Understanding the role of myostatin and apitegromab
Myostatin is a protein primarily found in skeletal muscle that acts as a negative regulator of muscle growth. Its primary function is to limit muscle mass, and when it is inhibited, muscle growth can occur. In many neuromuscular disorders, including Spinal Muscular Atrophy (SMA), muscle weakness and atrophy are significant components of the disease pathology that are not fully addressed by current treatments.
The unique mechanism of apitegromab
Unlike some other myostatin inhibitors, apitegromab (also known as SRK-015) is a fully human monoclonal antibody that selectively targets the inactive or latent form of myostatin rather than the active form. It binds to promyostatin, a precursor of myostatin, and prevents it from being activated by the protein tolloid. By blocking myostatin activation in the muscle tissue, apitegromab essentially 'turns off' the signal that inhibits muscle growth. This approach is designed to complement existing therapies for SMA, which primarily focus on increasing levels of the survival motor neuron (SMN) protein and preserving motor neurons, rather than directly acting on muscle health.
Apitegromab's development for spinal muscular atrophy
Spinal Muscular Atrophy (SMA) is a genetic disease that leads to progressive loss of motor neurons, causing debilitating muscle weakness and atrophy. Current SMN-targeted therapies have significantly improved outcomes, but progressive muscle weakness persists as a major concern. Apitegromab is being investigated as an adjunctive treatment to address this remaining muscle deficit.
Clinical trial findings
Clinical trials, including the Phase 2 TOPAZ and Phase 3 SAPPHIRE studies, have investigated the use of apitegromab in nonambulatory patients with Type 2 and Type 3 SMA. In the Phase 3 SAPPHIRE trial, apitegromab demonstrated statistically significant and clinically meaningful improvements in motor function, as measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE), when added to standard-of-care SMN-targeted therapies. These improvements were observed as early as eight weeks and were sustained over time. An ongoing extension study, ONYX, is continuing to evaluate the drug's long-term safety and efficacy.
Key features of apitegromab treatment:
- Investigational status: It is currently under regulatory review and has not been approved for any use.
- Muscle-targeted mechanism: It inhibits myostatin to promote muscle growth, complementing nerve-focused treatments.
- Target population: Primarily nonambulatory patients with Type 2 and Type 3 SMA, aged 2 and older.
- Administration: Given via intravenous (IV) infusion every four weeks.
- Adjunctive therapy: It is studied for use alongside existing SMN-targeted treatments like nusinersen or risdiplam.
Apitegromab vs. other SMA treatments: A comparison
While several treatments for SMA are available or in development, they work differently from apitegromab. Apitegromab's muscle-directed mechanism is a key differentiator.
| Feature | Apitegromab | Nusinersen (Spinraza) | Risdiplam (Evrysdi) | Onasemnogene abeparvovec (Zolgensma) |
|---|---|---|---|---|
| Mechanism of Action | Inhibits myostatin activation to promote muscle growth. | Increases SMN protein levels by modulating splicing of SMN2 RNA. | Increases SMN protein levels systemically by modulating splicing of SMN2 RNA. | A one-time gene therapy that delivers a functional copy of the SMN1 gene. |
| Target | Primarily focuses on improving muscle mass and function. | Targets motor neurons and nervous system to preserve nerve cells. | Targets motor neurons and nervous system, and also distributed to the brain and spinal cord. | Delivers a new gene to motor neuron cells to produce SMN protein. |
| Administration | IV infusion, typically monthly. | Intrathecal injection into the spinal fluid. | Oral solution, taken daily. | One-time IV infusion. |
| Indications | Investigational for Type 2 and 3 SMA. Also explored for other neuromuscular conditions. | Approved for all SMA types across all ages. | Approved for all SMA types across all ages. | Approved for pediatric SMA patients under 2 years of age. |
Safety profile and regulatory status
Across multiple clinical trials, apitegromab has been generally well-tolerated. The most frequently reported adverse events have been consistent with the underlying SMA patient population, and serious adverse events were not considered related to the drug. Common side effects included headache, pyrexia, upper respiratory tract infections, and nasopharyngitis.
On September 23, 2025, Scholar Rock received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) for its Biologics License Application (BLA) for apitegromab. Critically, the CRL was not due to safety or efficacy concerns related to the drug but was solely a result of observations at a third-party manufacturing facility. The observations were not specific to apitegromab and related to a facility that Novo Nordisk acquired. This means the delay is related to external manufacturing issues and not the drug's core performance in clinical trials.
Future potential and next steps
While the FDA approval timeline faces a delay due to manufacturing issues, the positive clinical data from trials like SAPPHIRE remain a significant development for the SMA community. Scholar Rock is actively working to resolve the manufacturing issues and resubmit its application. Additionally, the European Medicines Agency (EMA) is reviewing its application for marketing authorization. Research is also exploring apitegromab's potential in other indications, such as Duchenne muscular dystrophy and as an adjunctive therapy for metabolic conditions to preserve muscle mass.
The outlook for apitegromab
The development of apitegromab marks a potential shift in the therapeutic landscape for SMA by addressing the persistent challenge of muscle weakness. By offering a muscle-targeted approach to complement existing therapies that focus on motor neuron health, it holds promise for providing sustained and meaningful improvements in motor function and quality of life. Despite a temporary regulatory setback related to manufacturing, the clinical evidence supports its potential role as a new treatment option for those living with later-onset SMA.
For more information on the company's research pipeline, visit the official website: Scholar Rock.
Conclusion
Apitegromab is an investigational anti-myostatin monoclonal antibody showing potential as a complementary therapy for later-onset SMA, targeting the underlying issue of muscle atrophy. Its positive Phase 3 clinical trial results demonstrated improved motor function in patients already on SMN-targeted treatments. The recent Complete Response Letter from the FDA was related to manufacturing site observations, not the drug's safety or efficacy, indicating a delay rather than a rejection of its therapeutic merit. The therapy represents an important new direction in SMA treatment by directly addressing muscle function and could offer substantial benefits to patients once regulatory hurdles are cleared.
