RARE Daily

BridgeBio Scores RPPD for Limb-Girdle Muscular Dystrophy Therapy

June 18, 2024

Rare Daily Staff

The U.S. Food and Drug Administration granted Rare Pediatric Disease designation to BridgeBio Pharma’s experimental treatment, BBP-418, for limb-girdle muscular dystrophy type 2I/R9, which primarily affects children.

Limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9) is a monogenic autosomal recessive disease caused by partial loss of function mutations in the fukutin-related protein (FKRP) gene, and FKRP mutations impair glycosylation of alpha-dystroglycan (αDG), a protein associated with stabilizing muscle cells. Clinical manifestations typically present as a skeletal myopathy affecting the lower and then upper limbs, which is commonly later accompanied by respiratory muscle and cardiac muscle involvement.

Individuals who harbor a homozygous L276I genotype typically develop disease manifestations during late childhood with progression to loss of independent ambulation (25 percent), assisted ventilation (10 percent), and cardiomyopathy (30 percent) in adulthood. Cardiomyopathy is progressive. Individuals with other FKRP genotypes typically have an earlier childhood onset with a more severe clinical course, rapid loss of mobility by 20 years of age, more frequent cardiac involvement (60 percent), and eventual respiratory failure by 30 years of age in nearly all cases.

BridgeBio said it has surpassed its interim analysis enrollment target and expects topline interim data from its phase 3 registrational study FORTIFY in individuals with LGMD2I/R9 in 2025.

FORTIFY is a randomized, double-blind, placebo-controlled phase 3 study evaluating the safety and efficacy of BBP-418, an investigational oral therapy in development for the treatment of individuals living with LGMD2I/R9. The study includes a planned interim analysis at 12 months focused on assessing glycosylated αDG as a surrogate endpoint to support Accelerated Approval. The primary endpoint to be evaluated at 36 months is the North Star Assessment (NSAD) for limb-girdle type muscular dystrophies and is designed to provide confirmatory clinical data. BridgeBio is continuing to enroll FORTIFY in the United States, United Kingdom, Europe, and Australia.

BridgeBio plans to pursue Accelerated Approval for BBP-418 based on the use of glycosylated αDG levels as a surrogate endpoint in LGMD2I/R9. Furthermore, the FDA indicated that the company’s approach to measure glycosylated αDG levels via a novel, validated muscle tissue-based bioassay appears reasonable. A peer-reviewed manuscript providing details on the novel, multiplexed, fluorescence-based Western Blot assay was recently published in the Journal of Muscle Research and Cell Motility.

“Reduced glycosylated αDG is the primary molecular driver of LGMD2I/R9, a serious, progressively debilitating disease that weakens the muscles causing many affected people to become fully dependent on a caregiver, while also threatening their cardiac and respiratory function,” said Douglas Sproule, chief medical officer of ML Bio Solutions, a BridgeBio affiliate that is focused on developing BBP-418 for LGMD2I/R9. “We hope to continue to serve individuals through expeditious enrollment of the phase 3 FORTIFY study and look forward to continuing to partner with the FDA to accelerate development of a potential new therapeutic option for people living with LGMD2I/R9.”

The FDA grants Rare Pediatric Disease designation to incentive development of new treatments for serious or life-threatening diseases that primarily affect children ages 18 years or younger with fewer than 200,000 people affected in the U.S. The RPDD program allows for a sponsor who receives an approval to qualify for a priority review voucher (PRV) that can be deemed to receive an expedited six-month priority review for any subsequent marketing application or may be sold or transferred. Recently PRV sales have garnered about $100 million.

Photo: Douglas Sproule, chief medical officer of ML Bio Solutions

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