effectiveness barriers related to genetic testing.” (opens the source at this quote in a new tab)

Procedures performed before a correct diagnosis

“For 67% of patients, unnecessary invasive procedures (biopsies) were performed; 68% received inappropriate therapies.” (opens the source at this quote in a new tab)

“62.7% of patients received iatrogenic harm, with surgeries (26.9%), biopsies (25.4%), and punctures (17.9%) being the most common iatrogenic injuries experienced.” (opens the source at this quote in a new tab)

Recommendation for electronic health record prompts for ACVR1 testing

“And we recommend developing intelligent alert modules within electronic health record (EHR) systems to trigger FOP diagnostic prompts and recommendations for ACVR1 genetic testing based on symptom keywords such as'progressive joint stiffness'.” (opens the source at this quote in a new tab)

Price of ACVR1 genetic testing and cost of the diagnostic pathway

No evidence found.

Status of palovarotene in the international clinical guideline

“Palovarotene, an RAR -γ agonist, has been approved in the United States, Canada, UAE, Australia, and Russia but not approved in Europe.” (opens the source at this quote in a new tab)
“Regulatory-approved medications have been approved by at least 1 regulatory authority (eg, US Federal Drug Administration, or FDA). Currently, only chronic and episodic use of palovarotene (Sohonos) has received limited regulatory approval.” (opens the source at this quote in a new tab)

Chronic and flare-up dosing regimen

“Initiate flare-up treatment at the onset of the first symptom indicative of a FOP flare-up or substantial high-risk traumatic event likely to lead to a flare-up (e.g., surgery, intramuscular immunization, mandibular blocks for dental procedures, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses).” (opens the source at this quote in a new tab)
“The recommended SOHONOS daily dosage for patients under 14 years of age is weight-based ranging from 2.5 mg to 5 mg daily (see Table 1).” (opens the source at this quote in a new tab)

Premature epiphyseal closure and growth monitoring

“Premature epiphyseal closure was identified by scheduled imaging in 27% of subjects who were less than 18 years of age at enrollment and was more common in younger compared with older subjects (31% in subjects between 8/10 years to 14 years and no subjects 14 years or older).” (opens the source at this quote in a new tab)
“Continued monitoring is recommended every 6 to 12 months until patients reach skeletal maturity or final adult height.” (opens the source at this quote in a new tab)
“SOHONOS is not recommended for use in patients younger than 8 years of age for females and 10 years of age for males because of the potential for premature epiphyseal closure.” (opens the source at this quote in a new tab)

Mucocutaneous and bone adverse reactions

“Mucocutaneous adverse reactions including dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation [skin peeling], and dry eye occurred in most (98%) patients treated with SOHONOS.” (opens the source at this quote in a new tab)
“In FOP clinical trials, SOHONOS resulted in decreased vertebral bone mineral content and bone density, and an increased risk of radiologically observed vertebral (T4 to L4) fractures in treated adult and pediatric patients compared to untreated patients.” (opens the source at this quote in a new tab)

Prespecified and post hoc analyses of the phase 3 MOVE trial

“During the prespecified analysis at month 18 of the phase III MOVE trial (interim analysis 3; IA3), which represents the most complete dataset from this trial, no statistically significant difference was found in the mean volume of annualized new HO in patients treated with palovarotene in MOVE compared with untreated patients from the NHS, leading to a temporary suspension of the study.” (opens the source at this quote in a new tab)
“Subsequent post hoc analyses showed that the mean annualized new HO volume was 54% lower in MOVE compared with the NHS (weighted linear mixed effects [wLME] analysis, p = .039), supporting the approval of palovarotene in patients with FOP in several countries.” (opens the source at this quote in a new tab)

