FDA Approves Higher-Dose SPINRAZA® (Nusinersen) Regimen for Spinal Muscular Atrophy
Biogen Inc. has announced a significant regulatory milestone with the approval of a new high-dose regimen of SPINRAZA (nusinersen) by the U.S. Food and Drug Administration for the treatment of Spinal Muscular Atrophy (SMA). This latest approval represents an important evolution in SMA treatment, offering patients and healthcare providers an additional dosing strategy designed to enhance therapeutic outcomes while maintaining a well-established safety profile.
The newly approved high-dose regimen includes two formulations—50 mg/5 mL and 28 mg/5 mL—and builds upon more than a decade of clinical experience with the original 12 mg dosing regimen of SPINRAZA. Since its initial approval, SPINRAZA has played a transformative role in SMA care, becoming one of the first disease-modifying therapies available for this rare and often life-limiting neuromuscular disorder. The introduction of a higher-dose option reflects ongoing efforts to optimize treatment strategies in response to the evolving needs of patients and clinicians.
Advancing SMA Treatment Through Dose Optimization
The high-dose regimen of SPINRAZA was specifically developed to deliver greater concentrations of nusinersen during both the loading and maintenance phases of treatment. This approach aims to maximize therapeutic exposure in the central nervous system, where the drug works by increasing the production of survival motor neuron (SMN) protein—deficient in individuals with SMA.
Under the new regimen, patients who are initiating treatment will receive an accelerated loading schedule consisting of two 50 mg doses administered 14 days apart. This is followed by ongoing maintenance doses of 28 mg given every four months. For patients already receiving the standard 12 mg (low-dose) regimen, transitioning to the high-dose protocol involves a single loading dose, after which they continue maintenance dosing at the same four-month interval.
This flexible dosing structure is intended to accommodate both newly diagnosed individuals and those already undergoing treatment, providing continuity of care while offering the potential benefits of increased drug exposure.
Clinical Evidence Supporting Approval
The FDA’s decision to approve the high-dose regimen was primarily based on findings from the Phase 2/3 DEVOTE clinical trial program, a comprehensive, three-part study designed to evaluate the safety, tolerability, and efficacy of higher doses of nusinersen.
In the pivotal cohort of the DEVOTE study, treatment-naïve symptomatic infants with SMA who received the high-dose regimen demonstrated statistically significant improvements in motor function. These improvements were measured using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), a widely used and validated scale for assessing motor skills in infants with SMA.
When compared to a prespecified matched untreated (sham) group derived from the earlier ENDEAR study—one of the foundational trials supporting the original approval of SPINRAZA—the results were striking. Infants treated with the high-dose regimen achieved a mean improvement of +15.1 points, while the untreated group experienced a decline of -11.1 points. This translated into a mean difference of 26.19 points, with a highly statistically significant p-value (p<0.0001), underscoring the robust efficacy of the higher-dose approach.
Expert Perspectives on Clinical Impact
Leading clinicians and researchers in the field of neuromuscular disorders have highlighted the importance of this development. Richard Finkel, director of the Center for Experimental Neurotherapeutics at St. Jude Children’s Research Hospital, emphasized that optimizing nusinersen dosing builds upon a therapy already proven to change lives.
According to Dr. Finkel, the high-dose regimen not only demonstrated meaningful clinical benefits but also maintained a safety profile consistent with prior experience. He expressed confidence that this new dosing strategy will play a critical role in the future of SMA care, potentially improving outcomes for a broader range of patients.
From the company’s perspective, Priya Singhal, Executive Vice President and Head of Development at Biogen, noted that the approval reflects years of continued innovation and collaboration with the SMA community. She highlighted that the development of the high-dose regimen was made possible by the extensive clinical data generated over more than 10 years of SPINRAZA use, reinforcing Biogen’s commitment to advancing treatment options.
Safety Profile and Adverse Events
Importantly, the safety findings from the DEVOTE study indicate that the high-dose regimen is generally consistent with the established safety profile of the low-dose version of SPINRAZA. This continuity is crucial for clinicians considering transitioning patients to the new dosing strategy.
The most commonly reported adverse events among patients receiving the high-dose regimen—particularly in those with infantile-onset SMA—included pneumonia, COVID-19, aspiration pneumonia, and malnutrition. These events occurred in at least 10% of treated patients and were observed more frequently than in the historical sham-control group from the ENDEAR study.
It is worth noting that COVID-19 was not identified during the time period when the ENDEAR trial was conducted, reflecting differences in the healthcare landscape rather than treatment-related risk alone.
Beyond these findings, SPINRAZA continues to carry warnings associated with similar antisense oligonucleotide therapies. These include an increased risk of bleeding complications and potential kidney toxicity. As a result, healthcare providers are advised to conduct routine blood and urine tests prior to initiating treatment and before each subsequent dose to monitor for these risks.
