What the EC Decision on High-Dose Spinraza Means for SMA Care

The European Commission (EC) recently granted marketing authorization for a high-dose regimen of nusinersen (Spinraza; Biogen), marking a notable regulatory milestone in the treatment landscape for spinal muscular atrophy (SMA). The approval introduces a revised dosing strategy designed to deliver higher drug exposure earlier in treatment, reflecting a growing recognition that preserving motor neurons as early and as robustly as possible may translate into improved long-term outcomes.

Developed by Biogen, the newly approved high-dose regimen is supported by data from the Phase 2/3 DEVOTE program (NCT04089566) and its ongoing extension, as well as emerging real-world and post-approval evidence. In a conversation with NeurologyLive^®, Stephanie Fradette, PharmD, head of neuromuscular development at Biogen, discussed the clinical significance of this EC approval, what the DEVOTE and RESPOND studies reveal about unmet need in SMA, and how these findings may help refine treatment strategies across different SMA phenotypes and prior-therapy settings.

NeurologyLive: How significant is this approval for the SMA community, its patients, and those who treat the disease? 

Stephanie Fradette, PhD: Despite the remarkable therapeutic advancements over the past decade, the field has come to understand that there is still critical unmet need. Biogen has remained focused on the pursuit of better outcomes for people living with SMA, and development of the high dose regimen of SPINRAZA (nusinersen) is a significant step in our efforts to advance patient care.

Results from the DEVOTE study have illustrated the potential for the high dose regimen of SPINRAZA to enable clinically meaningful improvements while maintaining a safety profile that is similar to the approved 12 mg regimen. Specifically, results from the pivotal cohort showed that treatment-naïve, symptomatic infants who received the high dose regimen experienced significantly greater slowing of neurodegeneration, as measured by reductions in neurofilament, significantly greater improvements in motor function, and prolonged event-free survival, as compared to the prespecified, matched sham comparator group from the ENDEAR study.

Though the study wasn’t designed (adequately sized) to compare the high dose regimen with the approved 12 mg regimen, the high dose group experienced a more rapid slowing of neurodegeneration, as measured by reductions in neurofilament, and a trend of a lower risk of death or permanent ventilation. Part B of DEVOTE also included a smaller cohort of treatment-naïve children with later-onset SMA. Again, we saw a faster slowing of neurodegeneration and trends favoring the higher dose regimen over the 12mg regimen in these participants.

Results from the open-label cohort of participants already receiving SPINRAZA 12 mg for approximately 4 years reported additional improvement in function after transitioning to the high dose regimen, irrespective of phenotype, functional status, and age. Importantly, the higher dose regimen had a safety profile broadly consistent with that of the currently approved 12mg regimen.

In the DEVOTE study, the most common adverse events that occurred in at least 10% of participants treated with the high dose regimen and occurred at least 5% more frequently than the matched sham group were pneumonia, COVID-19, pneumonia aspiration, and malnutrition.

With two major market approvals in hand and filings under review in other countries, we are deeply committed to bringing the high dose regimen to people living with SMA around the world as quickly as possible.

What were the major takeaways from RESPOND, and how significant is it to have a positive phase 4 study considering where this disease was 10-15 years ago? 

Over the past decade, Biogen has been working with the SMA field to understand the remaining unmet need and develop advancements for people living with SMA. As the treatment landscape is evolving, so are the goals for treatment – with physicians looking to improve outcomes by preserving the greatest number of motor neurons as possible.

As described in the manuscript published in The Journal of Clinical Investigation, available preclinical and autopsy data suggest only a subset of motor neurons are transduced (or treated) with gene therapy. Those motor neurons that are not transduced remain subject to degeneration over time consistent with natural disease progression. This was the foundation of the question evaluated in the RESPOND study – whether nusinersen-driven increases in SMN protein in untransduced motor neurons could unlock additional clinical benefits for individuals with SMA.

RESPOND was a two-year, Phase 4 open-label study to evaluate nusinersen in infants and toddlers with SMA who have suboptimal clinical status after treatment with Zolgensma (n=46), as defined by study investigators. At the start of the study, nearly all children had investigator-reported suboptimal motor function, with most exhibiting suboptimal status in multiple domains swallowing or feeding ability, respiratory function). They also had objective signs of active neurodegeneration, indicated by elevated levels of plasma neurofilament light chain (NfL), and severe denervation, reflected by low compound muscle action potential (CMAP) values.

The study had limitations, notably that observed improvements cannot be directly attributed to nusinersen treatment as all participants had received gene therapy prior to enrollment and RESPOND was not designed as a comparative study. The definition of suboptimal clinical status was based on investigators’ assessments, which could be subjective and was not established by a clear consensus.

After more than nine months of follow-up, nearly all RESPOND participants (35 of 37) experienced clinically relevant improvements motor milestones (HINE-2) and motor function (CHOP-INTEND). Fifty-two percent of the participants (14 of 27) who could not sit independently at baseline (when they enrolled in the study) gained the ability to do so. All participants with elevated NfL levels also experienced a rapid decline in neurofilament levels, indicating reduction in active neurodegeneration. In the safety set of the RESPOND study (n=46), 80% of participants reported at least one adverse event, with the majority being mild to moderate in severity and deemed not related to study drug.

The data from the RESPOND study are highly informative to the field as physicians work to improve the SMA treatment paradigm.

Transcript edited for clarity.

REFERENCE
1. Biogen Receives European Commission Approval for High Dose Regimen of SPINRAZA® (nusinersen) for Spinal Muscular Atrophy. Biogen. News Release. January 12, 2026. Accessed January 13, 2026. https://investors.biogen.com/news-releases/news-release-details/biogen-receives-european-commission-approval-high-dose-regimen