Month-48 efficacy and safety of palovarotene

“Across 48 mo, mean annualized new HO volume was numerically lower (46.4%) in palovarotene-treated patients compared with untreated patients; however, this difference was not significant (nominal p = .0585).” (opens the source at this quote in a new tab)
“The proportions of patients with new HO and number of affected body regions were similar in palovarotene-treated patients and untreated patients (significance not assessed); flare-up rates were consistent with published literature.” (opens the source at this quote in a new tab)
“In 80 patients aged <18 yr in MOVE, palovarotene treatment occurred for a mean (SD) of 166.0 (75.2) wk; 24 (30.0%), all aged <14 yr, had premature physeal closure events.” (opens the source at this quote in a new tab)

Refusal of marketing authorisation in the European Union

“At the time of the initial evaluation, the Agency considered that no firm conclusions could be drawn on the benefits of the medicine, as the applicant’s conclusion was based on a post-hoc analysis which was neither scientifically nor clinically justified and pre-specified study objectives were not met.” (opens the source at this quote in a new tab)
“Regarding safety, the risk of premature physeal closure (a disruption to the areas of new bone growth in the end of long bones, which keeps them from growing normally), which is a known risk with retinoid treatment in growing patients, could not adequately be mitigated with the risk minimisation measures proposed by the company.” (opens the source at this quote in a new tab)

Regulatory review history in Canada and the United States

“Palovarotene was first reviewed and approved by the Health Canada in January 2022.” (opens the source at this quote in a new tab)
“The FDA advisory committee voted 10 in favor and 4 against the evidence showing palovarotene to be effective for blocking new HO formation in FOP, and voted 11 for and 3 against the evidence showing that the benefits of palovarotene outweighed the risks for treating patients with FOP.” (opens the source at this quote in a new tab)

Prespecified square-root transformed analysis did not reach significance at interim analysis 3

“Prespecified futility criteria were met using this analysis method at IA2; however, following post hoc results obtained at IA2, Bayesian analysis of nontransformed data was reconsidered at IA3 when all patients had completed 18 months of follow-up.” (opens the source at this quote in a new tab)
“At IA3, the prespecified Bayesian analysis fitted a 5% reduction in square-root transformed annualized volume of new HO in palovarotene-treated patients in MOVE versus NHS participants untreated beyond standard of care.” (opens the source at this quote in a new tab)
“The post hoc Bayesian analysis fitted a 36% reduction in non-transformed mean annualized volume of new HO in palovarotene-treated patients compared with NHS participants (probability of any reduction in new HO: 99.4%) (Supplemental Fig. S6).” (opens the source at this quote in a new tab)

Comparability of MOVE and its external natural history control

“Baseline demographics and characteristics for the MOVE Principal Enrolled Population (N = 99) and NHS comparator population (N = 111) showed more individuals aged <18 years in MOVE (75/99 [75.8%]) than in the NHS (66/111 [59.5%]); the two populations were otherwise similar (Table 1).” (opens the source at this quote in a new tab)
“Among these 39 patients who contributed data to both studies, mean annualized new HO volume was 54% lower with palovarotene compared with their prior phase receiving no treatment beyond standard of care in the NHS (Supplemental Fig. S7).” (opens the source at this quote in a new tab)

Phase 3 OPTIMA trial: new lesions and flare-ups

“There were a total of 19 new HO lesions observed in 5/21 (24%) patients receiving placebo compared to 2 total lesions in 2/23 (9%) patients or 1 lesion in 1/19 (5%) patients treated with PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively, at Week 56 (see Table 2).” (opens the source at this quote in a new tab)
“The number of clinician-assessed flare-ups through Week 56 was 9, 53, and 66 for PASATRU 10 mg/kg, 3 mg/kg, and placebo, respectively.” (opens the source at this quote in a new tab)
“Changes in the proportion of patients with patient-reported flare-ups through Week 56 were not significantly different between placebo and PASATRU treatment groups.” (opens the source at this quote in a new tab)

