An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy

An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Spinal Muscular Atrophy

This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA).

Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.

This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, sponsorship of the trial was transferred to Biogen.

Key Inclusion Criteria:

• Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
• Clinical signs attributable to SMA
• Able to complete all study procedures, measurements, and visits and parent/patient has adequately supportive psychosocial circumstances, in the opinion of the Investigator
• Estimated life expectancy > 2 years from Screening
• Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

Key Exclusion Criteria:

• Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period
• Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator
• Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
• Hospitalization for surgery (e.g. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study
• Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
• History of brain or spinal cord disease that would interfere with lumbar puncture procedures or cerebrospinal fluid (CSF) circulation
• Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter
• History of bacterial meningitis
• Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4
• Dosing with ISIS 396443 in clinical study ISIS 396443-CS10
• Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG) at the Screening visit, as assessed by the Site Investigator that would render the subject unsuitable for inclusion
• Treatment with investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of screening. Any history of gene therapy or cell transplantation
• Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia) that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures.

NOTE: Other protocol defined inclusion/exclusion criteria may apply.