FDA Accepts sNDA for Higher Dosing Regimen of Nusinersen for Spinal Muscular Atrophy

Stephanie Fradette, PharmD

According to a new announcement, the FDA has accepted Biogen’s supplemental new drug application (sNDA) for a higher, potentially more efficacious dose regimen of nusinersen (Spinraza) for patients with spinal muscular atrophy (SMA). The company also reported that the European Medicines Agency (EMA) has validated the application for the higher dose as well.¹

The higher dose nusinersen regimen 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 to the standard approved nusinersen regimen. The regulatory submission was based on findings from the phase 2/3 DEVOTE study (NCT04089566), a randomized, controlled, dose-escalating trial that comprised of 145 participants across ages and SMA types at 42 sites around the globe.

Nusinersen, an antisense oligonucleotide, was first approved by the FDA as a treatment for pediatric and adults with SMA in December 2016.² In the latest data from DEVOTE, treatment with the agent at higher doses show significant improvements in motor function as well as slowed neurodegeneration in patients previously treated and treatment-naïve with infantile-onset or later-onset SMA. Initial data from Part C (n = 40) of the study also showed motor function enhancements after transitioning to the higher dose regimen, with mean increases of 1.8 points on the Hammersmith Functional Motor Scale-Expanded (HFMSE) and 1.2 points on Revised Upper Limb Module (RULM) at day 302.³

"We are pleased to announce that our applications for the higher dose regimen of nusinersen are now under review in the US and Europe," Stephanie Fradette, PharmD, head of the neuromuscular development unit at Biogen, said in a statement.¹ "This milestone reflects our steadfast commitment to advance treatment options for individuals with SMA, and we expect that this higher dose regimen will offer meaningful benefits to patients and their families. We are deeply thankful for the unwavering support of the trial participants, their families, site staff, and the SMA community without whom these advancements would not have been possible."

DEVOTE comprised of 3 parts: an open-label safety evaluation cohort (Part A), a double-blind, active control randomized treatment cohort (Part B), followed by an open-label treatment cohort (Part C). Topline data from Part B announced in early 2024 showed that the higher dose met its primary end point at 6 months in treatment-naïve symptomatic infants with SMA, compared with a matched sham control group from the phase 3 ENDEAR study (NCT02193074). At the conclusion of the study, results revealed that those on the higher dose had a significant improvement in the primary end point of change in Children’s Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores from baseline to 6 months (least squares mean difference, 26.19. P <.0001).⁴

The company reported new secondary analysis data comparing the efficacy of the higher-dose nusinersen regimen to both the matched sham group and the standard 12-mg nusinersen regimen. Although the study lacked sufficient power to detect statistically significant differences between the higher-dose and 12-mg regimens, findings generally favored the higher-dose regimen across most comparisons.

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Data presented at the 2024 WMS Annual Congress highlighted a 94% reduction in plasma neurofilament light chain (NfL) levels from baseline to day 183 in the higher-dose group, compared with a 30% reduction in the sham group (P < .0001). Notably, the higher-dose regimen achieved more rapid reductions in NfL, with significantly greater reductions observed by day 64 compared to the 12-mg group (nominal P = .0050).³

At day 302, patients receiving the higher dose experienced a 19.6-point improvement on the CHOP-INTEND scale, while those on the 12-mg regimen saw a 21.6-point improvement (least-squares mean difference, -1.94; P = .8484). Similarly, the higher-dose group showed a modest but nonsignificant improvement in the Hammersmith Infant Neurological Exam section 2 (HINE-2) compared to the 12-mg group (least-squares mean difference, 0.58; P = .1734).

The higher-dose regimen significantly reduced the risk of death or permanent ventilation by 67.8% compared with the sham group (HR, 0.322; P = .0006) and by 29.9% compared to the 12-mg regimen (HR, 0.701; P = .2775). This trend was accompanied by improved survival rates and reductions in hospitalizations and serious respiratory events. In later-onset participants from Part B of the study, those treated with the higher dose showed numerically greater improvements in motor function, as measured by the HFMSE and RULM scales, compared with the 12-mg group at day 302. These improvements were also evident when compared with matched 12-mg and sham control groups from the phase 3 CHERISH study (NCT02292537).

Thomas Crawford, MD

The higher-dose regimen was generally well-tolerated throughout the DEVOTE study, with a safety profile similar to the 12-mg regimen. The most common adverse events (AEs) included respiratory infections, fever, constipation, and headaches, with similar frequencies observed between the 50/28-mg and 12-mg treatment arms. Severe AEs leading to study withdrawal or death were reported only in the Part B treatment-naïve cohort, occurring in 20% (n = 10), 24% (n = 6), and 55% (n = 11) of patients in the 50/28-mg, 12-mg, and sham groups, respectively.

"Continued progress to improve upon the remarkable initial successes in SMA necessitates an innovative approach," Thomas Crawford, MD, codirector of the Muscular Dystrophy Association Clinic at Johns Hopkins Medicine, said in a statement.¹ "Today’s announcement is a significant step forward for the community. Results from the DEVOTE study have shown us that the higher dose regimen of nusinersen can enable meaningful clinical benefits while maintaining a safety profile broadly consistent with the approved 12 mg regimen."

In late 2024, NeurologyLive^®and Cure SMA put on a panel featuring experts in SMA to discuss diagnostics, newborn screening, clinical recommendations for SMA, treatment selection, and much more. In the clip below, panelists Mary Schroth, MD, FAAP, FCCP;

Kapil Arya, MD; and Juan Francisco Vazquez Costa, MD, PhD, discuss optimizing treatment access in SMA, including the need for national or local protocols, insurance approvals and close collaboration with families to optimize patient outcomes when using therapies like nusinersen.

REFERENCES
1. FDA and EMA Accept Applications for Higher Dose Regimen of Nusinersen in SMA. News release. Biogen. January 23, 2025. Accessed January 23, 2025. https://www.biospace.com/press-releases/fda-and-ema-accept-applications-for-higher-dose-regimen-of-nusinersen-in-sma
2. FDA approves spinraza (nusinersen) for the treatment of spinal muscular atrophy in pediatric and adult patients. News release. FDA. December 23, 2016. Accessed January 23, 2025. accp1.org/accp1/5publications_and_news/fda_approves_spinraza.aspx
3. 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 January 23, 2025. https://investors.biogen.com/news-releases/news-release-details/new-higher-dose-nusinersen-efficacy-and-safety-data-presented
4. 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 January 23, 2025. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-positive-topline-results-study-higher-dose