Warnings for infection and epistaxis

“Skin and soft tissue infections requiring treatment and/or hospitalization, including abscesses and cellulitis [see Adverse Reactions (6.1)], have occurred in patients receiving PASATRU in clinical trials.” (opens the source at this quote in a new tab)
“In clinical trials in the FOP population, one serious case of spontaneous epistaxis occurred that required hospitalization for nasal packing and application of a clotting agent.” (opens the source at this quote in a new tab)

Phase 2 LUMINA-1 trial

“The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met ( P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027).” (opens the source at this quote in a new tab)
“Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out.” (opens the source at this quote in a new tab)

Guideline classification before approval

“Blocks Activin A signaling through mutant ACVR1/ALK2” (opens the source at this quote in a new tab)
“Not applicable at Present time; Ongoing Phase III clinical trial” (opens the source at this quote in a new tab)

Recommended prednisone regimen for acute flare-ups

“Class I medications can be considered for acute flare-ups involving the major joints of the appendicular skeleton. The immediate use of prednisone at a dose of 2 mg/kg/d (up to 100 mg) can be considered as a single daily dose for a maximum of 4 d. For maximum beneficial effect, the prednisone should be started within 24 h of the onset of a flare-up, which corresponds to the earliest phase of acute inflammatory infiltration into skeletal muscle. If the flare-up is more than 2 days old, prednisone is generally less effective.” (opens the source at this quote in a new tab)

Prophylaxis after injury and before procedures

“Corticosteroid prophylaxis is recommended for significant blunt muscle trauma, as prophylaxis for a potential flare or as treatment of an active flare. The usual recommended dose is prednisone 2 mg/kg/d per oral × 4 d, with a maximum dose of 100 mg/d.” (opens the source at this quote in a new tab)
“Corticosteroid prophylaxis is recommended for dental and surgical procedures.” (opens the source at this quote in a new tab)

Restrictions on axial flare-ups and chronic use

“Prednisone should generally not be used for flare-ups on the chest or trunk, as it is difficult to judge the exact onset of a new flare-up. Prolonged or chronic use of corticosteroids is of no benefit, is harmful systemically, and should not be considered.” (opens the source at this quote in a new tab)

Submandibular flare-ups as a medical emergency

“Flare-ups of the anterior neck beneath the chin (submandibular) can compromise breathing and swallowing and should be considered a medical emergency. Submandibular flare-ups require early identification. Provide high-dose steroids immediately (Solumedrol 80 mg intravenously or Dexamethasone 15 mg intravenously).” (opens the source at this quote in a new tab)

Symptomatic role without evidence of flare-up prevention

“There is no definitive evidence that chronic treatment with COX-2 inhibitors or NSAIDs prevents or ameliorates flare-ups in FOP. However, COX-2 inhibitors or oral/topical NSAIDs may be helpful for symptomatic management of flare-ups and chronic arthropathy when corticosteroids are not indicated.” (opens the source at this quote in a new tab)

Use after corticosteroids and associated precautions

“When prednisone is discontinued (or if a flare-up existing for more than 48 h is being considered for treatment), symptomatic treatment may be considered with a non-steroidal anti-inflammatory agent (NSAID). A COX-2 inhibitor can be used instead of a traditional NSAID ( Table 1 ). As with all NSAIDs, GI precautions should prevail. If long-term use of a COX-2 inhibitor is considered, serum liver and kidney function tests should be monitored.” (opens the source at this quote in a new tab)

Back and chest flare-ups

“Consider non-steroidal anti-inflammatory medications (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors (oral or topical) with assiduous gastrointestinal (GI) precautions. Use analgesics, muscle relaxants, and local applications of ice packs, as needed. Avoid narcotic analgesia.” (opens the source at this quote in a new tab)

Celecoxib dosing

“Peds and Adults: 100–200 mg po bid for maintenance, at discretion of M.D.” (opens the source at this quote in a new tab)

