Written By: Gayatri Bhor BPharm
Reviewed By: Pharmacally Editorial Team
On September 23, 2025, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Biogen regarding its supplemental New Drug Application (sNDA) for a higher-dose regimen of Spinraza (Nusinersen). The proposed regimen involves two 50-mg loading doses given two weeks apart, followed by 28-mg maintenance doses every four months.
The FDA requested additional updates to the application’s Chemistry, Manufacturing and Controls (CMC) module. No concerns were raised about the clinical safety or efficacy data, which were based on results from the Phase 2/3, DEVOTE trial (NCT04089566). Biogen confirmed that the requested information is “readily available” and plans to resubmit.
Clinical Basis for Higher-Dose Spinraza Application
The FDA submission was supported by the DEVOTE trial (NCT04089566), a three-part Phase 2/3 study. Part A, a safety lead-in, confirmed the tolerability of the higher dose in a small group of patients. Part B, the pivotal efficacy arm focusing on infantile-onset SMA, demonstrated a significant benefit; with a least squares mean difference of +26.2 points in the CHOP-INTEND score at Day 183 for the 50/28 mg regimen compared with matched sham controls. Secondary measures, including the Hammersmith Infant Neurological Examination (HINE-2) and reductions in neurofilament light chain (NfL), also favored the higher dose. Part C provided additional safety and pharmacokinetic data, confirming that the regimen was generally well tolerated and showing no new safety signals. Investigators noted that adverse events observed in the study were consistent with the underlying disease and aligned with Spinraza’s established safety profile.
FDA’s Complete Response Letter
On September 23, 2025, the FDA issued a Complete Response Letter (CRL) to Biogen. The agency requested additional updates to the Chemistry, Manufacturing and Controls (CMC) section of the application. Importantly, the letter did not cite concerns about the clinical safety or efficacy data.
A CRL does not constitute a rejection of the therapy’s benefit–risk profile. Instead, it signals that the application cannot be approved in its current form and requires further technical documentation related to manufacturing processes, quality testing, or labeling before approval can proceed.
Biogen’s Response
Biogen stated that the information requested by the FDA is readily available and confirmed its intention to resubmit the application without delay. The company emphasized that no additional clinical trials have been requested and re-stated its confidence in the DEVOTE results.
Japan’s Pharmaceuticals and Medical Devices Agency has already approved the higher-dose regimen, and the European Medicines Agency is actively reviewing it, highlighting international regulatory status of Spinraza.
Dr. Priya Singhal MD, MPH, Head of Development at Biogen, commented on the situation, stating that while the outcome was unexpected, the company remains committed to making the high-dose regimen available to people living with SMA. She added that Biogen is working diligently to provide the necessary information to the FDA.
This CRL represents a procedural halt rather than a rejection of the higher-dose strategy. Given that the clinical data remain strong and no new safety issues were identified, the resubmission process is expected to focus on technical compliance.
If Spinraza is approved in coming months, the 50/28 mg regimen could offer SMA patients a more potent version of a proven therapy while keeping the same four-month maintenance interval.
References
Biogen Provides Regulatory Update on High Dose Regimen of Nusinersen, 23 September 2025, Biogen, https://investors.biogen.com/news-releases/news-release-details/biogen-provides-regulatory-update-high-dose-regimen-nusinersen
Study of Nusinersen (BIIB058) in Participants with Spinal Muscular Atrophy (DEVOTE), ClinicalTrials.gov ID NCT04089566, https://clinicaltrials.gov/study/NCT04089566
Finkel RS, Day JW, Pascual Pascual SI, et al, DEVOTE Study Group, DEVOTE Study Exploring Higher Dose of Nusinersen in Spinal Muscular Atrophy: Study Design and Part A Results. J Neuromuscul Dis. 2023;10(5):813-823. Doi: 10.3233/JND-221667. PMID: 37393513; PMCID: PMC10578235.