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This article summarizing the results of the SAPPHIRE trial, a double blind, placebo-controlled, phase 3 clinical trial on the safety and efficacy of apitegromab (myostatin inhibitor) in patients with spinal muscular atrophy (SMA) type 2 and 3. The study was conducted in 9 countries, at 48 sites, and enrolled 188 patients (156 aged 2-12 years and 32 aged 13-21 years). Patients’ Hammersmith Functional Motor Scale-Expanded (HFMSE) scores were 10–45 at baseline, and all had received at least 10 months of nusinersen or at least 6 months of risdiplam therapy. 

Participants in 2–12 years age group were randomly assigned to receive apitegromab 20 mg/kg, apitegromab 10 mg/kg, or placebo (1:1:1) every 4 weeks by intravenous infusion; participants in 13–21 years age group randomly received apitegromab 20 mg/kg or placebo (2:1) every 4 weeks. A total of 128 participants received apitegromab and 60 received placebo. The primary endpoint of the study was the change from baseline in HFMSE at 12 months. Motor function evaluations were performed before dosing on study days 1, 57, 113, 169, 225, 281, and 365. At 12 months, the least squares mean difference in HFMSE change from baseline was 1.8 points (95% CI 0·30 to 3·32; p=0·019) for apitegromab (20 mg/kg and 10 mg/kg) versus placebo (least squares mean 0·6 vs –1·2), favoring apitegromab. Motor function as measured by HFMSE, improved in patients receiving apitegromab and worsened in placebo group, despite continuing SMN-targeted therapy.

The incidence and severity of adverse events were similar between apitegromab and placebo.

Muscle-targeting therapy is a novel approach to improve motor function in patients with SMA and overall, in neuromuscular disorders. Myostatin is important in regulating muscle mass. After decades of research, previous attempts to target myostatin were not successful due to toxic effects and lack of selectivity in the approach. 

At present, there are no approved therapies that specifically target muscle tissue in patients with either genetic or acquired neuromuscular disorders. Current treatments for SMA target motor neuron degeneration by increasing expression of the survival motor neuron (SMN) protein, therefore slowing disease progression. These treatments do not address the accompanying muscle atrophy. Despite SMN-targeted therapy, patients often retain functional deficits, and motor decline may continue. Apitegromab, a myostatin inhibitor, has been shown to promote muscle growth. 

This study provides level 1 evidence that apitegromab significantly improves motor function compared to placebo in nonambulatory patients with type 2 or 3 spinal muscular atrophy.

This is the first placebo-controlled clinical study to show functional benefit of selective myostatin inhibition in any disease. By selectively targeting latent myostatin precursors, apitegromab minimizes off-target effects and has favorable safety profile. 

Crawford TO, Darras BT, Day JW, et al. Safety and Efficacy of Apitegromab in Patients With Spinal Muscular Atrophy Types 2 and 3: The Phase 2 TOPAZ Study. Neurology. 2024;102(5):e209151. doi:10.1212/WNL.0000000000209151