Phase 3 RESILIENT Study of SMA Agent Taldefgrobep Alfa Completes Enrollment

Lindsey Lair, MD

Patient enrollment for the phase 3 RESILIENT study (NCT05337553) assessing Biohaven Pharmaceuticals’ agent taldefgrobep alfa in patients with spinal muscular atrophy (SMA) has completed, according to a recent announcement. The trial, which includes 180 patients across 9 countries, assesses the effects of the fully human recombinant protein in patients already on a stable dose of nusinersen (Spinraza; Biogen), risdiplam (Evrysdi; Genentech), and/or have a history of treatment with onasemnogene abeparvovec-xioi (Zolgensma; Novartis).¹

The placebo-controlled, double-blind study assesses the safety and efficacy of taldefgrobep alfa over a 48-week treatment period, with changes in the 32-item Motor Function Measure (MFM-32) total score as the primary end point. Otherwise known as BHV-2000, the agent is designed to bind to myostatin and acts as an activin 2b receptor antagonist, offering potential benefits in fat mass, increased lean mass, and improvements in multiple metabolic parameters.

"We are thrilled to complete enrollment in this pivotal trial for SMA as it brings us one step closer to advancing a novel muscle targeting therapy for patients with SMA," Lindsey Lair, MD, vice president and clinical development lead for the SMA program, Biohaven, said in a statement.¹ "Despite recent advances in SMA genetic treatments, patients still experience weakness and impairments in quality of life that can be alleviated by enhancing muscle mass and function, on top of what is delivered by current standard of care treatments."

Taldefgrobep alfa, a muscle-targeted experimental treatment, is different from previously approved agents for SMA. Currently options for the disease include risdiplam or nusinersen, SMN2 mRNA splicing modifiers, and Zolgensma, an SMN-enhancing, adeno-associated virus vector (AAV) gene therapy that replaces the function of the missing or nonworking SMN1 gene. If it were to enter the market, taldefgrobep alfa would become the first approved muscle-directed therapy for the neuromuscular disorder.

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Prior to the renaming of taldefgrobep alfa, the agent was evaluated in several studies of other neuromuscular disorders, including the phase 2/3 SPITFIRE trial (NCT03039686) of Duchenne muscular dystrophy. Using a cohort of 166 ambulatory boys with DMD, preliminary data showed that the therapy was not going to meet its primary end point of change in North Star Ambulatory Assessment score, prompting Roche, who also entered a separate agreement with Bristol Myers Squibb (the original developers of taldefgrobep alfa or BMS-986089) in 2017 for the rights of BMS-986089 (also known as RG6206 at the time), to discontinue the trial.²

"While we have had good progress with current therapies, a high unmet need for safe and effective supportive treatments for SMA remains, as many patients still experience significant weakness and reduced levels of functioning," Kenneth Hobby, president, Cure SMA, said in a statement.¹ "We appreciate the partnership of investigators, patients, and researchers to expedite the development of new efficacious therapies that will work in combination with current options to help restore muscle strength and function."

In 2022, when Biohaven initiated RESILIENT, Lair sat down with NeurologyLive^® to discuss the parameters, and why taldefgrobep alfa stands as a promising candidate. In the video below, she discussed more on the mechanism action of the agent and how it could be used in combination with other previously approved therapies.

REFERENCES
1. Biohaven completes enrollment in pivotal phase 3 study of taldefgrobep alfa in spinal muscular atrophy. News release. Biohaven Pharmaceuticals. September 14, 2023. Accessed September 20, 2023. https://www.prnewswire.com/news-releases/biohaven-completes-enrollment-in-pivotal-phase-3-study-of-taldefgrobep-alfa-in-spinal-muscular-atrophy-301927251.html
2. Wagner KR, Wong BL, Byrne BJ, et al. A phase 1b/2 study of the anti-myostatin adnectin RG6206 (BMS-986089) in ambulatory boys with Duchenne muscular dystrophy: a 72-week treatment update. Neurology. 2019;92(15 Supplement).