A Study to Learn About the Effect of Nusinersen (BIIB058) Given as Injections to Children With Spinal Muscular Atrophy (SMA) Who Were Previously Treated With Onasemnogene Abeparvovec (RESPOND)

A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec

In this study, researchers will learn more about the use of nusinersen (BIIB058) in participants with spinal muscular atrophy (SMA). This study will focus on children under the age of 3 who were previously treated with the gene therapy onasemnogene abeparvovec but are still facing health challenges related to their disease.

The main goal of the study is to learn about the effect nusinersen has on muscle and movement ability (motor function). The main question researchers want to answer is:

- What score do participants have on the HINE Section 2 Motor Milestones test after treatment?

The Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones is an assessment that tests movements in different positions. This includes grasping, kicking, head control, rolling, sitting, crawling, standing, and walking.

Researchers will use a group of tests to study body movements, reflexes, balance, and coordination. They will also record if participants need help with breathing.

Researchers will also learn more about the safety of nusinersen. They will check participants for adverse events and changes in vital signs, heart tests, and laboratory tests including blood and urine tests.

The study will be done as follows:

• Participants will be screened to check if they can join the study.
• Each participant will receive 4 initial doses of 12 mg of nusinersen on Days 1, 15, 29, and 64 of the Treatment Period. Then, they will receive 12 mg doses once every 4 months.
• The total number of doses of nusinersen will be 9.
• Nusinersen will be given through a lumbar puncture, which involves injecting the drug into the fluid around the spinal cord in the lower back.
• The treatment period will last for up to 95 weeks (close to 2 years).
• There will be a follow-up safety period that lasts about 4 months.
• In total, participants will have up to 14 study visits. Participants will stay in the study for up to 115 weeks.

The primary objective of this study is to evaluate the clinical outcomes following treatment with nusinersen in participants with spinal muscular atrophy (SMA) who previously received onasemnogene abeparvovec.

The secondary objectives of this study are to evaluate the safety and tolerability; clinical outcomes and pharmacodynamics (PD) of nusinersen treatment in participants with SMA who previously received onasemnogene abeparvovec.

Key Inclusion Criteria:

For all participants:

• Genetic documentation of 5q SMA homozygous gene survival motor neuron 1 (SMN1) deletion or mutation, or compound heterozygous mutation
• SMN2 copy number of ≥1
• ≤36 months of age at the time of first Nusinersen dose
• Must have previously received onasemnogene abeparvovec per the approved label or local/regional regulations ≥2 months prior to first Nusinersen dose
• Must have suboptimal clinical status per the Investigator

Additional Criteria for Subgroups A and B:

• <300 days of age at the time of first Nusinersen dose
• SMN2 copy number of 2

Additional Criteria for Subgroup A:

• SMA symptom onset ≤4 months (120 days) of age
• Must have received intravenous (IV) onasemnogene abeparvovec at >6 weeks to ≤6 months (43 days to 180 days) of age
• Must have received IV onasemnogene abeparvovec after SMA symptom onset

Additional Criteria for Subgroup B:

• Must have received IV onasemnogene abeparvovec at ≤6 weeks (42 days) of age

Key Exclusion Criteria:

For all participants:

• Prior exposure to Nusinersen
• Ongoing severe or serious AEs related to onasemnogene abeparvovec
• Treatment with an investigational drug, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to study; any prior or current treatment with any survival motor neuron 2 (SMN2)-directed splicing modifier; prior antisense oligonucleotide treatment or cell transplantation; gene therapy for the treatment of SMA other than onasemnogene abeparvovec. Note: treatment with onasemnogene abeparvovec as part of an investigational study is allowed

Additional Criteria for Subgroups A and B:

• Weight-for-age is below the third percentile, based on WHO Child Growth Standards at the time of receiving onasemnogene abeparvovec. Adjustments for the gestational weight of premature babies enrolled in Subgroups A and B are allowed provided IV onasemnogene abeparvovec was dosed per the approved label or per local/regional regulations.

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