Community Response and Advocacy Perspective
Patient advocacy organizations have also welcomed the approval as a meaningful step forward. Kenneth Hobby, President of Cure SMA, reflected on the transformative impact SPINRAZA has had since its initial approval nearly a decade ago.
He described the original introduction of SPINRAZA as a turning point that reshaped expectations within the SMA community, offering hope where few treatment options previously existed. The approval of the high-dose regimen, he noted, represents continued progress in addressing unmet needs and improving quality of life for individuals living with SMA.
Hobby also emphasized Biogen’s ongoing engagement with the SMA community, acknowledging the company’s role as a committed partner in advancing research and supporting patients and families affected by the disease.
Global Regulatory Progress
In addition to the United States, the high-dose regimen of SPINRAZA has already received regulatory approval in several international markets, including the European Union, Switzerland, and Japan. Biogen has indicated that it is actively working with regulatory authorities and national health agencies worldwide to expand access to this new dosing option.
This global effort underscores the widespread recognition of the potential benefits associated with higher-dose nusinersen therapy and reflects a coordinated push to ensure that patients across different regions can benefit from advancements in SMA care.
Understanding SPINRAZA and Its Role in SMA
SPINRAZA (nusinersen) is an antisense oligonucleotide therapy administered via intrathecal injection, meaning it is delivered directly into the cerebrospinal fluid surrounding the spinal cord. Its mechanism of action involves modifying the splicing of the SMN2 gene, enabling increased production of functional SMN protein.
This protein is essential for the survival of motor neurons, which are progressively lost in individuals with SMA. By restoring SMN protein levels, SPINRAZA helps preserve motor neuron function, thereby improving or stabilizing muscle strength and motor abilities.
The therapy is approved for use in both pediatric and adult patients, making it one of the most widely applicable treatments for SMA across different age groups and disease severities.
The FDA approval of the high-dose SPINRAZA regimen marks an important advancement in the ongoing evolution of SMA treatment. By offering a new dosing option that enhances drug exposure while maintaining a familiar safety profile, Biogen is providing clinicians with additional flexibility to tailor therapy to individual patient needs.
As research continues and real-world data accumulate, the high-dose regimen may further refine the standard of care for SMA, building on the strong foundation established by SPINRAZA over the past decade. For patients and families affected by SMA, this development represents not only scientific progress but also renewed hope for improved outcomes and quality of life.
With its continued focus on innovation, collaboration, and patient-centered care, Biogen remains at the forefront of efforts to address the challenges of rare neurological diseases and to expand the possibilities of treatment for conditions like spinal muscular atrophy.
About the DEVOTE Study
DEVOTE was a Phase 2/3 randomized, controlled, dose-escalating study designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of SPINRAZA when administered at a higher dose (50/28 mg). The study enrolled 145 participants across ages and SMA types at approximately 42 sites around the world. DEVOTE included 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) to assess the safety and tolerability of transitioning participants from the currently approved dose of SPINRAZA 12 mg to the higher dose regimen being tested in the study.
Part B was comprised of a pivotal cohort in treatment-naïve patients with infantile-onset SMA (n=75), and a supportive cohort in treatment-naïve patients with later-onset SMA (n=24). The primary endpoint of Part B measured the change from baseline on CHOP-INTEND at six months, comparing the high dose regimen of nusinersen to a matched, untreated sham control group from the Phase 3 ENDEAR study. ENDEAR is one of the two pivotal studies that formed the basis of regulatory approval for SPINRAZA 12 mg.
Part C was an open-label evaluation of the higher dose regimen in children and adults who transitioned from SPINRAZA 12 mg to the 50 mg/5 mL and 28 mg/5 mL regimen (n=40).
About SPINRAZA
The High Dose Regimen of SPINRAZA® (nusinersen) comprising a 50 mg/5 mL loading dose and 28 mg/5 mL maintenance dose injections is currently approved in the U.S., European Union, Switzerland, and Japan to treat infants, children and adults with spinal muscular atrophy (SMA). SPINRAZA 12 mg/5 mL injection is approved for SMA in more than 71 countries.1 SPINRAZA is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.
The Low Dose Regimen of SPINRAZA has shown efficacy across ages and SMA types with a well-established safety profile based on data in patients treated up to 10 years,2,3 combined with unsurpassed real-world experience. The most common adverse events observed in clinical studies were respiratory infection, fever, constipation, headache, vomiting and back pain. Laboratory tests can monitor for renal toxicity and coagulation abnormalities, including acute severe low platelet counts, which have been observed after administration of some ASOs.
Biogen licensed the global rights to develop, manufacture and commercialize SPINRAZA from Ionis Pharmaceuticals, Inc. (Nasdaq: IONS).
About Biogen
Founded in 1978, Biogen is a leading biotechnology company that pioneers innovative science to deliver new medicines to transform patients’ lives and to create value for shareholders and our communities. We apply deep understanding of human biology and leverage different modalities to advance first-in-class treatments or therapies that deliver superior outcomes. Our approach is to take bold risks, balanced with return on investment to deliver long-term growth.
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