Biogen’s Nusinersen Shows Efficacy in SMA Compared With Sham Treatment at Experimental Higher Dose
The data come from the pivotal part B cohort of the phase 2/3 DEVOTE clinical trial.
Biogen’s nusinersen (Spinraza), a marketed antisense oligonucleotide (ASO) therapy for the treatment of spinal muscular atrophy (SMA), has demonstrated efficacy compared with a sham treatment when evaluated at a higher dose than that approved for use by the FDA.1
The data come from the pivotal part B cohort of the phase 2/3 DEVOTE clinical trial (NCT04089566), in which 75 patients with infantile-onset SMA who had not previously received treatment for their disease were randomly assigned in a 2:1 ratio to receive either the experimental higher dose or the FDA-approved dose of nusinersen. The experimental higher dose consists of a loading regimen of two 50-mg doses administered 14 days apart and maintenance doses of 28 mg given every 4 months. On the other hand, the FDA-approved dosing regimen consists of 4 loading doses at 12 mg and maintenance doses at 12 mg every 4 months.
DEVOTE’s primary end point compared the change from baseline on the Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) at 6 months posttreatment for patients treated at the higher dose in part B of DEVOTE to a matched, untreated sham control group from the phase 3 ENDEAR clinical trial (NCT02193074). Biogen reported that DEVOTE met this end point, with a statistically significant improvement on CHOP-INTEND observed in the patients treated at the experimental compared with those given the sham treatment (least squares mean difference: 26.19; P <.0001). Biogen also noted that, across secondary end points, the outcomes favored the experimental dose regimen versus the sham treatment. The company additionally stated that the outcomes for key biomarker and efficacy measures trended in favor of the higher dose regimen versus the FDA-approved regimen.
In terms of safety, the experimental dose regimen was characterized as “generally well-tolerated." Adverse events (AEs) were noted to be generally consistent with the established safety profile of nusinersen and the disease itself. Notably, 30 patients (60%) who received the experimental dose in part B of DEVOTE experienced serious AEs (SAEs) and 18 patients (72%) who received the FDA-approved dose in part B experienced SAEs.
“While there has been remarkable progress in the treatment of SMA, there remains significant unmet need,” Stephanie Fradette, PharmD, the head of the Neuromuscular Development Unit at Biogen, said in a statement.1 “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. 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.”
Earlier this year, Biogen reported data from a separate study, RESPOND (NCT04488133), which evaluated nusinersen in patients with SMA who had unmet needs remaining after previous treatment with onasemnogene abeparvovecgene (Zolgensma), an adeno-associated virus vector-based gene therapy approved by the FDA for the treatment of SMA.2,3 The findings, which were presented at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida, indicated that improvements in motor function were obtained in these patients after treatment with the ASO therapy.
“Our evolving understanding of gene therapy indicates there may be an opportunity for better outcomes,” study coauthor Crystal Proud, MD, a pediatric neurologist at Children’s Hospital of the King’s Daughters, said in a statement.2 “Improvements in motor function together with decreases in neurofilament levels seen after treatment with SPINRAZA in RESPOND show that we may be able to further maximize benefits for patients.”
