FDA Approves Atebrioz (zilurgisertib), an Oral ALK2 Inhibitor, for Fibrodysplasia Ossificans Progressiva
核心洞察
The FDA approved Atebrioz (搜索) (zilurgisertib) tablets at 100 mg once daily to reduce total new heterotopic ossification volume in patients aged 12 and older with FOP.
In the Phase 2 PROGRESS study, mean total new HO lesion volume fell 3.2 cm3 with zilurgisertib versus a 24.6 cm3 increase with placebo at Week 24.
Zilurgisertib was generally well tolerated, with headache, arthralgia, upper respiratory tract infection, epistaxis and nausea as the most common adverse reactions.
The U.S. Food and Drug Administration has approved Atebrioz (搜索) (zilurgisertib) tablets to reduce the volume of total new heterotopic ossification (HO) in adult and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva (搜索) (FOP), Mirum Pharmaceuticals and Incyte announced. The recommended dose is 100 mg administered orally once daily.
Atebrioz (搜索) is a once-daily oral activin receptor-like kinase 2 (ALK2 (搜索)) inhibitor designed to target the disease-driving pathway at the center of FOP biology. In people living with FOP, pathogenic variants in the ACVR1 (搜索) gene result in abnormal activation of ALK2, which leads to the formation of bone in muscles, tendons, ligaments and other soft tissues through heterotopic ossification. As HO lesions develop and accumulate over time, they can progressively restrict movement and lead to significant disability.
The drug was developed by Incyte and licensed to Mirum for worldwide development and commercialization.
Efficacy in the PROGRESS Study
Approval was based on data from Cohort 1 of the PROGRESS study, a global, randomized, double-blind, placebo-controlled Phase 2 trial evaluating zilurgisertib in patients with FOP. Cohort 1 enrolled 63 patients aged 12 years and older who were randomized 1:1 to receive zilurgisertib 100 mg once daily or placebo during a 24-week double-blind treatment period, followed by an open-label extension.
Efficacy was established based on total new HO lesion volume, which includes expansion of baseline HO lesion burden as well as any new discrete HO that developed during the 24-week double-blind period. At Week 24, mean total new HO lesion volume decreased by 3.2 cm3 in patients receiving zilurgisertib compared with an increase of 24.6 cm3 in placebo-treated patients. Treatment effects were maintained through Week 48 of the open-label extension.
"FOP is a lifelong disease in which the accumulation of HO leads to increasing disability and loss of function," said Robert Pignolo, M.D., Ph.D., Robert and Arlene Kogod Professor of Geriatric Medicine at the Mayo Clinic College of Medicine and lead investigator for the PROGRESS study. "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."
Safety Profile
Zilurgisertib was generally well tolerated during the 24-week placebo-controlled period. The most common adverse reactions were headache, arthralgia, upper respiratory tract infection, epistaxis and nausea. Most adverse events were mild or moderate in severity, and no adverse events led to treatment discontinuation or dose reduction.
The prescribing information states that Atebrioz (搜索) can cause fetal harm based on data from animal studies. Patients of reproductive potential should use effective contraception and should immediately discontinue Atebrioz and contact their healthcare provider if pregnancy occurs.
Access and Regulatory Milestones
Atebrioz (搜索) 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.
With the approval, the FDA also issued a Rare Pediatric Disease Priority Review Voucher to Incyte. The voucher can be used for a subsequent drug application that would not otherwise qualify for a priority review.
"Today marks an important milestone for people living with FOP, bringing a new treatment option to adult and pediatric patients living with this devastating disease," said Chris Peetz, Chief Executive Officer at Mirum. "At Mirum, we are driven to serve rare disease communities where the unmet need is significant and the opportunity to make a difference is profound."
"For families living with FOP, having additional treatment options means having greater flexibility in managing a complex, lifelong disease," said Michelle Davis, Executive Director at the International Fibrodysplasia Ossificans Progressiva (搜索) Association (IFOPA). "Every person's experience with FOP is different, and expanding treatment options gives patients, families and their physicians the opportunity to consider what may be right for their individual needs."
Ongoing Development
In the European Union, a marketing authorization application for zilurgisertib is under review by the European Medicines Agency (搜索), supported by data from Cohort 1 of the PROGRESS study in patients aged 12 years and older.
The PROGRESS pediatric development program continues to evaluate the safety and efficacy of zilurgisertib in younger patients. Enrollment is completed in Cohort 2 of children aged 6 to under 12 years, and enrollment is underway in Cohort 3 of children aged 2 to under 12 years.
FOP is an ultra-rare, progressive genetic disease affecting approximately 300 people in the United States and 900 worldwide. Symptoms typically become apparent in early childhood, and the number and volume of HO lesions increase over time, progressively restricting movement and limiting mobility, daily function and independence.