Baseline Characteristics and Updates for Phase 3 FORTIFY Study of BBP-418 in LGMD

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In the study, most participants are aged 18-60, with 53% female and 73.1% carrying the c.826C>A mutation, while 15 patients are aged 12-18.

FORTIFY is a phase 3 double-blind, placebo-controlled study (NCT05775848) that tests the therapeutic efficacy and safety of BBP-418 (BridgeBio), an investigational oral substrate supplementation therapy, in individuals with limb-girdle muscular dystrophy type 2I (LGMD2I/R9). Newly announced baseline characteristics from the study show that most patients included are within the ages of 18-60 and are carriers of the common mutation c.826C>A.¹

Presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific conference, held March 16-19, in Dallas, Texas, the study includes 112 patients with genetically confirmed LGMD2I/R9 who are randomly assigned 1:1 to either oral BBP-418 or placebo. Within the study cohort, 15 patients range between 12-18 years, while the remaining 97 are 18-60 years. Overall, 53% of the study participants are female and 73.1% of patients carry the common mutation c.826C>A.

The poster, presented by Ada Lee, MD, executive medical director at ML Bio Solutions, an affiliate of BridgeBio, showed that the mean age of patients in the study was 35.8 years (SD, 12.22). Spanning 22 sites across the U.S., U.K., and Australia, the trial tests change in North Star Ambulatory Assessment (NSAA), a common tool for neuromuscular disorders, as the primary end point, over a 36-month period. More notably, the study will also test the effect of BBP-418 on glycosylated aDG, the hallmark of the disease at a molecular level, at 12 months, as a surrogate end point to support accelerated approval.

On September 30, 2024, or LGMD Awareness Day, the company announced that they completed enrollment for FORTIFY, with a topline data readout expected to come in 2025.² Participants are excluded if they have significant medical conditions unrelated to LGMD2I/R9, including moderate to severe renal impairment (eGFR <60 mL/min/1.73 m²), or if they recently underwent or plan to undergo scoliosis surgery that could interfere with assessments. Other exclusions include prior gene therapy for LGMD2I/R9, recent use of systemic corticosteroids or experimental therapies, active suicidal ideation, or conditions contraindicating muscle biopsy. Pregnant or breastfeeding individuals, or those planning to conceive during the study and 12 weeks after treatment, will also be ineligible.

In a previously completed phase 2 study, treatment with BBP-418 resulted in significant increases in aDG among patients with LGMD2i, highlighting its potential to address the root cause of the disease. Preliminary data from 12 participants published in late 2022 showed that BBP-418 was well tolerated, with a 43% increase in glycosylated aDG and significant creatine kinase (CK) reductions. CK levels declined 70% across all cohorts at 90 days, with a 77% reduction at 180 days for cohorts 1 and 2. Notably, 75% achieved CK levels at least twice the normal range, with only 1 participant failing to achieve a 50% reduction.³

In Part 1 of this open-label study, 14 enrolled individuals with LGMD2i, both ambulatory and nonambulatory, were split into 3 ascending dose cohorts (cohort 1: 6 g daily, n = 4; cohort 2: 6 g twice daily, n = 4; cohort 3: 12 g twice daily, n = 6) and treated over a 3-month period. During Part 2 of the study, all patients received 12 g twice daily for 3 months, with weight adjusted for lower-weight patients. Nine of 12 patients were ambulatory, completing the 10-meter walk test (10MWT) in under 12 seconds. After 90 days, all cohorts showed a 3% (0.08 m/s) increase in 10MWT speed, with a 4% (0.12 m/s) increase at 180 days for cohorts 1 and 2. At 6 months, results compared favorably to natural history data, which showed a 0.12 m/s decline in the same patients prior to enrollment.

At the 2023 Annual Congress of World Muscle Society, 21-month results from the phase 2 study further supported BBP-418’s development in LGMD2i/R9. Among the topline findings included a large (≥80%) sustained reduction in CK over the extended treatment period, as well as stabilization in NSAA scores and ambulatory measures. In addition, the therapy was shown to be well tolerated with longer-term treatment, and did not result in any treatment-related serious adverse events (SAEs) or dose limiting toxicities.⁴

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REFERENCES
1. Lee A. Baseline characteristics of participants in FORTIFY: a Phase 3 study to evaluate safety, tolerability, and efficacy of BBP-418 in LGMD2I/R9. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19; ABSTRACT P222
2. BridgeBio Completes Enrollment of FORTIFY, Phase 3 Registrational Study of BBP-418 in Limb-girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9). News release. BridgeBio. September 30, 2024. Accessed March 14, 2025. https://bridgebio.com/news/bridgebio-completes-enrollment-of-fortify-phase-3-registrational-study-of-bbp-418-in-limb-girdle-muscular-dystrophy-type-2i-r9-lgmd2i-r9/
3. Preliminary results from MLB-01-003: an open-label phase 2 study of BBP-418 in patients with Limb girdle muscular dystrophy type 2i. Presented at: MDA 2022; March 13-16; Nashville, TN. Poster 63.
4. BridgeBio Pharma Shares Positive Long-Term Data from an Ongoing Phase 2 Study, which Support the Potential Use of Glycosylated Alpha-dystroglycan (⍺DG) Levels as a Surrogate Endpoint in Limb-girdle Muscular Dystrophy Type 2I/R9 (LGMD2I/R9). News release. BridgeBio. October 9, 2023. Accessed March 14, 2025. https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-pharma-shares-positive-long-term-data-ongoing-phase-2