Zilurgisertib

1. INDICATIONS AND USAGE 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). 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).

12.1. Mechanism of Action 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.

2. DOSAGE AND ADMINISTRATION • Recommended starting dosage: 100 mg orally once daily with or without food. • 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. 2.1. Pregnancy Testing Prior to Treatment with ATEBRIOZ Verify that females of reproductive potential are not pregnant prior to initiating ATEBRIOZ. 2.2. Recommended Dosage and Administration The recommended dosage of ATEBRIOZ is 100 mg orally once daily with or without food. 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. Do not administer ATEBRIOZ with grapefruit, pomelo, or juices containing these fruits. 2.3.

4. CONTRAINDICATIONS ATEBRIOZ is contraindicated in pregnancy. ATEBRIOZ can cause fetal harm when administered to a pregnant woman. Pregnancy.

5. WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: Can cause fetal harm. Verify females of reproductive potential are not pregnant prior to initiating ATEBRIOZ and advise of the potential risk to a fetus and to use effective contraception. Advise the patient to discontinue ATEBRIOZ immediately if pregnancy occurs during treatment and to contact their healthcare provider. 5.1. Embryo-Fetal Toxicity ATEBRIOZ is contraindicated during pregnancy. Based on its mechanism of action and findings from animal reproduction studies, ATEBRIOZ can cause fetal harm when administered to a pregnant woman.

6. ADVERSE REACTIONS Most common adverse reactions (≥ 10%): headache, arthralgia, upper respiratory tract infection, epistaxis, and nausea. 6.1. Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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. Patients who completed the 24‑week double‑blind period entered the 292-week open-label extension.

7. DRUG INTERACTIONS CYP3A4 Inhibitors: Reduce ATEBRIOZ dosage to 50 mg orally once daily when used concomitantly with a strong CYP3A4 inhibitor. CYP3A4 Inducers: Avoid concomitant use of ATEBRIOZ with strong or moderate CYP3A4 inducers. MATE1 and MATE2-K Substrates: Avoid concomitant use of ATEBRIOZ with MATE1 and MATE2-K substrates (e.g., metformin). 7.1. Effect of Other Drugs on ATEBRIOZ Strong CYP3A4 Inhibitors Reduce the ATEBRIOZ dosage to 50 mg once daily when used concomitantly with a strong CYP3A4 inhibitor. ATEBRIOZ is a CYP3A4 substrate. Strong CYP3A4 inhibitors increase zilurgisertib exposure, which may increase the risk of ATEBRIOZ adverse reactions. Strong and Moderate CYP3A4 Inducers Avoid concomitant use of ATEBRIOZ with strong or moderate CYP3A4 inducers.

Store ATEBRIOZ tablets at 20ºC to 25ºC (68ºF to 77ºF), excursions permitted between 15ºC and 30ºC (59ºF and 86ºF).