Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C).

The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).

Key Inclusion Criteria:

Part A, B and C:

- Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound heterozygote)

Part A:

• Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of age (i.e., later-onset SMA)
• Age 2 to ≤ 15 years, inclusive, at the time of informed consent

Part B:

• Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) should have age > 1 week to ≤ 7 months (≤ 210 days) at the time of informed consent

• Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):

  • Age 2 to < 10 years at the time of informed consent
  • Can sit independently but has never had the ability to walk independently
  • HFMSE score ≥ 10 and ≤ 54 at Screening

Part C:

- Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening

Part C Cohort 1:

- Participants of any age (individuals ≥18 years of age at Screening must be ambulatory)

Part C Cohort 2:

• Participants ≥18 years of age at Screening (can be ambulatory or nonambulatory)
• HFMSE total score ≥4 points at Screening
• RULM entry item A score ≥3 points at Screening

Key Exclusion Criteria:

Part A, B and C:

• Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
• Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or of an implanted central nervous system (CNS) catheter
• Hospitalization for surgery, pulmonary event, or nutritional support within 2 months prior to Screening or planned within 12 months after the participant's first dose

Part A:

• Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
• Medical necessity for a gastric feeding tube
• Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 gene (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation

Part B:

• Treatment with an investigational drug including but not limited to the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any SMN2-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation

• Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):

  • Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
  • Medical necessity for a gastric feeding tube

• Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset): Signs or symptoms of SMA present at birth or within the first week after birth

Part C:

• Concurrent or previous participation and/or administration of nusinersen in another clinical study
• Concomitant or previous administration of any SMN2-splicing modifier (excluding nusinersen) or gene therapy, either in a clinical study or as part of medical care.
• Concurrent or previous participation in any interventional investigational study for any other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.