LGMD Agent BBP-418 Improves Ambulation and Pulmonary Function Across Subgroups in Phase 3 FORTIFY Interim Analysis

Newly presented data from the prespecified 12-month interim analysis of the phase 3 FORTIFY trial (NCT05775848) revealed that BBP-418 (BridgeBio) treatment led to significant improvements in ambulation and pulmonary function in individuals with limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9). The findings, presented at the 2026 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Annual Meeting, held September 29 to October 2, in Orlando, Florida, showed that treatment effects held across prespecified patient subgroups.¹

LGMD2I/R9 is an autosomal recessive disorder caused by pathogenic variants in the FKRP gene. These variants impair glycosylation of alpha-dystroglycan (αDG), leading to progressive muscle damage and cardiopulmonary decline. There are currently no approved therapies for the condition. BBP-418 is designed to restore αDG glycosylation and stabilize muscle integrity during contraction.

Presented by lead author Katherine D. Mathews, MD, professor of pediatrics and neurology at the University of Iowa Carver College of Medicine, FORTIFY is an ongoing, randomized, double-blind, placebo-controlled, 36-month study. The study enrolled individuals aged 12 to 60 years (18 to 60 years in Europe) with genetically confirmed, symptomatic LGMD2I/R9 who weighed more than 30 kg. Both ambulatory and nonambulatory individuals were eligible.

A total of 74 participants were randomized to BBP-418 and 38 participants to placebo. Baseline characteristics were generally similar between arms: mean age was 37.1 years in the BBP-418 group and 33.3 years in the placebo group, and approximately 74% of each arm were homozygous for the common L276I variant. At the time of analysis, no participant in the BBP-418 arm had discontinued treatment.

Overall, the trial met its primary interim end point. BBP-418 produced a 1.8-fold increase in mean glycosylated αDG from baseline at month 3 (P <.001), which was sustained through month 12 (P <.001 vs placebo). Mean glycosylated αDG in the BBP-418 arm rose from 22.7% of control at baseline to 44.5% at 12 months, while levels in the placebo arm remained near 20%. These biomarker results were first announced in topline form in October 2025.²

Serum creatine kinase (CK) fell by 82% from baseline to month 12 among BBP-418-treated participants. The least squares (LS) mean difference vs placebo was −2055.6 U/L (99% CI, −2811.7 to −1299.4; P <.001). At 12 months, 59.6% of BBP-418-treated participants had CK levels below 2 times the upper limit of normal, and 38.3% had levels within the normal range.

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On functional measures, BBP-418-treated participants improved 100-meter timed test (100MTT) velocity by 0.14 m/s from baseline to month 12, while placebo-treated participants declined by 0.12 m/s, for a between-group difference of 0.27 m/s (P <.001). BridgeBio previously reported that this difference corresponded to BBP-418-treated individuals completing the 100MTT approximately 31 seconds faster than those receiving placebo, with separation evident as early as 3 months.³ Forced vital capacity (FVC) increased by approximately 3% predicted with BBP-418 and declined with placebo, for a between-group difference of 5% predicted (P = .007).

Prespecified subgroup analyses showed consistent benefit with BBP-418 vs placebo across all analyzable subgroups for αDG glycosylation, serum CK, 100MTT velocity, and FVC. The subgroups were defined by genotype (L276I homozygous vs other FKRP genotypes), age (12 to <18 vs 18 to 60 years), and baseline FVC (≥80% vs 40%-80% predicted).

BBP-418 was generally well tolerated. Diarrhea was the most common treatment-emergent adverse event (TEAE), occurring in 39.2% of BBP-418-treated participants and 52.6% of placebo-treated participants, and all cases were grade 1 or 2. Grade 3 or 4 TEAEs occurred at similar rates in the 2 arms (5.4% vs 5.3%). No participant discontinued BBP-418 because of a TEAE, and there were no deaths or treatment-related serious TEAEs.

On the basis of the interim data, the FDA accepted BridgeBio's new drug application for BBP-418 with priority review and assigned a Prescription Drug User Fee Act target action date of November 27, 2026. If approved, BBP-418 would be the first approved therapy for any form of LGMD.⁴

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REFERENCES
1. Mathews KD, Sproule D, Lee A, et al. Phase 3 FORTIFY interim analysis: restoration of alpha-dystroglycan glycosylation and clinically meaningful functional improvement with BBP-418 in limb-girdle muscular dystrophy type 2I/R9. Presented at: 2026 AANEM Annual Meeting; September 29-October 2, 2026; Orlando, FL. Abstract 136.
2. BridgeBio reports positive phase 3 results for small molecule BBP-418 in LGMD2I/R9 FORTIFY study. News release. BridgeBio Pharma, Inc. October 27, 2025. Accessed September 30, 2026. https://investor.bridgebio.com/news/news-details/2025/BridgeBio-Reports-Positive-Phase-3-Results-for-Small-Molecule-BBP-418-in-LGMD2IR9-FORTIFY-Study/default.aspx
3. BBP-418 demonstrates consistent efficacy and favorable safety profile in phase 3 FORTIFY interim analysis in LGMD2I/R9. News release. BridgeBio Pharma, Inc. March 11, 2026. Accessed September 30, 2026. https://investor.bridgebio.com/news/news-details/2026/BBP-418-Demonstrates-Consistent-Efficacy-and-Favorable-Safety-Profile-in-Phase-3-FORTIFY-Interim-Analysis-in-LGMD2IR9/default.aspx
4. BridgeBio announces FDA acceptance and priority review of NDA for BBP-418 for LGMD2I/R9. News release. BridgeBio Pharma, Inc. May 27, 2026. Accessed September 30, 2026. https://www.biospace.com/press-releases/bridgebio-announces-fda-acceptance-and-priority-review-of-nda-for-bbp-418-for-lgmd2i-r9