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Thermo Fisher Scientific - Chemical Products

BridgeBio Pharma Moves Forward with Accelerated Approval Pathway in Limb-girdle Muscular Dystrophy Type 2I (LGMD2I/R9) Using Glycosylated Alpha-dystroglycan (⍺DG) Levels

Tuesday, August 01, 2023

BridgeBio Pharma, Inc., a biopharmaceutical company focused on genetic diseases and cancers, recently announced potential progress towards accelerated approval for BBP-418 in the United States. BBP-418 is an investigational oral substrate supplementation therapy intended for patients with limb-girdle muscular dystrophy type 2I (LGMD2I/R9). This advancement comes after discussions with the U.S. Food and Drug Administration (FDA) regarding a potential pathway for accelerated approval.

BridgeBio also reported that the Phase 3 FORTIFY clinical trial of BBP-418 has commenced, with the first patient with LGMD2I/R9 being dosed. The trial is a randomized, double-blind, and placebo-controlled study aimed at assessing the safety and efficacy of BBP-418. An interim analysis at 12 months will focus on evaluating glycosylated αDG as a surrogate endpoint, which could potentially support the accelerated approval process. At 36 months, the study will analyze the North Star Assessment for Dysferlinopathy (NSAD) and other secondary endpoints to provide further clinical data.

To support LGMD2I/R9 disease-modifying therapies, BridgeBio has developed a novel, validated bioassay to directly measure glycosylated αDG levels, which are critical in LGMD2I/R9 disease and can help monitor patient responses to treatment.

BBP-418 is designed to provide supraphysiological levels of an endogenous substrate upstream of the mutant FKRP enzyme. This process may increase residual enzyme activity, facilitating glycosylation of αDG and potentially stabilizing muscle cells during contraction, with the goal of preventing further muscle damage.

According to BridgeBio, data from an ongoing open-label Phase 2 study show promising results, suggesting that BBP-418 is well-tolerated and may positively impact key endpoints.

LGMD2I/R9 patients currently lack FDA-approved specific treatments, and existing options primarily offer supportive care. The Phase 3 FORTIFY trial brings hope to the LGMD community for disease-modifying treatments.

BridgeBio plans to present updated results on their novel bioassay and Phase 2 clinical trial at the Annual Congress of the World Muscle Society in October 2023. If approved, BBP-418 could become the first orally administered therapy for patients with LGMD2I/R9.

BridgeBio is actively collaborating with the FDA to address the challenges associated with LGMD2I/R9 drug development, including the potential use of glycosylated αDG levels as a surrogate endpoint to support accelerated approval.

Limb-girdle Muscular Dystrophy Type 2I (LGMD2I/R9) is a monogenic autosomal recessive disease caused by partial loss of function mutations in the fukutin-related protein (FKRP) gene. These mutations lead to impaired glycosylation of αDG, a protein essential for stabilizing muscle cells. The disease is

characterized by skeletal myopathy affecting the lower limbs initially, which later progresses to involve the upper limbs. Respiratory muscle and cardiac muscle involvement may also occur.

Patients with a homozygous genotype typically develop disease manifestations during late childhood. As the disease progresses, about 25% of cases lose independent ambulation, 10% require assisted ventilation, and approximately 30% experience cardiomyopathy in adulthood. Cardiomyopathy is a progressive condition, with an annual loss of 0.4% of left ventricular ejection fraction (LVEF).

On the other hand, patients with heterozygous genotypes experience an earlier onset of symptoms during childhood and have a more severe clinical course. By the age of 20, mobility is rapidly lost, and about 60% of cases exhibit cardiac involvement. Nearly all individuals with a heterozygous genotype develop respiratory failure by the age of 30.

Currently, there are no specific FDA-approved treatments for LGMD2I/R9, and available options primarily focus on supportive care. However, ongoing research, such as the Phase 3 FORTIFY trial of BBP-418, seeks to provide potential disease-modifying treatments for patients with this condition, offering hope for improved management and outcomes.

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