FDA Gives Complete Response Letter for Higher-Dose of SMA Therapy Nusinersen

According to a new announcement from Biogen, the FDA has handed the company a complete response letter (CRL) over its submission for a higher, potentially more effective, dose of nusinersen (Spinraza), an approved therapy for children with spinal muscular atrophy (SMA).¹

In the letter, the FDA requested an update to the technical information be included in the Chemistry Manufacturing and Controls module of the supplemental new drug application (sNDA) but did not cite any deficiencies in the clinical data presented in the package. The agency gave some potential resolutions for the submission, and Biogen is planning to resubmit the application as soon as information becomes ready.

"While this outcome was unexpected, we remain committed to bringing the high dose regimen to people living with SMA,” Priya Singhal, MD, MPH, head of development at Biogen, said in a statement.¹ "We are working diligently to provide the necessary information to the FDA."

Nusinersen, originally FDA-approved in 2016, was the first approved disease-modifying therapy for SMA. The proposed higher dose regimen for the medication includes a faster loading phase with two 50 mg doses administered 14 days apart, followed by a higher maintenance dose of 28 mg every 4 months, compared with the standard approved nusinersen regimen, which comes in a 12 mg/5 mL injection.

The sNDA for a higher dose of nusinersen was backed by findings from the phase 2/3 DEVOTE trial (NCT04089566), a randomized, controlled, dose-escalating study of 145 patients with SMA across 42 sites around the globe. DEVOTE comprised of 3 parts: an open-label safety extension cohort (Part A), a double-blind, active control randomized treatment cohort (Part B), followed by an open-label treatment cohort (Part C).^2,3

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In DEVOTE, the higher dose nusinersen cohort met its primary end point at 6 months, with treatment-naïve symptomatic infants with SMA achieving a statistically significant improvement in motor function relative to a prespecified matched sham control group from the phase 3 ENDEAR study (NCT02193074), the trial nusinersen was originally approved off. Among patients on high dose nusinersen (n = 75), there were statistically significant improvements in Children’s Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) observed from baseline to 6 months (least squares mean difference, 26.19; P <.0001).

Additional data from DEVOTE showed that the higher dose regimen continued to outperform other doses and sham across secondary end points and other key biomarker and efficacy measures. In addition, the higher dose regimen was reportedly safe and well tolerated, with adverse events (AEs) that were consistent with SMA as well as the known safety profile of nusinersen. Notably, the percentage of serious AEs was lower in the higher dose regimen group (n = 30; 60%) as compared with the approved 12 mg dose group (n = 18; 72%).

At the 2024 WMS Annual Congress, investigators reported that patients on the higher-dose regimen demonstrated a 94% reduction in plasma neurofilament light chain (NfL) levels from baseline to day 183, compared with a 30% reduction in the sham group (P < .0001). These reductions occurred more rapidly than with the 12-mg dose, with significant differences already apparent by day 64 (nominal P = .0050). By day 302, CHOP-INTEND scores improved by 19.6 points in the higher-dose group and 21.6 points in the 12-mg group (LS mean difference, –1.94; P = .8484), while HINE-2 improvements were modest and not statistically significant (LS mean difference, 0.58; P = .1734).⁴

The higher-dose regimen significantly reduced the combined risk of death or permanent ventilation by 67.8% compared with sham (HR, 0.322; P = .0006) and by 29.9% compared with the 12-mg dose (HR, 0.701; P = .2775). These findings aligned with improved survival rates, fewer hospitalizations, and reduced serious respiratory events. In later-onset patients from Part B, the higher-dose group also showed numerically greater gains on the HFMSE and RULM motor scales versus the 12-mg dose, with benefits reinforced by comparisons to matched sham and 12-mg controls from the CHERISH phase 3 study.

REFERENCES
1. Biogen Provides Regulatory Update on High Dose Regimen of Nusinersen. News release. Biogen. September 23, 2025. Accessed September 24, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-provides-regulatory-update-high-dose-regimen-nusinersen
2. FDA and EMA Accept Applications for Higher Dose Regimen of Nusinersen in SMA. News release. Biogen. January 23, 2025. Accessed September 24, 2025. https://www.biospace.com/press-releases/fda-and-ema-accept-applications-for-higher-dose-regimen-of-nusinersen-in-sma
3. Biogen Announces Positive Topline Results from Study of Higher Dose Regimen of Nusinersen, Showing Significant Benefit in Treatment of SMA. News Release. Biogen. Published September 4, 2024. Accessed September 24, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-positive-topline-results-study-higher-dose
4. New Higher Dose Nusinersen Efficacy and Safety Data Presented at World Muscle Society Congress, Highlight Potential to Maximize Benefit of Nusinersen in SMA. News Release. Biogen. Published October 8, 2024. Accessed September 24, 2025. https://investors.biogen.com/news-releases/news-release-details/new-higher-dose-nusinersen-efficacy-and-safety-data-presented