Review section

Field	Value
Drug	Atebrioz (zilurgisertib)
Indication reviewed	Fibrodysplasia ossificans progressiva
Therapeutic category	Activin receptor-like kinase-2 (ALK2) inhibitors
Manufacturer	Mirum Pharmaceuticals
Regulatory status	Approved September 25, 2026
Data as of	September 27, 2026
Prepared by	To be completed by the reviewing plan
Review status	Draft for pharmacy and therapeutics committee review

Indications

Table 1. FDA-approved indications

Indications	Atebrioz (zilurgisertib)
“reduce the volume of total new heterotopic ossification (HO) in adults and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva (FOP)”	✓

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)

Pharmacokinetics

Table 2. Pharmacokinetic parameters

Generic Name(s)	Bioavailability	Protein Binding	Metabolism	Excretion	Half-Life
Zilurgisertib	Not reported	“62.6%”	“predominantly metabolized by CYP3A4 and to a minor extent by CYP2D6”	“49% of the dose was recovered in feces (10% unchanged) and 38.5% in urine (28% unchanged)”	“27.4 hours (23%)”

How the label reports pharmacokinetic values

“Zilurgisertib pharmacokinetics are presented as geometric mean (coefficient of variation [%CV]), unless otherwise specified.” (opens the prescribing information at this quote)

Drug interactions

Table 3. Major drug interactions

Generic Name(s)	Interaction	Mechanism
Zilurgisertib	Strong CYP3A4 inhibitors	“ATEBRIOZ is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase zilurgisertib exposure”“which may increase the risk of ATEBRIOZ adverse reactions.”“Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased the geometric mean Cmax and AUC of zilurgisertib 1.28-fold and 2.13-fold, respectively”“Reduce the ATEBRIOZ dosage to 50 mg once daily when used concomitantly with a strong CYP3A4 inhibitor”
Zilurgisertib	Mild or moderate CYP3A4 inhibitors	“No change in ATEBRIOZ dosage is needed when used concomitantly with a mild or moderate CYP3A4 inhibitor”“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.”
Zilurgisertib	Strong or moderate CYP3A4 inducers	“Avoid concomitant use of ATEBRIOZ with strong or moderate CYP3A4 inducers.”“Strong or moderate CYP3A4 inducers decrease zilurgisertib plasma concentrations”“which may reduce the effectiveness of ATEBRIOZ.”“Coadministration of rifampin (a strong CYP3A4 inducer) decreased zilurgisertib Cmax and AUC by 56% and 79%, respectively”“Concomitant use of efavirenz (a moderate CYP3A4 inducer) is predicted to decrease zilurgisertib Cmax and AUC by 25% and ~60%, respectively”
Zilurgisertib	Strong and moderate CYP2D6 inhibitors	“Coadministration of paroxetine (a strong CYP2D6 inhibitor) and duloxetine is predicted to have negligible effect on zilurgisertib exposure.”
Zilurgisertib	P-gp, BCRP, and MRP2 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	Grapefruit and pomelo	“Do not administer ATEBRIOZ with grapefruit, pomelo, or juices containing these fruits.”
Zilurgisertib	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.”“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.”

Abbreviations: AUC=area under the plasma concentration-time curve; BCRP=breast cancer resistance protein; Cmax=maximum plasma concentration; CYP=cytochrome P450; MATE=multidrug and toxin extrusion protein; MRP2=multidrug resistance-associated protein 2; P-gp=P-glycoprotein

Adverse drug events

Table 4. Adverse drug events reported in 10% or more of patients through Week 24

Adverse Event	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 patients

“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)

Dosing and administration

Table 5. Usual dosing regimens

Generic Name	Usual Adult Dose	Usual Pediatric Dose	Availability
Zilurgisertib	“The recommended dosage of ATEBRIOZ is 100 mg orally once daily with or without food”	“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.”“The safety and effectiveness of ATEBRIOZ have not been established in pediatric patients younger than 12 years of age.”	“ATEBRIOZ Tablets: 25 mg of zilurgisertib”

See the current prescribing information for full details.

Effectiveness

Table 6. Comparative clinical trials

Study and Drug Regimen	Study Design and Demographics	Study Size and Duration	End Points	Results
Study 1 (NCT05090891): “randomized 1:1 to treatment with ATEBRIOZ 100 mg or placebo once daily for 24 weeks”	“randomized, double-blind, placebo-controlled trial”“Randomization was stratified by baseline CAJIS score (< 18 or 18-23).”“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.”“The median age of enrolled patients was 16 years (range: 12 to 64 years), 56% were 12 to 16 years of age, 51% were female, 56% were White, 5% were Black/African American, 29% were Asian”	“Sixty-three patients (28 adults and 35 pediatric patients aged 12 years of age and older)”“once daily for 24 weeks followed by a 292-week open label extension (OLE) period of ATEBRIOZ 100 mg treatment”	“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.”	“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).”

Abbreviations: CAJIS=Cumulative Analogue Joint Involvement Scale; CI=confidence interval; FOP=fibrodysplasia ossificans progressiva; HO=heterotopic ossification; SD=standard deviation

Protocol primary endpoint, which the prescribing information does not report

“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)

“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)

Review section

1Indications

Table 1. FDA-approved indications

Age limit of the indication

2Pharmacokinetics