FDA and EMA Accept Biogen's Application for Higher-Dose Nusinersen (Spinraza) in SMA
核心洞察
The FDA and EMA have accepted applications for a higher dose regimen of nusinersen (Spinraza) for treating spinal muscular atrophy (搜索) (SMA).
The new regimen involves a faster loading phase with two 50 mg doses and a higher maintenance dose of 28 mg every four months.
The applications are based on the DEVOTE study, demonstrating potential clinical benefits and a safety profile consistent with the approved 12 mg regimen.
Biogen's supplemental New Drug Application (sNDA) for a higher dose regimen of nusinersen, marketed as Spinraza, has been accepted by the U.S. Food and Drug Administration (FDA) and validated by the European Medicines Agency (EMA) for the treatment of spinal muscular atrophy (搜索) (SMA). This regulatory milestone marks a significant step forward in the ongoing effort to improve treatment options for individuals affected by this debilitating neuromuscular disease. The applications are based on data from the Phase 2/3 DEVOTE study, which evaluated the safety, tolerability, pharmacokinetics, and efficacy of the higher dose regimen.
The proposed higher dose regimen consists of a more rapid loading phase, involving two 50 mg doses administered 14 days apart, followed by a higher maintenance dose of 28 mg every four months. This contrasts with the currently approved Spinraza regimen, which involves four loading doses of 12 mg over approximately 60 days, followed by maintenance doses of 12 mg every four months. The new regimen aims to provide a more efficient and potentially more effective treatment approach for SMA patients.
Clinical Evidence from the DEVOTE Study
The applications are supported by data from the Phase 2/3 DEVOTE study (NCT04089566), a randomized, controlled, dose-escalating trial that enrolled 145 participants across various ages and SMA types at approximately 42 sites worldwide. The study was divided into three parts:
- Part A: An open-label safety evaluation cohort.
- Part B: A double-blind, active control randomized treatment cohort.
- Part C: An open-label treatment cohort to assess the safety and tolerability of transitioning participants from the currently approved 12 mg dose of Spinraza to the higher dose regimen.
In the pivotal Part B cohort, which included treatment-naïve patients with infantile-onset SMA (n=75), the higher dose regimen demonstrated statistically significant improvements in motor function at six months, as measured by the Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND). These results were compared to a matched, untreated sham control group from the Phase 3 ENDEAR study, one of the pivotal studies that formed the basis of regulatory approval for the currently approved 12 mg Spinraza regimen. Furthermore, secondary outcomes from the DEVOTE trial showed favorable trends for the higher dose regimen in biomarker and efficacy measures compared to the 12 mg dose. Safety data indicated that adverse events were consistent with SMA and Spinraza’s established profile.
Expert Opinions and Community Impact
"Continued progress to improve upon the remarkable initial successes in SMA necessitates an innovative approach," said Thomas Crawford, M.D., co-director of the Muscular Dystrophy Association Clinic at Johns Hopkins Medicine. "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."
Stephanie Fradette, Pharm.D., Head of the Neuromuscular Development Unit at Biogen, stated, "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."
About Spinraza and SMA
Spinraza, an antisense oligonucleotide (ASO), is designed to target the underlying cause of motor neuron loss by continuously increasing the amount of full-length survival motor neuron (搜索) (SMN) protein produced in the body. It is administered directly into the central nervous system, where motor neurons reside, to deliver treatment where the disease starts. Spinraza is currently approved in more than 71 countries to treat infants, children, and adults with SMA, and more than 14,000 individuals have been treated with Spinraza worldwide.
SMA is a rare genetic disease characterized by a loss of motor neurons in the spinal cord and lower brain stem, resulting in severe, progressive muscle atrophy and weakness. It affects approximately one in every 10,000 babies worldwide and is a leading genetic cause of infant mortality. The severity of SMA can vary, with some individuals experiencing symptoms at birth or early infancy (Type 1), while others develop symptoms later in childhood or adulthood.
With the acceptance of these applications by the FDA and EMA, the higher dose regimen of nusinersen is now under review, offering hope for improved outcomes for individuals living with SMA.