Guideline position on off-label medications

“Class II Medications can be considered on off-label use with caution, at the physician’s discretion.” (opens the source at this quote in a new tab)
“There is no definitive evidence that these medications prevent or ameliorate HO after flare-ups in FOP. These medications may be considered for patients with severe, intractable FOP flare-ups.” (opens the source at this quote in a new tab)

Bisphosphonates

“There is no definitive evidence that bisphosphonates prevent or ameliorate flare-ups in FOP. However, IV bisphosphonates may be considered for the prevention of corticosteroid-associated bone loss.” (opens the source at this quote in a new tab)

“No randomized placebo-controlled trials have been conducted to date to demonstrate efficacy; one case series suggests there may be benefits for decreasing intensity of flares, but data are anecdotal.” (opens the source at this quote in a new tab)

Case-series evidence for tofacitinib and canakinumab

“In an FOP case series by Nikishina et al. 2023, levels of IL-1RA decreased in 4/5 individuals (80%) and increased in 1/5 (20%), suggesting that at least part of the mechanism of action in FOP is related to suppression of inflammatory cytokines.” (opens the source at this quote in a new tab)
“In an FOP uncontrolled case series of 4 patients by Haviv et al. 2024, flare activity was reduced by 61%-89%.” (opens the source at this quote in a new tab)

Rapamycin: case reports without disease-modifying benefit

“Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP.” (opens the source at this quote in a new tab)
“She was treated with rapamycin (1 mg/m[2] ) for three months with a desired rapamycin trough level between 7 and 13 μg/L. Despite the treatment regimen, there was no discernible improvement.” (opens the source at this quote in a new tab)
“Following a minor rejection episode at age 10, cyclosporine was discontinued and rapamycin (sirolimus) was begun at a dose of 1–2 mg/m[2] (adjusted to therapeutic trough levels of 6–15 μg/L) for the next 18 years till the time of this report. Despite 18 years of daily rapamycin therapy, and episodic use of glucocorticoids, flare-ups and HO progressed spontaneously or following minor soft tissue trauma (Fig. 2).” (opens the source at this quote in a new tab)
“In both patients, FOP progressed despite the use of rapamycin.” (opens the source at this quote in a new tab)

Approaches with no role or that are contraindicated

“There is no evidence of efficacy with these agents. The use of these approaches is contraindicated in the management of FOP.” (opens the source at this quote in a new tab)
“The chronic use of antiangiogenic agents, calcium binders, colchicine, fluoroquinolone antibiotics, propranolol, mineralization inhibitors, PPAR-γ antagonists, and TNF-α inhibitors currently has no role in the management of FOP.” (opens the source at this quote in a new tab)

“This approach is ineffective and contraindicated in the treatment of FOP.” (opens the source at this quote in a new tab)

Focus of present management

“However, present management is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, optimization of residual function, and monitoring and treating co-morbidities.” (opens the source at this quote in a new tab)

Avoidance of flare-up triggers, biopsies, and elective surgery

“The prevention of flare-ups and heterotopic bone formation involves multimodal approaches. This includes the recognition and avoidance of known causes of flare-ups: contact sports, soft tissue injuries, blunt muscle trauma, muscle fatigue, muscle stretching, IM injections and immunizations, biopsies, removal of heterotopic bone, all non-emergent surgical procedures, and viral illnesses.” (opens the source at this quote in a new tab)
“If FOP is suspected, all elective procedures such as surgeries, biopsies, and IM immunizations should be deferred until a definitive diagnosis is confirmed.” (opens the source at this quote in a new tab)
“Avoid surgery, except in emergencies. Always avoid surgery to remove heterotopic bone.” (opens the source at this quote in a new tab)

Immunization route and venous access

“Immunization by subcutaneous administration is recommended for all vaccines that can be administered by that route. Avoid all IM immunizations and intranasal influenza immunizations with live vaccines as they may precipitate flare-ups of FOP.” (opens the source at this quote in a new tab)
“Central lines, PICC lines, and arterial punctures may cause HO and should be avoided unless critical for the patient’s medical management.” (opens the source at this quote in a new tab)

