Dosing Commenced in Phase 3 FORTIFY of Limb-Girdle Muscular Dystrophy Type 2i

Tahseen Mozaffar, MD

In recent news, BridgeBio Pharma announced its first patient dosed in its phase 3 FORTIFY clinical trial (NCT05775848) of BBP-418, an investigational oral substrate supplementation therapy in development for limb-girdle muscular dystrophy type 2I (LGMD2I/R9).¹ As of now, the company has initiated over half of the planned clinical sites in the United States and is currently in the process of opening more sites in Europe and Australia to support global registration.

The company also recently met with the FDA to discuss the use of glycosylated α-dystroglycan levels, which are central to LGMD2I/R9 disease, as a surrogate end point in FORTIFY. Based on this meeting with the agency, BridgeBio Pharma believes that there is potential for an accelerated approval pathway for BBP-418, with findings from the ongoing open-label phase 2 study (NCT04800874) as supportive data. Findings from the study thus far have suggested that the treatment may be well-tolerated and have a positive impact on key end points.²

“As a physician who regularly treats people with LGMD2I/R9, I found the results observed in the phase 2 trial of BBP-418 very encouraging, and I am pleased we’ve been able to dose the first patient in the phase 3 trial. I am hopeful that we will see impact for these patients similar to the phase 2, because patients with LGMD2I/R9 are significantly affected by progressive, debilitating muscle weakness that impinges heavily upon quality of life and eventually leads to functional dependence,” Tahseen Mozaffar, MD, professor of neurology and pathology & laboratory medicine at University of California, Irvine, said in a statement.¹

READ MORE: FDA Clears NS-050/NCNP-03 for Phase 1/2 Trial of Duchenne Muscular Dystrophy

FORTIFY is a randomized, double-blind, placebo-controlled study aimed at investigating the safety and efficacy of BBP-418. The trial has a planned interim analysis at 12 months to assess glycosylated αDG as a surrogate end point with the potential of the results to support an accelerated approval. Patients will be assessed on the North Star Assessment for Dysferlinopathy (NSAD) and several other secondary end points, with findings expected to be announced in late 2024/early 2025 as confirmatory clinical data.

BridgeBio developed a novel, validated bioassay to directly measure glycosylated ⍺DG levels, and may enable monitoring of responses to disease-modifying therapies in patients with LGMD2I/R9. The company noted in a statement that it is committed to collaborating with the FDA to address any challenges that are associated with drug development for LGMD2I/R9, including the potential use of a surrogate end point to support an accelerated approval.¹

“There are no FDA approved specific treatments for LGMD2I/R9 and current treatments are only supportive. The LGMD community is hopeful that we will soon transition from supportive care to disease modifying treatments for LGMDs. Living with a progressive disease like LGMD2I/R9 means that each of us is, day by day, losing the ability to be independent and do the things that we love. Many of us live in fear of the future. The launch of the phase 3 study provides our community with a beacon of needed hope,” Kathryn Bryant Knudson, founder and president of The Speak Foundation, said in a statement.¹

The therapy is designed to provide supraphysiological levels of an endogenous substrate upstream of the mutant FKRP enzyme to assist the drive of residual activity of the enzyme to glycosylate αDG. Thus, the goal of using BBP-418 is to stabilize the muscle cells during contraction, and to potentially stop any further muscle damage.

Updated findings from the phase 2 clinical trial and of the company’s novel bioassay will be presented at the 2023 Annual Congress of the World Muscle Society (WMS), held October 3-7, in Charleston, South Carolina.¹

“Currently, our phase 2 data suggest that glycosylated αDG levels are improved and sustained over time following treatment with BBP-418. In addition to the effect on αDG, we have also observed consistent improvement in clinical endpoints such as increased NSAD score, increased 10-meter walk test velocity and reduced time to complete 100-meter timed test compared to baseline,” Douglas Sproule, MD, MSc, chief medical officer of ML Bio Solutions, a BridgeBio affiliate focused on developing BBP-418 for LGMD2I/R9, said in a statement.¹ “The meeting with the FDA was both positive and productive in discussing the potential use of glycosylated αDG levels as a surrogate endpoint in our clinical trial. I am encouraged by the collaboration from the FDA, including the clear feedback received regarding the information needed to support the use of αDG as a reasonably likely surrogate endpoint. We look forward to working with the agency to bring this treatment to patients as quickly as possible.”

Previously, Sproule and colleagues presented preliminary results from the phase 2 study of BBP-418 for LGMD2I at the annual Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held in Dallas, Texas, March 19-22, 2023.³ At the conference, Sproule sat down with NeurologyLive® in an interview to talk about the recent advancements in clinical care with neuromuscular diseases including LGMD. He also spoke about molecular testing for diagnosis in LGMD. In addition, he talked about the pathway to treatments such as the development of gene therapies and how industry partners help move the field forward in research. 

REFERENCES
1. BridgeBio pharma announces opportunity for accelerated approval pathway in limb-girdle muscular dystrophy type 2i (lgmd2i/r9) based on glycosylated alpha-dystroglycan (⍺dg) levels and announces first patient dosed in fortify phase 3 study. News Release. BridgeBio Pharma. Published July 31, 2023. Accessed August 9, 2023. https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-pharma-announces-opportunity-accelerated-approval
2. BridgeBio announces positive phase 2 data for Limb-girdle muscular dystrophy type 2i (LGMD2i). News release. BridgeBio Pharma. March 14, 2022. Accessed August 9, 2023. https://www.globenewswire.com/en/news-release/2022/03/14/2402463/0/en/BridgeBio-Pharma-Announces-Positive-Phase-2-Data-for-Limb-girdle-Muscular-Dystrophy-Type-2i-LGMD2i.html
3. Sproule D, Harper A, Langeslay R, et al. 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 2023; March 19-22; Dallas, Texas. Poster 139.