MDA 2025: Apitegromab safely improves SMA motor function
Phase 3 SAPPHIRE study is basis of recent FDA application
Apitegromab, a muscle-strengthening therapy up for approval in the U.S., led to gains in motor function in a clinical trial for people with spinal muscular atrophy (SMA) who took disease-modifying therapies.
Data from the trial, called SAPPHIRE (NCT05156320), formed the basis of Scholar Rock‘s recent application asking the U.S. Food and Drug Administration to approve apitegromab for SMA.
“These new data from the SAPPHIRE trial reinforce apitegromab’s potential as a transformative muscle-targeted therapy by demonstrating statistically significant and clinically meaningful improvements in motor function for individuals living with SMA,” Jay Backstrom, MD, president and CEO of Scholar Rock, said in a company press release.
Backstrom said Scholar Rock is “urgently preparing to commercialize apitegromab in the U.S., Europe and additional countries where patients with SMA can benefit from therapy.”
Results from SAPPHIRE were presented at the Muscular Dystrophy Association (MDA) conference in a poster and talk titled, “Efficacy and safety of apitegromab in individuals with type 2 and type 3 spinal muscular atrophy evaluated in the phase 3 SAPPHIRE trial.”
SMA is chiefly caused by mutations that lead to a low production of the SMN protein. As a result, the nerve cells that control movement, called motor neurons, sicken and die, leading to symptoms like muscle weakness. Disease-modifying therapies, which target the root cause of the disease by boosting SMN protein production, can slow SMA’s progression, but many patients continue to have muscle weakness that affects their daily lives.
“While the gains possible with SMN-targeting therapies is dramatic, there remains residual weakness, and functional decline is now evident in many people with SMA. The impact that this weakness has on SMA patients’ ability to maintain their daily activities and independence is substantial,” said Thomas O. Crawford, MD, principal investigator on the SAPPHIRE study at Johns Hopkins University, who presented the data at the meeting.
Testing apitegromab
Apitegromab is an antibody-based therapy given by infusions into the bloodstream every four weeks. It’s designed to strengthen muscles by blocking myostatin, a protein that normally acts to limit muscle growth.
SAPPHIRE enrolled more than 180 children and young adults with SMA types 2 or 3. To be eligible, patients needed to be able to sit independently and already be on disease-modifying therapies Spinraza (nusinersen) or Evrysdi (risdiplam).
Among the participants, 156 were ages 2 to 12. These patients were randomly assigned to apitegromab at one of two doses (10 or 20 mg/kg) or a placebo. The remaining 32 patients, ages 13 to 21, were randomly assigned to apitegromab at 20 mg/kg or a placebo. The main goal was to assess the impact on scores on the Hammersmith Functional Motor Scale Expanded (HFMSE), a standardized measure of motor function.
In patients given apitegromab, the average HFMSE scores tended to increase over a year, but tended to decrease over time in those given a placebo. A divergence between the two groups was evident after about two months and became more dramatic over time.
By the end of the study, average HFMSE scores had improved by 0.6 points with apitegromab and worsened by 1.2 points with a placebo — a statistically significant difference of 1.8 points.
Among children ages 2 to 12, nearly a third (30.4%) given apitegromab saw an increase in HFMSE score of at least 3 points, whereas only 12.5% of those on a placebo saw such a gain. This improvement in HFMSE reflects “statistically significant and clinically meaningful improvements in motor function,” the researchers wrote in their poster.
“It works,” Crawford said. “It’s statistically significant and it’s clinically meaningful to the patients.”
The effect of apitegromab on HFMSE scores was similar across age groups and similar among those on different types of SMN-targeting therapies. In the younger patients, the results were generally similar with both tested doses.
“We are thrilled with the consistency of clinical benefit demonstrated across important outcome measures in all patient subgroups,” Backstrom said.
Gains in motor function
Biomarker data indicated apitegromab inhibited myostatin as designed. This trial is the first time any myostatin-targeting therapy has been shown to improve motor function in a placebo-controlled clinical trial, the researchers said.
“The findings from the SAPPHIRE trial are very exciting as they support the hypothesis that targeting muscle can provide functional improvement for patients with SMA on top of SMN-targeted therapy,” Crawford said.
Apitegromab also tended to outperform the placebo on other motor function measures, including assessments of motor milestones and scores on a measure of arm and hand function called the Revised Upper Limb Module (RULM). Differences in these measures weren’t statistically significant however, meaning that mathematically there’s a non-negligible possibility the difference could be due to random chance. Crawford said RULM scores tended to change somewhat slowly, so a longer follow-up might be needed to detect a statistically meaningful effect. Still, the trends favored apitegromab.
“Importantly, the improvements in function were observed consistently across multiple validated metrics used to assess patient functional outcomes in SAPPHIRE,” Crawford said.
Apitegromab was generally well tolerated. No serious side effects related to the therapy were reported and no one quit the study early due to side effects of apitegromab. According to Crawford, all the patients have elected to continue into an extension study where they’re all being treated with apitegromab.
Note: The SMA News Today team is providing live coverage of the 2025 MDA Clinical & Scientific Conference March 16-19 in Dallas. Go here to see the latest stories from the conference.
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