Anesthesia precautions

“An expert anesthesiologist experienced in general anesthesia for FOP patients must be consulted pre-operatively in all cases. If general anesthesia is required, an awake intubation by nasotracheal fiber-optic technique should be performed because of cervical spine fusions, jaw motion limitations, sensitive airway, and risk of inducing an obstructing neck flare-up.” (opens the source at this quote in a new tab)

Physical and occupational therapy and assistive care

“Passive range of motion to restore or improve joint range of motion is strictly prohibited. An assessment of ambulatory aids may be indicated. Warm water hydrotherapy may be helpful.” (opens the source at this quote in a new tab)
“Perform periodic OT evaluations for assistive devices, as activities of daily living are likely to change over time.” (opens the source at this quote in a new tab)
“Singing, swimming, and incentive spirometry are strongly encouraged to maintain lung function.” (opens the source at this quote in a new tab)

Summary: limitations of therapies available before and after the 2026 approvals

The international clinical guideline states that no medication has been proven to alter the natural history of fibrodysplasia ossificans progressiva and that its evidence-based statements are "generally moderate to low". Its management rests on injury avoidance and symptomatic treatment of flare-ups; corticosteroids are limited to 4-day courses started within 24 hours of onset, and no definitive evidence shows that NSAIDs, COX-2 inhibitors, bisphosphonates, or off-label agents prevent flare-ups or heterotopic ossification. The guideline predates the approvals of garetosmab-grts (August 2026) and zilurgisertib (September 2026) and lists both as investigational Class III agents.

Until 2026, palovarotene was the only approved therapy. Its approval rested on post hoc analyses against an external natural history control after the prespecified month-18 analysis showed no statistically significant difference, and at month 48 the 46.4% lower annualized new HO volume was not significant (nominal p = .0585). Premature physeal closure occurred in 24 of 80 participants younger than 18 years (30.0%), all younger than 14 years, and the European Medicines Agency refused marketing authorisation. Garetosmab-grts is labeled for adults only, requires intravenous infusion every 4 weeks, and did not show a statistically significant difference in new HO volume. Zilurgisertib is not established in patients younger than 12 years. No approved therapy is labeled for females younger than 8 years or males younger than 10 years. Fidrisertib, a second ALK2 inhibitor, did not meet its primary endpoint in 113 participants.

No medication proven to alter the natural history

“At the present time, there are limited treatments for FOP.” (opens the source at this quote in a new tab)
“PHYSICIANS TREATING PATIENTS WHO HAVE FOP SHOULD KEEP IN MIND THAT NONE OF THESE MEDICATIONS (OR ANY OTHER MEDICATIONS TO DATE) HAVE BEEN PROVEN TO ALTER THE NATURAL HISTORY OF FOP” (opens the source at this quote in a new tab)

Strength of the evidence behind guideline recommendations

“As FOP is an ultra-rare condition, evidence-based statements are generally moderate to low.” (opens the source at this quote in a new tab)
“In the absence of clear evidence-based research from controlled clinical trials, it is difficult to advocate a particular therapy with enthusiasm.” (opens the source at this quote in a new tab)

Standard of care limited to symptom management, and constraints in growing patients

“The current standard of care (SoC) for FOP is limited to symptom management and flare-up prevention.” (opens the source at this quote in a new tab)
“This may limit the ability to treat growing patients with palovarotene and thus highlights the need for additional disease-modifying therapies for these individuals.” (opens the source at this quote in a new tab)

Multiple pathway nodes under investigation, with no approach yet established as most effective

