BridgeBio Pharma has announced the completion of enrollment for the Phase 3 FORTIFY study, evaluating BBP-418 as a potential treatment for Limb-girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9). This marks a significant milestone in the development of a therapy for this rare and debilitating genetic disease, with topline data from the interim analysis expected in 2025.
FORTIFY Trial Details
The FORTIFY study (NCT05775848) is a randomized, double-blind, placebo-controlled Phase 3 trial designed to assess the safety and efficacy of BBP-418, an investigational oral therapy. The trial exceeded its target enrollment, reflecting the high unmet need for effective treatments for LGMD2I/R9. The study includes a planned interim analysis at 12 months, primarily focused on assessing glycosylated alpha-dystroglycan (αDG) as a surrogate endpoint to potentially support Accelerated Approval in the U.S.
The primary endpoint, evaluated at 36 months, is the North Star Assessment (NSAD) for limb-girdle type muscular dystrophies, designed to provide confirmatory clinical data supporting the efficacy of BBP-418. The trial involves adolescents and adults, ages 12 to 60, with LGMD2i, who are receiving BBP-418 twice daily at 9 g or 12 g doses, depending on body weight, or a placebo.
BBP-418 Mechanism of Action
LGMD2I/R9 is caused by mutations in the fukutin-related protein (FKRP) gene, which impairs the glycosylation of alpha-dystroglycan (αDG), a protein crucial for stabilizing muscle cells. BBP-418, also known as ribitol, is designed to enhance the activity of the FKRP enzyme, thereby increasing alpha-dystroglycan glycosylation and improving motor function in LGMD2I/R9 patients.
Regulatory Designations and Potential Approval Pathway
BBP-418 has received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations from the FDA, as well as Orphan Drug Designation from the European Medicines Agency (EMA). These designations are intended to support and accelerate the development of potential therapies for serious and/or rare conditions.
Douglas Sproule, M.D., M.Sc., Chief Medical Officer of ML Bio Solutions, a BridgeBio company, stated, "Based on multiple encouraging discussions with the FDA, we believe there is an opportunity to pursue Accelerated Approval in the U.S. for BBP-418 in LGMD2I/R9 based on a potential surrogate endpoint biomarker of glycosylated αDG at the time of the interim analysis."
If successful, BBP-418 could be the first approved disease-modifying therapy for individuals living with LGMD2I/R9 in the U.S. Furthermore, consistent with the Rare Pediatric Designation from the FDA, if BBP-418 is approved, BridgeBio may qualify for a Priority Review Voucher.
Clinical Trial Data
Previous clinical trial data, including a Phase 2 trial (NCT04800874), have shown promising results. Early results from the Phase 2 trial indicated no serious side effects related to the treatment. At 15 months, three severe adverse events due to the underlying disease were recorded, but deemed unrelated to the treatment. Overall, the 14 adverse events deemed possibly or probably related to the therapy were generally mild digestive issues, including diarrhea, and no patient discontinued the trial.
Efficacy data from the Phase 2 trial showed that all three dosing regimens of BBP-418 led to significantly higher ratios of glycosylated alpha-dystroglycan, by 43% on average. A marker of muscle damage called creatine kinase was reduced with the treatment. BBP-418 therapy also improved the walking ability of LGMD2i patients, as seen with all three doses on the 10-meter walk test.
The Unmet Need in LGMD2I/R9
LGMD2I/R9 is a monogenic autosomal recessive disease caused by loss-of-function mutations in the FKRP gene. These 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, commonly accompanied by respiratory and cardiac muscle involvement.
Kelly Brazzo, CEO of CureLGMD2i Foundation, noted, "For patients with LGMD2I/R9, there are currently no approved treatment options, but the promise seen in the rapid enrollment of this clinical trial provides hope for patients and their families that this may change in the future."
