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21O Interim analysis from the ongoing Phase 3 FORTIFY study of BBP-418 for individuals living with LGMD2I/R9 suggests benefit across functional and cardiac endpoints
Abstract   Peer reviewed

21O Interim analysis from the ongoing Phase 3 FORTIFY study of BBP-418 for individuals living with LGMD2I/R9 suggests benefit across functional and cardiac endpoints

Damon Bass, Katherine D. Mathews, Tahseen Mozaffar, Volker Straub, Robert D. Henderson, Douglas Sproule, Ada Lee, Amy Rainey, David Paul, Tricia Blankenbiller, …
Neuromuscular disorders : NMD, Vol.67(Suppl 1), 107363
09/29/2026
DOI: 10.1016/j.nmd.2026.107363

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Abstract

Limb-girdle muscular dystrophy 2I/R9 (LGMD2I/R9) is an autosomal recessive disorder caused by pathogenic FKRP variants that impair α-dystroglycan (αDG) glycosylation, leading to progressive, irreversible muscle degeneration and cardiopulmonary decline. No approved therapies exist. BBP-418 is an oral small molecule glycosylation substrate therapy designed to restore αDG glycosylation and stabilize muscle integrity during contraction. FORTIFY (NCT05775848) is an ongoing randomized, double-blind, placebo-controlled phase 3 study evaluating BBP-418 in LGMD2I/R9. An interim analysis assessed change from baseline (CFB) in glycosylated αDG (% of control) in muscle at 3 and 12 months. Other alpha-controlled endpoints included CFB in serum creatine kinase (CK), 100-meter timed test (100MTT), and forced vital capacity (FVC) at 12 months. Additional non-alpha controlled endpoints were the NSAD, 10MWT, PUL 2.0, patient-reported outcomes (PROMIS), cardiac biomarkers, and echocardiographic measures. The safety of BBP-418 was also assessed. Treatment with BBP-418 increased glycosylated αDG 1.8-fold vs placebo at Month 3, which was sustained through Month 12 (P<0.0001). CK decreased by 82% with BBP-418 vs placebo at Month 12 (P<0.0001). Significant and clinically meaningful functional improvements were observed in 100MTT velocity (+0.14 m/s from baseline in treated participants; treatment difference +0.27 m/s vs placebo; P<0.0001) and FVC (+3% predicted from baseline in treated participants; treatment difference +5% predicted vs placebo; P=0.0071). In adults (PROMIS-57), Month 12 least-squares (LS) mean (95% CI) differences in T scores were nominally statistically significant for BBP-418 vs placebo for anxiety (−3.7 [−6.9 to −0.6]; P=0.021) and fatigue (−3.7 [−6.9 to −0.5]; P=0.023), with favorable trends across other domains. In pediatric patients (PROMIS-37), fatigue, anxiety, and physical function favored BBP-418. Exploratory cardiac analyses showed that high-sensitivity troponin I decreased more with BBP-418 than placebo at Month 12 (LS mean, −62.5 ng/L; n=49, and LS mean, −44.8 ng/L; n=20, respectively), and of those with elevated high-sensitivity troponin I at baseline, more participants treated with BBP-418 than placebo achieved normalized levels at Month 12 (8/8 vs 4/10; P=0.0248). Stable or improved ejection fraction was more frequent with BBP-418 (54%) than placebo (25%; P=0.0262). Clinically meaningful QTc prolongation was not observed in a completed phase 1 QT/QTc study. BBP-418 has demonstrated an acceptable safety profile to date; diarrhea events were Grade 1/2 and did not lead to BBP-418 discontinuation. No new clinically meaningful cardiac safety signals were identified. Together, these findings show alpha-controlled biochemical, functional, and pulmonary benefits, with supportive patient-reported and exploratory cardiac findings alongside an acceptable safety profile to date, supporting BBP-418’s potential as the first disease-modifying therapy for LGMD2I/R9.

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