“The development of therapies for FOP have focused on targeted inhibition of the ACVR1 receptor, ACVR1 ligands, BMP pathway signaling, preosseous chondrogenic anlagen of HO, and inflammatory triggers of disease activity (Figure 1).” (opens the source at this quote in a new tab)
“Currently, it is too early to determine which one of these approaches or combinations of approaches will be most effective in FOP, and all are being studied intensively in preclinical and/or clinical studies” (opens the source at this quote in a new tab)

Summary: anticipated position of an oral ALK2 inhibitor

Zilurgisertib is the second oral product and the third product overall approved for fibrodysplasia ossificans progressiva. It is taken once daily at home, with or without food, and tablets may be crushed into water, juice, apple sauce, or yogurt for patients who cannot swallow them. Its labeled population (12 years and older) includes adolescents aged 12 to 17 years, for whom garetosmab-grts is not labeled, and growing adolescents, for whom the palovarotene label carries a boxed warning for premature epiphyseal closure. Garetosmab-grts, by contrast, is given by intravenous infusion over 60 minutes every 4 weeks using an infusion pump. The international clinical guideline has not been updated since the 2026 approvals and classifies zilurgisertib as an investigational Class III agent. Zilurgisertib is expected to be commercially available in October 2026 through the Mirum Access Plus patient support program. No source identified in this review defines the order in which the three approved products should be used.

Oral administration, including crushed tablets

“Administer ATEBRIOZ tablets whole or crushed. If crushed, mix 4 tablets (100 mg total) with four tablespoons (60 mL) of water, orange juice, apple sauce, or plain yogurt and administer immediately.” (opens the prescribing information at this quote)

Intravenous administration of the activin A antibody

“PASATRU should be administered using an infusion pump to control the rate of infusion.” (opens the source at this quote in a new tab)

Commercial availability and investigator statement on adolescents

“Atebrioz is expected to be commercially available in the U.S. in October, with eligible patients paying as little as $0 per month through MAP.” (opens the source at this quote in a new tab)
“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.” (opens the source at this quote in a new tab)

Guideline classification before approval

“Class III Agents are compounds under development, being tested in clinical trials, and are not yet available for general use.” (opens the source at this quote in a new tab)
“ACVR1/ALK2 Signal Transduction Inhibitor, STI (Zilurgisertib; INCB000928) [Incyte; PROGRESS]” (opens the source at this quote in a new tab)

Variability of disease course among individuals

“However, there is great variability among individuals in terms of course and severity.” (opens the source at this quote in a new tab)
“Although there are common physical features shared by every person who has FOP, there are differences among individuals that may alter the potential benefits or risks of any medication or class of medications discussed here.” (opens the source at this quote in a new tab)

ACVR1 variant and eligibility in the pivotal trial

“An estimated 97% of individuals with FOP have this recurrent variant (ACVR1 R206H). Approximately 3% of affected individuals have different pathogenic variants in ACVR1” (opens the source at this quote in a new tab)

“Inclusion criteria included clinical diagnosis of FOP, patient-reported FOP disease activity within 1 year of the screening visit (i.e., FOP flare-ups, worsening joint function, or radiographic progression of HO), and a baseline Cumulative Analogue Joint Involvement Scale (CAJIS) score ≤ 23.” (opens the prescribing information at this quote)

Age and disease severity of the enrolled population

“The median age of enrolled patients was 16 years (range: 12 to 64 years), 56% were 12 to 16 years of age” (opens the prescribing information at this quote)
“All patients had a baseline CAJIS score of ≤ 23 and 84% of patients had a score < 18 (range: 2-22).” (opens the prescribing information at this quote)
“Clinical studies of ATEBRIOZ did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.” (opens the prescribing information at this quote)

Safety and exposure by age group

“Safety was similar between adults and adolescents; this was also observed during the OLE” (opens the source at this quote in a new tab)

“In pediatric patients with FOP (12 to 16 years of age), the estimated steady-state AUC and Cmax for zilurgisertib was 11478 nM·h and 883 nM, respectively.” (opens the prescribing information at this quote)

