Higher-Dose Nusinersen Boasts 6-Month Motor Improvement in Spinal Muscular Atrophy

A version of this article originally appeared on our sister site, NeurologyLive.

Stephanie Fradette, PharmD

(Credit- LinkedIn)

Recently announced topline data from the phase 2/3 DEVOTE study (NCT04089566) of nusinersen (Spinraza; Biogen) in the trial's 75-patient Part B cohort have shown that a higher dose of the therapy has met the primary end point of significant improvement in motor function in treatment-naïve infants with spinal muscular atrophy (SMA).¹ These gains were in comparison with a prespecified matched sham control group from the phase 3 ENDEAR study (NCT02193074).

Nusinersen was the first FDA-approved drug for the treatment of SMA in pediatric and adult patients, achieving the green light in December 2016. The antisense oligonucleotide targets continuously increases full-length SMN proteins produced in the body and is administered directly into the central nervous system.²

These new data revealed a significant improvement on the 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). The higher dose being investigated is a pair of 50-mg doses given 14 days apart, followed by a higher maintenance regimen of 28 mg every 4 months, compared with the approved nusinersen regimen of 12 mg.

Stephanie Fradette, PharmD, the head of the neuromuscular development unit at Biogen, said in a statement¹ that “while there has been remarkable progress in the treatment of SMA, there remains significant unmet need. Building on the well-characterized profile of Spinraza established over the past 10 years, we continue to explore the potential for maximizing efficacy outcomes while maintaining our commitment to safety,”

For the 3-part DEVOTE study, investigators enrolled 145 participants across ages and SMA types. In the Part B cohort, treatment-naïve children with infantile-onset SMA were randomly assigned 2:1 to high-dose nusinersen or the approved 12-mg regimen (which includes 4 loading doses and maintenance doses every 4 months). The ENDEAR study, which provided the comparative group, was 1 of the 2 pivotal studies that formed the basis of regulatory approval for nusinersen.

Additional data showed favor toward the high-dose regimen on secondary end points compared with sham and on key biomarker and efficacy measures compared with the approved regimen. Overall, the higher dose regimen was reported as generally well-tolerated among the participants, with adverse events (AEs) consistent with SMA and nusinersen's the known safety profile. The percentage of serious AEs was lower in the high-dose group (n = 30; 60%) compared with the 12-mg group (n = 18, 72%).

According to Biogen, further details on results from DEVOTE will be presented at upcoming medical conferences. “The encouraging topline results from DEVOTE show that the higher dose regimen can slow neurodegeneration faster, as shown by greater reductions in neurofilament at day 64 relative to the approved dose. Over time, the higher dose regimen led to meaningful clinical benefit in infants with symptomatic SMA. We look forward to sharing the detailed results with the SMA community and health authorities,” Fradette said in a statement.¹

REFERENCES
1. 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 4, 2024. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-positive-topline-results-study-higher-dose
2. FDA approves spinraza (nusinersen) for the treatment of spinal muscular atrophy in pediatric and adult patients. News release. FDA. December 23, 2016. Accessed March 15, 2021. accp1.org/accp1/5publications_and_news/fda_approves_spinraza.aspx