Thomas Crawford, MD, talks advancements for spinal muscular atrophy treatment

The pivotal phase 3 SAPPHIRE trial has provided the strongest evidence to date that apitegromab, an investigational myostatin inhibitor, can improve motor function in children with spinal muscular atrophy (SMA) who continue to experience weakness despite standard survival motor neuron (SMN)-targeted therapies.¹

SAPPHIRE enrolled 188 patients aged 2–21 years with nonambulatory type 2 or type 3 SMA across 48 hospitals in the U.S. and Europe. All participants were already receiving nusinersen or risdiplam. The primary analysis focused on children aged 2–12 years. At 12 months, patients treated with apitegromab achieved a least squares mean 1.8-point improvement on the Hammersmith Functional Motor Scale–Expanded (HFMSE) compared with placebo (0.6 vs –1.2; 95% CI, 0.30–3.32; P = .019).

WATCH MORE: Thomas Crawford, MD, highlights improved motor function with apitegromab for spinal muscular atrophy

Subgroup analysis showed that the 10 mg/kg dose drove most of the benefit, with a mean 2.2-point improvement versus placebo (P = .0121). The 20 mg/kg dose trended positive, but the 1.4-point mean difference did not reach statistical significance. Importantly, 30.4% of apitegromab-treated patients achieved an HFMSE gain of at least 3 points, compared with 12.5% of those on placebo. Adverse events, including headache, respiratory infections, and pyrexia, were balanced across treatment and placebo groups, and no treatment-related discontinuations occurred.

“These are children who remain profoundly weak despite transformative SMA therapies,” said Thomas Crawford, MD, professor of neurology at the Johns Hopkins University School of Medicine and study investigator. “By targeting the muscle, not the motor neuron, apitegromab provided measurable additional benefit. For families, even small improvements in strength can translate into meaningful gains in daily life.”

On top of the specific data associated with apitegromab, Crawford emphasized the broader implications related to SMA treatment.

“Pharma has been trying to manipulate the myostatin system for a decade without success. This is the first approach to show a clear benefit, and it could represent the start of something much larger.”

Despite the positive data, the FDA issued a Complete Response Letter (CRL) for apitegromab’s biologics license application in September 2025, citing observations at a third-party manufacturing facility. No concerns were raised about safety or efficacy, and Scholar Rock has indicated it will resubmit once corrective actions are complete. A decision from the European Medicines Agency is expected by mid-2026.²

Editor's note: Thomas Crawford, MD, has a relevant disclosure to Scholar Rock.

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