The FDA has approved apitegromab-mstn, a muscle-targeting therapy developed by Scholar Rock, for the treatment of spinal muscular atrophy (SMA) in adults and pediatric patients aged 2 years and older who are currently receiving an SMN2-targeted treatment. Marketed as ISEMBYLD, the agent becomes the first FDA-approved SMA therapy designed to directly target muscle loss, providing a treatment approach intended to complement therapies that address the motor neuron component of the disease.

The approval was supported primarily by findings from the phase 3 SAPPHIRE study (NCT05156320), a 52-week, randomized, double-blind, placebo-controlled trial that enrolled 188 patients aged 2 to 21 years who were unable to walk or move independently and were receiving an approved SMN2-targeted treatment.

In the primary efficacy analysis of patients aged 2 to 12 years, treatment with apitegromab 10 mg/kg resulted in a statistically significant difference in change from baseline on the Hammersmith Functional Motor Scale Expanded (HFMSE) compared with placebo at 52 weeks. Additionally, 34.2% of patients receiving the 10-mg/kg dose achieved at least a 3-point improvement in HFMSE compared with 13.5% of those receiving placebo.

Brian Lin, PhD, research director at the Muscular Dystrophy Association, recently told NeurologyLive that the significance of the approval extends beyond the observed motor-function gains and reflects a shift toward addressing multiple components of SMA.

“The significance really lies in the fact that [apitegromab] addresses a different pathway from what all the SMA restoration therapies have done.”

Lin noted that existing SMA therapies have largely focused on restoring SMN and supporting motor neuron survival, whereasapitegromab offers a complementary approach.

He added, “this is a therapy that can serve as a complementary therapy or a combination therapy and add on a certain level of efficacy beyond just what the SMN restoration therapies have really produced.”

SAPPHIRE’s Supportive Data

The phase 3 SAPPHIRE trial evaluated intravenous apitegromab at doses of 10 mg/kg or 20 mg/kg every 4 weeks against placebo, with all participants continuing an approved SMN2-targeted treatment. The primary analysis focused on participants aged 2 to 12 years.

At 52 weeks, patients receiving the 10-mg/kg dose demonstrated a greater improvement in HFMSE scores than those receiving placebo. The treatment difference was 2.2 points, with a nominal P value of .0121. In addition, 34.2% of patients receiving 10 mg/kg achieved at least a 3-point improvement in HFMSE compared with 13.5% of patients receiving placebo.

Although the magnitude of change on a motor-function scale may appear modest, Lin emphasized that relatively small changes had meaningful consequences.

“Even a couple point improvements in some of those motor skills can translate to a huge impact for the patients in terms of their independence and ability to do a lot of different motor activities.”

Michelle Allen-Sharpley, MD, director of the Pediatric Neuromuscular Program at Cedars-Sinai Guerin Children’s, similarly told NeurologyLive the importance of preventing further functional decline in a population living with a lifelong, progressive disease.

“If you compared patients to placebo, the placebo groups declined with their motor function, as you know, as expected with this condition, whereas treated patients had stability in their disease or prevention of further deterioration.”

Allen-Sharpley noted that this distinction is particularly relevant because patients may continue to experience weakness and functional limitations despite receiving effective SMN-directed treatment.

“Approximately 30% of treated patients had a greater than three point improvement in their scale, which is clinically meaningful.”

Targeting the Muscle Component of SMA

Mechanistically, apitegromab is a fully human monoclonal antibody that selectively binds pro/latent myostatin and inhibits its activation. Myostatin is a natural negative regulator of muscle growth; by inhibiting its activation, apitegromab is designed to promote muscle growth and enhance the function of surviving muscle fibers.

The mechanism distinguishes apitegromab from therapies such as nusinersen and risdiplam, which increase SMN protein production, as well as gene-replacement approaches that target the underlying motor neuron defect.

Allen-Sharpley described the distinction in terms of the two major components involved in producing movement.

“The SMN therapy is treatment of the nerves, whereas myostatin inhibition is sort of treatment of the muscle,” said Allen-Sharpley. “The muscle is the effector of the movement and now patients will have opportunity to receive therapies that affect both ends of that partnership.”

Identifying Patients Who May Benefit

Although the FDA indication encompasses adults and pediatric patients aged 2 years and older receiving an SMN2-targeted treatment, the strongest randomized evidence for motor-function improvement came from the younger population enrolled in the primary SAPPHIRE analysis.

Allen-Sharpley said the available data suggest that patients with greater residual muscle reserve may be particularly positioned to benefit from an additional muscle-directed therapy.

“The population that has the strongest evidence for benefit are those younger children, with SMA type 2 or nonambulatory type 3 patients who are already on an effective, SMN-directed therapy, but they have persistent symptoms, persistent weakness, and they have enough residual muscle fibers to still receive additional improvement.”

At the same time, she cautioned that treatment response may not be uniform across the broad population now covered by the FDA approval. Patients with more advanced disease or limited residual motor function may have less opportunity for measurable improvement, while the potential role of treatment in populations not represented in SAPPHIRE remains an area for further study.

Apitegromab is administered as a once-monthly intravenous infusion. Allen-Sharpley noted that because its effect on muscle signaling is not permanent, continued treatment would be required to maintain its effects.

Looking Beyond Motor Scales and Asking Long-Term Questions

Both clinicians also pointed to the importance of outcomes that extend beyond conventional measures of motor performance.Lin noted that measures of fatigue, endurance, activities of daily living, and quality of life can capture aspects of SMA that may not be fully reflected by motor scales.

For patients, improved endurance and reduced need for rest throughout the day could translate into greater independence even when changes on a standardized motor assessment appear relatively small.

The approval also leaves several questions for continued investigation, including how apitegromab performs across different ages and stages of SMA, how long functional benefits can be sustained, and which patients are most likely to derive meaningful benefit.

Longer-term studies may help clarify whether improvements can be maintained over time or whether patients eventually reach a functional plateau.Allen-Sharpley also pointed to the importance of studying populations that were not represented in SAPPHIRE, including younger children and patients with more advanced disease.

“We do know with the therapies that have been approved and are widely used, that the earlier you treat SMA, the better your outcome,” said Allen-Sharpley. “Combination therapy is certainly the futureand we as a community are working through what the best combination is for the right patient.”

Safety and Ongoing Considerations

In SAPPHIRE, the most common adverse reactions associated with ISEMBYLD included upper respiratory tract infections, vomiting, cough, other viral infections, headache, gastroenteritis, and pharyngitis. The FDA also identified an increased risk of fractures, including serious fractures, as an important safety consideration.

The FDA-approved labeling should therefore be referenced when discussing appropriate monitoring and treatment considerations, particularly as clinicians begin using apitegromab in broader real-world populations.

REFERENCES
1. Scholar Rock Announces FDA Approval of ISEMBYLD™ (apitegromab-mstn), the First and Only Muscle-Targeted Treatment for Children and Adults with Spinal Muscular Atrophy (SMA). Scholar Rock. News Release. September 11, 2026. Accessed September 11, 2026. https://investors.scholarrock.com/news-releases/news-release-details/scholar-rock-announces-fda-approval-isembyldtm-apitegromab-mstn