A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of BIIB115

A Randomized, Blinded, Placebo-Controlled, Phase 1 Single Ascending Dose Study in Healthy Adult Male Volunteers and an Open-Label Multiple Ascending Dose Study in Pediatric SMA Participants Previously Treated With Onasemnogene Abeparvovec (Zolgensma™) to Evaluate the Safety, Tolerability, and Pharmacokinetics of BIIB115

The primary objective of the study is to evaluate the safety and tolerability of single ascending dose of BIIB115 administered via intrathecal (IT) bolus injection to healthy male participants in Part A and multiple ascending doses of BIIB115 administered via IT bolus injection to pediatric Spinal Muscular Atrophy (SMA) participants previously treated with onasemnogene abeparvovec in Part B. The secondary objective of the study is to evaluate the pharmacokinetics (PK) of single-dose of BIIB115 administered via IT bolus injection to healthy male participants in Part A and multiple ascending doses of BIIB115 administered via IT bolus injection to pediatric SMA participants who previously received onasemnogene abeparvovec in Part B.

This is a first-in-human (FIH) study to evaluate the safety, tolerability, and PK of BIIB115, and consists two parts. Part A includes cohorts 1 through 4, where healthy volunteer (HV) participants will be assigned to receive a single dose of either BIIB115 or placebo. This part will have a 4-week Screening Period, a Treatment Period, and a 13-month Follow-up Period. The study duration for each participant will be approximately 14 months. Part B includes cohorts 5 and 6, where pediatric participants with SMA will be assigned to receive 2 doses of BIIB115. This part will have a 4-week Screening Period, a Treatment Period, and a 24-month Follow-up Period. The study duration for each participant will be approximately 25 months. The study will be conducted in approximately 20 sites globally.

Sequential for Parts A and B, parallel for Cohorts 1-4 within Part A, parallel for Cohorts 5-6 within Part B

Participants will receive a single dose of BIIB115-matching placebo, via IT bolus injection, on Day 1.

Pediatric SMA participants previously treated with onasemnogene abeparvovec will receive two doses of BIIB115, Dose 3, via IT bolus injection at two separate time points.

Pediatric SMA participants previously treated with onasemnogene abeparvovec will receive two doses of BIIB115, Dose 4, via IT bolus injectionat two separate time points.

An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A serious adverse event (SAE) is any untoward medical occurrence that at any dose results in death, in the view of the investigator, places the participant at immediate risk of death (a life-threatening event), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or is a medically important event.

Parts A and B: Area Under the Concentration-Time Curve from Time 0 to Last Measurable Concentration (AUC0-last) of BIIB115 in Serum

Parts A and B: Area Under the Concentration-Time Curve from Time 0 to Infinity (AUCinf) of BIIB115 in Serum

Key Inclusion Criteria: Part A: Male healthy participants aged 18 to 55 years, inclusive Have a body mass index of 18 to 30 kilograms per meter square (kg/m^2), inclusive Must be in good health as determined by the investigator, based on medical history and screening evaluations Part B: Age 0.5 to 12 years old, inclusive, at the time of informed consent Weight ≥7 kg at the time of informed consent Genetic diagnosis of SMA (5q SMA homozygous survival motor neuron 1 (SMN1) gene deletion or mutation or compound heterozygous mutation) Survival motor neuron 2 (SMN2) copy number ≥1 Must have received intravenous (IV) onasemnogene abeparvovec per the approved label or per guidelines including the steroid regimen and monitoring specified therein Treatment with onasemnogene abeparvovec ≥180 days prior to first BIIB115 dose Potential for improvement due to suboptimal clinical status secondary to SMA, as determined by the Investigator Key Exclusion Criteria: Part A: Any reason, anatomical or otherwise (including abnormal hematology/coagulation), that presents increase of risk of complication from multiple lumbar puncture (LP) procedures required for dosing and CSF collection, per the investigator discretion History of any clinically significant cardiac, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, or renal disease, or other major disease, as determined by the Investigator Chronic, recurrent, or serious infection, as determined by the investigator, within 90 days prior to screening or between screening and Day -1 Current enrollment or a plan to enroll in any interventional clinical study of a drug, biologic, or device, in which an investigational treatment or approved therapy for investigational use is administered within 3 months (or 5 half-lives of the agent, whichever is longer) prior to randomization Part B: Severe or serious AEs related to onasemnogene abeparvovec therapy that are ongoing during Screening Interval of <180 days between onasemnogene abeparvovec therapy and first BIIB115 dose Ongoing steroid treatment following onasemnogene abeparvovec at time of screening History of drug induced liver injury or liver failure per Hy's law definition History of thrombotic micrangiopathy Treatment with any SMN2-splicing modifier (nusinersen or risdiplam) after receiving onasemnogene abeparvovec. Treatment with nusinersen <12 months from the first dose of BIIB115. Any reason, anatomical or otherwise (including abnormal hematology/coagulation), that presents increase of risk of complication from the LP procedures, CSF circulation, or safety assessments, including a history of hydrocephalus or implanted shunt for CSF drainage. Permanent ventilation, defined as tracheostomy or ≥16 hours ventilation /day continuously for >21 days in the absence of an acute reversible event NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

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