FDA Hands Scholar Rock Complete Response Letter for Spinal Muscular Atrophy Agent Apitegromab

Following observations from a routine inspection at Catalent Indiana’s facility, the FDA has issued Scholar Rock a complete response letter (CRL) for the biologics license application (BLA) of apitegromab, an investigational monoclonal antibody for the treatment of spinal muscular atrophy (SMA). Scholar noted that these inspection findings were not specific to the agent and that the CRL did not cite concerns regarding its efficacy, safety, or the third-party drug substance manufacturer.¹

According to Scholar Rock’s second-quarter 2025 earnings announcement, Catalent submitted a comprehensive response to the FDA in early August 2025 and continued implementing corrective actions while providing the agency with progress updates. Scholar Rock reported that it plans to resubmit the BLA for apitegromab after the FDA confirms remediation of the manufacturing findings, anticipating that the agency will review the application once those issues are resolved.

“While we are disappointed that the availability of a muscle-targeted treatment approach for patients with SMA has been delayed, we remain enthusiastic about the transformative potential of apitegromab,” Kenneth Hobby, president at Cure SMA, said in a statement.¹ “Muscle strength and motor function are significant unmet needs for many in the SMA community and are fundamental to independence. A gain in motor function can allow someone to participate in important activities of daily living from self-care to work and social interactions, and as such, we urgently await the availability of the first-ever treatment with the potential to address the muscular component of SMA.”

The company's BLA for apitegromab was supported by data from the pivotal phase 3 SAPPHIRE trial (NCT05156320) as well as the phase 2 TOPAZ trial (NCT03921528).² SAPPHIRE enrolled 188 patients aged 2 to 21 years with SMA who received an SMN-targeted treatment, either nusinersen (Spinraza; Biogen) or risdiplam (Evrysdi; Genentech), to assess the safety and efficacy of apitegromab for 52 weeks. All told, apitegromab met its primary end point in the trial, achieving a statistically significant and clinically meaningful improvement in motor function, measured by the Hammersmith Functional Motor Scale Expanded (HFMSE), compared with placebo.³

In SAPPHIRE, the mean difference in change from baseline on the HFMSE was 1.8 points (P = .019) for all patients aged 2 to 21 years receiving apitegromab at 10 mg/kg or 20 mg/kg (n = 106) compared with placebo (n = 50). In this group, patients treated with 20 mg/kg of apitegromab (n = 53) showed a 1.4-point mean difference compared with placebo (P = .11). Subgroup analyses across age, type of SMN-targeted therapy, age at SMN-targeted therapy initiation, and geographic region demonstrated clinically meaningful and consistent improvements in motor function with apitegromab.

For secondary end points in the 2- to 12-year-old subgroup, patients treated with apitegromab demonstrated greater functional gains compared with placebo. At 52 weeks, 30.4% of patients receiving apitegromab achieved at least a 3-point improvement in HFMSE compared with 12.5% of placebo patients, whereas 19.6% achieved at least a 4-point improvement versus 6.3% on placebo. Additional positive trends were reported across other measures of motor function, including the Revised Upper Limb Module (RULM) and World Health Organization motor development milestones.

Previously presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas, and 2025 Cure SMA Research and Clinical Care Meeting, held June 24-26 in Orlando, Florida, apitegromab was well-tolerated across all age groups, with no new safety findings observed.^4,5 Additionally, the company noted that safety profile was consistent with that observed in the phase 2 TOPAZ clinical trial NCT03921528), including an extension study with over 4 years of treatment as of the cut-off date.

In the phase 2 TOPAZ trial, 48-month data showed continued and sustained motor function in patients with SMA treated with apitegromab. At 48 months, a combination of 20 mg/kg of apitegromab and nusinersen, resulted in change of 5.3 points (95% CI, 1.5-9.2; n = 23) in HFMSE in nonambulatory patients aged 2-21. For those aged 2-12, the clinical effect was even greater, with changes of 6.4 points (95% CI, 1.8-11.0; n = 19).⁶

The analysis population pooled the nonambulatory patients and included patients who received either low dose (2 mg/kg) or high dose (20 mg/kg) apitegromab. A total of 11 patients in the population had scoliosis surgery during the study and their data was excluded from any HFMSE or RULM assessments at 48 months. Using the remaining patient cohort, the mean change in RULM for the 2-21 age group (n = 22) was 3.6 points (95% CI, 2.0-5.3) and 4.5 (95% CI, 2.7-6.3) for the 2-12 age group (n = 18).

In terms of prior safety data, treatment-emergent adverse events (TEAEs) were considered mild-to-moderate in severity, and were generally consistent with the underlying patient population. Headache, pyrexia, COVID-19, nasopharyngitis, and upper respiratory tract infection were among the 5 most common TEAEs recorded by participants. No patients displayed positive titers for apitegromab antibodies, and no deaths or suspected serious adverse reactions or hypersensitivity reactions were observed.

“We are continuing to work closely with Catalent Indiana on the FDA’s manufacturing observations so that we can resubmit the apitegromab BLA as soon as possible,” David L. Hallal, chairman and chief executive officer at Scholar Rock, said in a statement.¹ “We remain focused on working hand-in-hand with the FDA to pursue approval of the first and only muscle-targeted treatment for people living with SMA.”

REFERENCES
1. FDA Issues Complete Response Letter (CRL) for Apitegromab as a Treatment for Patients with Spinal Muscular Atrophy (SMA) Solely Related to Observations Identified at Catalent Indiana LLC Fill-Finish Facility. News Release. Scholar Rock. Published September 23, 2025. Accessed September 23, 2025. https://investors.scholarrock.com/news-releases/news-release-details/fda-issues-complete-response-letter-crl-apitegromab-treatment
2. FDA Grants Priority Review for Biologics License Application (BLA) and EMA Accepts Marketing Authorisation Application (MAA) for Apitegromab as a Treatment for Spinal Muscular Atrophy. News Release. Scholar Rock. Published March 25, 2025. Accessed September 22, 2025. https://investors.scholarrock.com/news-releases/news-release-details/fda-grants-priority-review-biologics-license-application-bla-and
3. Scholar Rock Reports Apitegromab Meets Primary Endpoint in Phase 3 SAPPHIRE Study in Patients with Spinal Muscular Atrophy (SMA). News Release. Scholar Rock. Published October 7, 2024. Accessed September 22, 2025. https://investors.scholarrock.com/news-releases/news-release-details/scholar-rock-reports-apitegromab-meets-primary-endpoint-phase-3
4. Scholar Rock Presents New Phase 3 SAPPHIRE Data at the 2025 Muscular Dystrophy Association Clinical & Scientific Conference. News Release. Scholar Rock. Published March 16, 2025. Accessed September 22, 2025. https://investors.scholarrock.com/news-releases/news-release-details/scholar-rock-presents-new-phase-3-sapphire-data-2025-muscular
5. Scholar Rock to Present Comprehensive Update at 2025 Annual Cure SMA Research and Clinical Care Meeting, Including Positive Results from Pivotal Phase 3 SAPPHIRE Trial. News Release. Scholar Rock. Published June 23, 2025. Accessed September 22, 2025. https://investors.scholarrock.com/news-releases/news-release-details/scholar-rock-present-comprehensive-update-2025-annual-cure-sma
6. Scholar Rock reports second quarter 2024 financial results and highlights business progress. News Release. Scholar Rock. Published August 8, 2024. Accessed September 22, 2025. https://investors.scholarrock.com/news-releases/news-release-details/scholar-rock-reports-second-quarter-2024-financial-results-and