A Study to Evaluate Higher Dose (HD) Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy Previously Treated With Risdiplam

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate motor function following treatment with HD nusinersen in participants with spinal muscular atrophy (SMA) previously treated with risdiplam. The secondary objective of this study is to evaluate the safety and tolerability of HD nusinersen in participants with SMA previously treated with risdiplam.

Official Title
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A Phase 3b Study to Evaluate Higher Dose Nusinersen (BIIB058) in Patients With Spinal Muscular Atrophy Previously Treated With Risdiplam

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Nusinersen


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Genetic documentation of 5q SMA homozygous survival motor neuron-1 (SMN1) gene deletion or mutation or compound heterozygous mutation. Diagnosis of later-onset SMA with symptom onset at age >6 months. Aged ≥15 to ≤50 years at the time of informed consent Body weight >20 kg. Received oral risdiplam per the approved label or per the managed access program as follows Nusinersen-naive participants must have had prior treatment with risdiplam for ≥6 months before enrollment. Nusinersen-experienced participants must have stopped nusinersen for ≥16 months and must have been on risdiplam for ≥12 months before enrollment. Able to perform the age-appropriate functional assessments in the study. RULM entry item A score ≥3. RULM total score ≥5 and ≤30 at Screening. Nonambulatory, defined as not able to walk 15 feet (4.57 meters) independently without support. Willing to stop risdiplam treatment. Willing and able to start treatment with HD nusinersen. Key Exclusion Criteria: Any major illness within 1 month before the screening examination or within 1 week prior to Screening and up to first dose administration. 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 CSF or of an implanted central nervous system catheter. Permanent tracheostomy or permanent ventilation at Screening. The medical necessity, as defined by the Investigator, for noninvasive ventilation such as bilevel positive airway pressure or continuous positive airway pressure outside of regular sleep hours for any reason other than proactive SMA management, at Screening. History of bacterial meningitis, viral encephalitis, or hydrocephalus. Ongoing medical condition that according to the Investigator would interfere with the conduct and assessments of the study. An example is a medical disability (e.g., wasting or cachexia, severe anemia, and respiratory parameters) that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures. Participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study. Treatment with an investigational drug, 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 gene therapy for the treatment of SMA. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Higher Dose Nusinersen<br>All participants in the core study period, previously treated with risdiplam (nusinersen-naive participants and nusinersen-experienced participants), will receive HD nusinersen, administered as 2 loading doses of 50 milligrams (mg) each, approximately 2 weeks apart, followed by maintenance doses of 28 mg approximately every 4 months. Following the core study period, participants may be given the opportunity to receive maintenance doses of 28 mg nusinersen administered approximately every 4 months up to 2 years during the optional long-term extension (LTE) period. | Drug: Nusinersen<br>* Administered as specified in the treatment arm<br>* Other names: Spinraza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total Revised Upper Limb Module (RULM) Score | The RULM is being utilized to assess upper limb functional abilities of participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living. The RULM is scored from 0 to 37 points, with higher scores indicating better function. | Up to Day 855 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have a causal relationship with the 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. An SAE is any untoward medical occurrence that at any dose results in death or in the view of the investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect, or is a medically important event. | Up to Day 1695 | 
| Number of Participants With Change in Clinical Laboratory Parameters, Electrocardiogram (ECG), Vital Signs and Pulse Oximetry from Baseline |  | Up to Day 1695 |