Apitegromab, an investigational monoclonal antibody that inhibits myostatin activation, demonstrated meaningful motor function improvements for children and adolescents with spinal muscular atrophy (SMA) in the pivotal phase 3 SAPPHIRE trial. The results, published in a September 2025 issue of The Lancet Neurology, underscore the potential of muscle-targeted therapy as an adjunct to existing SMN-directed treatments.¹

Apitegromab data in the SAPPHIRE trial

The study enrolled 188 nonambulatory patients with type 2 or type 3 SMA, ages 2 to 21 years, who were already receiving background therapy with nusinersen or risdiplam. At 12 months, children aged treated with apitegromab showed a least squares mean improvement of 1.8 points on the Hammersmith Functional Motor Scale–Expanded (HFMSE) compared with placebo (0.6 vs –1.2), meeting the primary endpoint.

Subgroup analysis revealed that patients on the 10 mg/kg dose achieved a 2.2-point mean improvement versus placebo (P = .0121), while those on 20 mg/kg showed a 1.4-point difference that did not reach statistical significance.²

Overall, 30.4% of apitegromab-treated patients improved by > 3 HFMSE points compared with 12.5% of placebo patients, highlighting clinically meaningful gains in strength and function. Secondary outcomes, including measures of upper limb mobility, also trended favorably. Apitegromab was well tolerated, with adverse events such as pyrexia, cough, headache, and nasopharyngitis reported at similar rates to placebo. No patients discontinued due to adverse events.²

Thomas Crawford, MD, professor of neurology at the Johns Hopkins University School of Medicine and SAPPHIRE investigator, said even modest functional gains can significantly impact patients’ lives.

“If I could make every child with SMA 20% stronger, it would be meaningful to their lives, because they’re profoundly weak,” he explained. “With SMA, a small difference — the ability to roll over, lift a head, or feed oneself — can change daily independence.”

Crawford emphasized the novelty of targeting muscle directly through myostatin inhibition, calling apitegromab “the first approach to show a benefit” in this pathway. “We showed that adding a drug not targeted to the motor neuron, but to the muscle, provides additional benefit,” he said.

While the SAPPHIRE data supported Scholar Rock’s biologics license application, the FDA issued a Complete Response Letter on September 23, 2025, citing observations at a third-party manufacturing facility, not concerns with apitegromab’s efficacy or safety. The company has pledged to resolve these issues and resubmit. A decision from the European Medicines Agency is anticipated by mid-2026.²

References:

1. Crawford T, Servais L, Mercuri E, et al. Safety and efficacy of apitegromab in nonambulatory type 2 or type 3 spinal muscular atrophy (SAPPHIRE): a phase 3, double-blind, randomised, placebo-controlled trial. The Lancet Neurology. September 2025. Accessed September 24, 2025. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(25)00225-X/abstract
2. Fitch J. FDA issues CRL for apitegromab for SMA, citing facility inspection. Contemporary Pediatrics. Published September 23, 2025. Accessed September 24, 2025. https://www.contemporarypediatrics.com/view/fda-issues-crl-for-apitegromab-for-sma-citing-facility-inspection