Biogen Receives Complete Response Letter from FDA for High Dose Nusinersen in Spinal Muscular Atrophy

Analysis reveals significant industry trends and economic implications

Release Date

2025-09-24

Category

Drug Approval Event

Reference

Source

Breakthrough Clinical Results

Biogen announced that the FDA issued a Complete Response Letter (CRL) for its supplemental New Drug Application (sNDA) for a high dose regimen of nusinersen (SPINRAZA) for treating spinal muscular atrophy (SMA). The FDA requested updated technical information in the Chemistry Manufacturing and Controls (CMC) module of the sNDA, but did not cite any deficiencies in the clinical data. Biogen is working to resubmit the application promptly and is collaborating with regulatory authorities worldwide to advance the high dose regimen. SPINRAZA is approved in over 71 countries for SMA treatment across all ages, with over 14,000 individuals treated worldwide.

Key Highlights

  • FDA issues Complete Response Letter for Biogen's sNDA for high dose nusinersen.
  • The CRL requests updated technical information related to Chemistry Manufacturing and Controls (CMC).
  • No clinical data deficiencies were cited by the FDA.
  • Biogen plans to resubmit the application promptly.

Risk Factors and Comorbidities

Top 3 Risk Factors and Comorbidities for Spinal Muscular Atrophy

Risk Factors for SMA

Spinal muscular atrophy (SMA) is primarily a genetic disease with specific risk factors:

  1. Mutations in the SMN1 gene - SMA is caused by deletions or mutations in the survival motor neuron gene (SMN1) located on chromosome 5q13. The SMN1 gene is deleted in almost 94% of SMA patients.

  2. Autosomal recessive inheritance - SMA is an autosomal recessive disorder, meaning that only homozygous SMN1 mutations cause the disease. Some patients without homozygous deletions present with a heterozygous deletion with a concomitant undetected point mutation on the non-deleted SMN1 allele.

  3. Disease severity - SMA type I and II are significant risk factors for complications such as hip displacement. Non-ambulatory status is associated with higher risk of complications, and clinically relevant scoliosis is an independent risk factor for hip displacement.

Major Comorbidities in SMA

SMA patients commonly experience several significant comorbidities:

  1. Respiratory system dysfunction - A major comorbidity related to both anxiety and depression in school-age SMA patients. Children with SMA Type 1 develop hypoventilation, pulmonary aspiration, and recurrent lower respiratory tract infections.

  2. Digestive system dysfunction - Significantly related to both anxiety and depression in school-age patients. Gastrointestinal problems and gastroesophageal reflux are common issues, with the latter associated with higher mortality.

  3. Skeletal deformity - Including severe scoliosis and hip displacement (HD). HD has a prevalence of 75.6% in SMA patients, with SMA type II and scoliosis being independent risk factors for HD.

Other notable comorbidities include metabolic syndrome (MetS) present in 25.0% of adult SMA patients, with central obesity being the most common component (69.7%), and psychological disorders with rates of anxiety and depression in school-age SMA patients at 40.0% and 25.2%, respectively.

The presence of these comorbidities is influenced by factors such as rehabilitation exercise, academic delay, specialized support from school, household income level, caregivers' subjective anxiety, and caregivers' expectations.

Understanding these risk factors and comorbidities is essential for comprehensive management of SMA patients and improving their quality of life through targeted interventions and supportive care.

Recent Studies

Recent Spinal Muscular Atrophy Studies

U-EXTEND Study (2022)

The Upper Extremity Examination for Neuromuscular Diseases (U-EXTEND) study introduced a novel, multimodal paradigm for measuring motor function in children with neuromuscular diseases including SMA. This study employed ultrasound techniques and wearable wireless sensor technology to capture quantitative data on muscle function. As of July 2022, the study had enrolled 44 participants (9 with SMA, 20 with DMD, and 15 healthy controls). The study aims to track the minimal clinically important difference over time to assess progress in novel treatments.

Wharton's Jelly MSC Study (2021)

This case-control study evaluated Wharton's jelly mesenchymal stem cells (WJ-MSC) administered as three intrathecal injections every two months. The study included 67 patients and reported promising safety outcomes with no serious adverse drug reactions. Efficacy outcomes showed median survival time increased two-fold across all groups. Three response types were observed in ALSFRS-R: decreased progression rate (31.3%), no change (49.3%), and increased progression (19.4%). Female sex and good response to first administration were significant predictors of efficacy.

Gene-Based Therapy Meta-Analysis (2024)

This systematic review analyzed 57 studies (n=3418) comparing three gene-based therapies for SMA types 1 and 2: - Onasemnogene abeparvovec - Risdiplam - Nusinersen

Efficacy outcomes showed superior survival rates with onasemnogene abeparvovec (95%) and risdiplam (86%) compared to nusinersen (60%). Onasemnogene abeparvovec significantly reduced need for ventilatory support (risk ratio=0.10). Motor function improvements were highest with onasemnogene abeparvovec (92%) and risdiplam (90%), compared to nusinersen (74%). Safety outcomes included headaches, vomiting, and gastrointestinal disorders as the most frequent adverse reactions.

Quantitative MRI Study (2021)

This study evaluated 13 SMA patients using a 3-T MRI protocol to assess muscle characteristics. Key findings showed significantly increased fat fraction in all upper arm muscles of SMA patients, which correlated negatively with muscle force. Reduced mean diffusivity was observed in the triceps brachii, with MD positively correlating with muscle force.

Dual Therapy Case Report (2024)

A retrospective report of four SMA cases treated with dual onasemnogene and risdiplam therapy found the combination to be generally well-tolerated. Safety outcomes included transient fatigue and weakness in two patients that resolved within one month. One patient was hospitalized with SARS-CoV-2 and post-viral pneumonia. All patients experienced objective and subjective improvement, though larger prospective trials are needed to determine comparative efficacy and identify rare adverse events.

Nusinersen Response Prediction Study (2021)

This study with 16 SMA patients (types 2 and 3) investigated whether baseline muscle impairment assessed by MRI could predict treatment response to nusinersen. After 15 months, seven individuals achieved minimally clinically important difference in HFMSE scores. The study found that baseline MRI score alone couldn't differentiate responders from non-responders, but patients with less severe scoliosis showed significantly better responses.

Company drugs in pipeline

Biogen's Drug Pipeline Indications

I'm unable to provide specific information about Biogen's drug pipeline or the indications they are targeting, as this information is not available in the reference materials I have access to.

To get accurate and up-to-date information about Biogen's current pipeline, I would recommend:

  1. Visiting Biogen's official website, which typically maintains a current section on their research and development activities
  2. Reviewing their latest investor presentations or quarterly reports
  3. Checking clinical trial registries like ClinicalTrials.gov where their ongoing studies would be listed
  4. Consulting recent pharmaceutical industry reports that analyze major companies' pipelines

Biogen is known as a biopharmaceutical company that has historically focused on developing therapies for neurological diseases and rare conditions, but specific details about their current pipeline would require the most recent company information.