Taldefgrobep Alpha Yields Encouraging Subgroup Signals Despite Missing Key Endpoints in SMA Trial

Cliff Bechtold

In a new update to the phase 3 RESILIENT-SMA study (NCT05337553), treatment with investigational taldefgromab alfa (Biohaven) did not meet its primary end point in patients with spinal muscular atrophy (SMA); however, it did show signals of efficacy in biomarker-defined subgroups. Based on its effect on myostatin reduction and body composition, the company intends to accelerate the drug into a placebo-controlled phase 2 study of patients with obesity using a user-friendly, self-administered autoinjector.

After 48 weeks of treatment, a prespecified subgroup analysis by race and ethnicity showed that Caucasian patients, which made up the largest study population (87%; n = 180), had a 2.2-point change from baseline in Motor Function Measurement-32 scale (MFM-32), the primary end point. In comparison, those on placebo and standard-of-care (SOC) treatment demonstrated a 1.1-point change (P <.039). The improvement associated with taldefgrobep in this subgroup was further increased to a 1.4-point placebo-adjusted change-from-baseline (P = .02) when analyzed by participants who had measurable myostatin levels at baseline.

"SMA is a devastating rare disease and although we are disappointed that taldefgrobep did not achieve a statistically significant difference in the broad study population on the MFM-32, we are encouraged that a majority subgroup did show a treatment benefit compared to the placebo arm,” Cliff Bechtold, Taldefgrobep Development Lead and president of Biohaven Ireland, said in a statement.¹ "The observed treatment effect on motor function, which had a similar magnitude on the MFM-32 after 1 year of treatment as approved therapies (i.e., risdiplam), along with the strong biomarker evidence of target engagement, suggests that taldefgrobep may play a potentially beneficial role in a majority subgroup population of SMA patients,"

He added, "taldefgrobep demonstrated an important beneficial effect on body composition which supports our plans to accelerate development in broader populations with obesity."

Taldefgrobep alfa, a muscle-targeted experimental treatment, is designed to bind to myostatin and acts as an activin 2b receptor antagonist, offering potential benefits in fat mass, increased lean mass, and metabolic parameters. Among Caucasian myostatin-positive patients, 50% of those on taldefgrobep were considered responders on MFM-32, defined as at least a 3-point change, in comparison with 30% of those on placebo + SOC.

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After 48 weeks of treatment, non-Caucasian participants (n = 26) had a higher-than-expected placebo response and did not separate from placebo on the MFM-32. Investigators wrote that the observed ethnic differences in therapy responsiveness may be explained by the significant presence of common genetic polymorphisms in non-Caucasian patients, which are thought to confer independence from myostatin inhibition. These polymorphisms could serve as an easily measurable biomarker for identifying patients with SMA most likely to benefit from taldefgrobep and other myostatin therapies.

The study also found that taldefgrobep significantly reduced total body fat mass compared with placebo + SOC at week 48 (P = .008), as measured by DXA. In the update, treatment with the age resulted in numerically greater increases in lean muscle mass and bone density. These effects were consistent across different races and baseline myostatin levels, suggesting taldefgrobep’s impact on fat mass is mediated not only through myostatin inhibition, but also by targeting activin A and other ligands. According to Biohaven, the therapy is the first myostatin blocker to favorably affect fat mass in patients with SMA, highlighting its potential for treating obesity more broadly.

The treatment was considered well-tolerated, with 97% of participants entering into the ongoing open-label extension. The company noted no treatment-related serious adverse events and that it will continue to engage in discussions with the FDA on the next steps for the treatment program.

Lindsey Lair, MD, MBA

"Biohaven remains committed to fighting rare diseases and will engage SMA experts and regulatory authorities regarding the full dataset from the RESILIENT study," Lindsey Lair, MD, MBA, vice president of neurology and clinical lead for SMA at Biohaven, said in a statement.¹ "We are extremely grateful to the international SMA community - especially the participants and their families, investigators and their teams, and patient advocacy groups who made the trial possible."

Taldefgrobep alfa was previously studied in a phase 2/3 trial (NCT03039686) of patients with Duchenne muscular dystrophy (DMD). Dubbed SPITFIRE, the study featured 166 ambulatory boys with DMD, using change in North Star Ambulatory Assessment score (NSAA) as the primary end point. Preliminary data from the trial revealed that the therapy was not going to meet its primary end point, prompting Roche, who entered a separate agreement with Bristol Myers Squibb (the original developers of taldefgrobep alfa) in 2017 for the rights of taldefgrobep alfa, to discontinue the trial.²

REFERENCES
1. Biohaven Provides Update on Taldefgrobep Alfa Development Program for Spinal Muscular Atrophy and Obesity. News release. Biohaven. November 25, 2024. Accessed November 25, 2024. https://www.prnewswire.com/news-releases/biohaven-provides-update-on-taldefgrobep-alfa-development-program-for-spinal-muscular-atrophy-and-obesity-302314979.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).