BridgeBio Pharma has announced positive topline results from its Phase 3 FORTIFY study of BBP-418, an investigational oral therapy for limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9), marking a significant milestone for patients with this rare genetic disorder who currently have no approved treatment options.
The randomized, double-blind, placebo-controlled study successfully met all primary and secondary interim analysis endpoints at 12 months, with BBP-418 demonstrating a well-tolerated safety profile consistent with previous studies.
Robust Biomarker and Clinical Improvements
The primary endpoint showed highly statistically significant results, with glycosylated alpha-dystroglycan (αDG) increasing by 1.8-fold from baseline at 3 months (p<0.0001) in BBP-418-treated patients compared to approximately no change in the placebo group. These improvements were sustained at 12 months (p<0.0001).
"I'm very excited to see that treatment with BBP-418 was associated with clinically meaningful improvements in motor and pulmonary function, along with robust restoration of αDG glycosylation," said Katherine Mathews, M.D., Professor of Pediatrics and Neurology at the University of Iowa's Roy J. and Lucille A. Carver College of Medicine. "This is such an important result for individuals living with LGMD2I/R9, which is a progressive muscular dystrophy."
BBP-418 also demonstrated substantial reductions in serum creatine kinase (CK), a marker of muscle breakdown, with an average reduction of 82% from baseline and a statistically significant difference versus placebo (p<0.0001) at 12 months.
Functional Improvements Across Key Measures
Patients treated with BBP-418 showed statistically significant, clinically meaningful improvements at 12 months across all key clinical endpoints studied. Ambulatory function, measured by the 100-meter timed test (100MTT), showed an increase in velocity of 0.14 m/s from baseline and 0.27 m/s versus placebo (p<0.0001).
Pulmonary function also improved significantly, with forced vital capacity (FVC) increasing by approximately 3% predicted volume from baseline and showing a difference of approximately 5% predicted volume versus placebo (p=0.0071).
The substantial increases in glycosylated αDG were observed both in individuals with the L276I homozygous genotype and other FKRP genotypes, suggesting broad applicability across the patient population.
Addressing a Critical Unmet Medical Need
LGMD2I/R9 is a monogenic autosomal recessive disease caused by partial loss of function mutations in the fukutin-related protein (FKRP) gene. These mutations impair glycosylation of alpha-dystroglycan, a protein associated with stabilizing muscle cells, leading to progressive muscle weakness and degeneration.
Clinical manifestations typically present as skeletal myopathy affecting the lower and then upper limbs, commonly followed by pulmonary muscle and cardiac muscle involvement. Individuals with the homozygous L276I genotype typically develop disease manifestations during late childhood, with progression to loss of independent ambulation in 25% of cases, assisted ventilation in 10%, and cardiomyopathy in 30% during adulthood.
For individuals with other FKRP genotypes, the clinical course is typically more severe, with earlier childhood onset, rapid loss of mobility by 20 years of age, more frequent cardiac involvement (60%), and eventual pulmonary failure by 30 years of age in nearly all cases.
Regulatory Pathway and Next Steps
BridgeBio intends to engage the FDA later this year to discuss the FORTIFY data and plans to submit a New Drug Application (NDA) for BBP-418 in the first half of 2026. The company will continue analyzing the full interim analysis dataset and plans to present detailed results at a future medical meeting.
BBP-418 has previously received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations from the FDA, as well as Orphan Drug Designation from the European Medicines Agency. If approved, BridgeBio may qualify for a Priority Review Voucher under the FDA's Rare Pediatric Designation.
"For individuals living with LGMD2I/R9, a condition that slowly takes away the strength, breathing, and independence of an individual, each day matters," said Douglas Sproule, M.D., M.Sc., Chief Medical Officer of ML Bio Solutions, a BridgeBio company developing BBP-418. "We are determined to move swiftly toward filing for approval, so that BBP-418, if approved, can become the first therapy to change the course of this devastating disease."
The positive FORTIFY results represent a potential breakthrough for the LGMD2I/R9 community, offering hope for the first targeted therapy that could alter the natural progression of this debilitating genetic disorder.