Age-dependent risk with the retinoic acid receptor gamma agonist

“In MOVE, the 80 patients aged <18 yr (age range: 4-17 yr) received palovarotene for a mean (SD) of 166.0 (75.2) wk. Of these, 24/80 (30.0%) had clinical events consistent with PPC, all of which occurred in those aged <14 yr” (opens the source at this quote in a new tab)

Pregnancy testing and contraception

“Verify that females of reproductive potential are not pregnant prior to initiating ATEBRIOZ” (opens the prescribing information at this quote)
“Advise females of reproductive potential to use effective contraception during treatment with ATEBRIOZ and for one week after the final dose.” (opens the prescribing information at this quote)
“Because of the potential for serious adverse reactions, including effects on bone development, in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ATEBRIOZ and for at least one week after the final dose.” (opens the prescribing information at this quote)

Medication and food interaction review

“CYP3A4 Inhibitors: Reduce ATEBRIOZ dosage to 50 mg orally once daily when used concomitantly with a strong CYP3A4 inhibitor.” (opens the prescribing information at this quote)
“CYP3A4 Inducers: Avoid concomitant use of ATEBRIOZ with strong or moderate CYP3A4 inducers.” (opens the prescribing information at this quote)
“MATE1 and MATE2-K Substrates: Avoid concomitant use of ATEBRIOZ with MATE1 and MATE2-K substrates (e.g., metformin).” (opens the prescribing information at this quote)
“Do not administer ATEBRIOZ with grapefruit, pomelo, or juices containing these fruits.” (opens the prescribing information at this quote)

Manufacturer patient support program

“MAP provides insurance coverage and access support, financial assistance for eligible patients, personalized patient support and educational resources for patients and caregivers.” (opens the source at this quote in a new tab)

Coordination with FOP specialists and clinical trial investigators

“Each patient should have a primary physician who is willing to consult with an FOP expert and help coordinate a local care team.” (opens the source at this quote in a new tab)
“Ask if patient is enrolled in any FOP Clinical Trials and communicate with principal investigator and regional FOP specialist.” (opens the source at this quote in a new tab)

Prescriber education and growth monitoring for palovarotene

“Sohonos Educational Program and must be completed by any healthcare professional who wants to prescribe Sohonos.” (opens the source at this quote in a new tab)

“Prior to starting treatment with SOHONOS, all growing pediatric patients should undergo baseline assessment of skeletal maturity via hand/wrist and knee x-rays, standard growth curves and pubertal staging.” (opens the source at this quote in a new tab)

Postmarketing requirements and commitments in the approval letter

No evidence found.

Pediatric development in children younger than 12 years

“The PROGRESS development program also continues to advance, with enrollment completed in Cohort 2 of children aged 6 to <12 years, and enrollment underway in Cohort 3 of children aged 2 to <12 years.” (opens the source at this quote in a new tab)

“The safety and effectiveness of ATEBRIOZ have not been established in pediatric patients younger than 12 years of age.” (opens the prescribing information at this quote)

Carcinogenicity studies not conducted before approval

“Long-term carcinogenicity studies have not been conducted with zilurgisertib. In a 6-month repeat-dose toxicity study, rats orally administered zilurgisertib developed dose-dependent basophilic foci of cellular alterations (potential preneoplastic findings) and hepatic iron accumulation in the liver (at exposures comparable to clinical exposure).” (opens the prescribing information at this quote)
“The clinical relevance of these findings, including the potential carcinogenic risk in humans treated with zilurgisertib, is uncertain.” (opens the prescribing information at this quote)

European marketing authorisation application

“In the European Union, a marketing authorization application (MAA) for zilurgisertib is currently under review by the European Medicines Agency (EMA), supported by data from Cohort 1 (patients aged 12 years and older) of the PROGRESS study.” (opens the source at this quote in a new tab)

Open-label extension of the pivotal trial

“Patients who completed the 24-week double-blind period entered the 292-week open-label extension” (opens the prescribing information at this quote)

“The open-label period of PROGRESS for adolescents and adults is ongoing, and enrollment of younger age groups has begun” (opens the source at this quote in a new tab)

Iron parameters during long-term treatment

“Compared to placebo, ATEBRIOZ-treated patients experienced mean increases in serum iron, hemoglobin, and transferrin saturation levels; the mean values for all three measures remained within the normal range.” (opens the prescribing information at this quote)
“Based on the data through Week 100, the increases in serum iron and transferrin saturation with ATEBRIOZ were not associated with signs or symptoms of iron overload.” (opens the prescribing information at this quote)

Pregnancy exposure registry

No evidence found.

Post-marketing registry for the retinoic acid receptor gamma agonist

“Finally, the FOPal registry (NCT06089616) has been started and will collect long-term information about safety and efficacy in patients taking palovarotene.” (opens the source at this quote in a new tab)

Summary: outcomes reported for zilurgisertib

In the 24-week double-blind period of PROGRESS, total new HO volume (new lesions plus expansion of existing lesions) decreased by a mean of 3.2 cm³ with zilurgisertib and increased by 24.6 cm³ with placebo. The registered primary endpoint, the proportion of participants with new HO lesions, was 1 of 32 (3.1%) with zilurgisertib and 5 of 30 (16.7%) with placebo (P=0.0986). Mean volume of new lesions was 0.003 cm³ with zilurgisertib and 6.57 cm³ with placebo, and mean annualized new flares were 2.34 and 4.55. No new lesions were reported in either group from Week 24 to Week 48 of the open-label extension. The effect of these radiographic changes on joint function, mobility, and survival has not been reported, and no consensus threshold defines a clinically meaningful reduction in new HO volume.

Labeled efficacy at Week 24: total new HO volume

“At Week 24, the mean change (SD) from baseline in total new HO volume was −3.2 cm³ (19.9) in the zilurgisertib group and +24.6 cm³ (51.9) in the placebo group, resulting in a Hodges-Lehmann treatment difference of −15.8 cm³ (95% CI: -32.1, -6.0).” (opens the prescribing information at this quote)

Registered primary endpoint and new lesion volume at Week 24

“At Week 24, 1 of 32 patients in the zilurgisertib group had new lesions versus 5 of 30 patients in the placebo group (primary endpoint, P=0.0986; Figure 2)” (opens the source at this quote in a new tab)
“Smaller new lesion volume (cm3) with ZGB vs PBO at Week 24 (mean [SD]): 0.003 [0.02] vs 6.57 [20.70]); P<0.0001” (opens the source at this quote in a new tab)
“Fewer mean (SD) annualized new flares by Week 24 with ZGB vs PBO (2.34 [6.06] vs 4.55 [7.71])” (opens the source at this quote in a new tab)

Durability through Week 48 of the open-label extension

“No patients had new lesions during the OLE period from Week 24 to 48” (opens the source at this quote in a new tab)
“From baseline to Week 24, total lesion volume decreased in the zilurgisertib group but increased in the placebo group, while from Week 24 to 48, total lesion volume decreased from baseline in both groups” (opens the source at this quote in a new tab)

Relation of new HO volume to function

“Currently, there is no consensus on a threshold for a clinically meaningful reduction in new HO volume in patients with FOP, and this warrants further research.” (opens the source at this quote in a new tab)
“reducing the volume of new HO over time may help slow the progression of functional disability, and preventing even small volumes of new HO in certain joints may be crucial for maintaining patients’ mobility and quality of life.” (opens the source at this quote in a new tab)

Disease course without disease-modifying therapy

“Most patients with FOP are confined to a wheelchair by the third decade of life and require lifelong assistance with activities of daily living. The median estimated life expectancy is 56 yr. Death often results from complications of thoracic insufficiency syndrome.” (opens the source at this quote in a new tab)