The objectives of this study are to evaulate the safety, tolerability, and pharmacokinetics of multiple doses of ISIS 396443 administered intrathecally to patients with Spinal Muscular Atrophy (SMA).
1.1 Primary Objective
To examine the safety and tolerability of multiple doses of ISIS 396443 administered intrathecally to patients with SMA.
1.2 Secondary Objective
To examine the cerebral spinal fluid (CSF) and plasma pharmacokinetics of multiple doses of ISIS 396443 administered intrathecally to patients with SMA.
1.3 Exploratory Objective
To examine the effects of multiple doses of ISIS 396443 administered intrathecally to patients with SMA on biomarkers and clinical outcomes related to SMA.
This study will test the safety, tolerability, and dose-range finding of multiple doses of ISIS 396443 administered as IT injections by lumbar puncture (LP). Three dose levels (3 mg, 6 mg, 9 mg) will be evaluated sequentially. Each dose level will be studied in a cohort of 8 subjects where all subjects will receive ISIS 396443. Within each cohort, no more than 4 subjects >7 years of age at screening will be enrolled. Cohort 1: 3 mg ISIS 396443 on Day 1, 29, 85, IT injection, (n=8) Cohort 2: 6 mg ISIS 396443 on Day 1, 29, 85, IT injection, (n=8) Cohort 3: 9 mg ISIS 396443 on Day 1 and 85, IT injection, (n=8) After Informed consent/assent is obtained, subjects will undergo a Screening evaluation no greater than 28 days prior to first dose administration at which their eligibility for the study will be examined. Subjects who meet the eligibility criteria will be admitted to the study center on Study Day 1, undergo pre-dose evaluations, and then receive an LP injection of study drug (ISIS 396443). The subject will remain at the study center for at least 24 hours post-injection for safety monitoring and laboratory specimen collection. Subjects in Cohorts 1 and 2 will return to the study center on Days 29 and 85 for follow-up evaluations and subsequent injections. Subjects in Cohort 3 will return to the study center on Day 85 for follow-up evaluations and a subsequent injection. Following LP injections on study Days 29 and 85, subjects will not stay overnight in the hospital but will be monitored for at least 6 hours post-injection before leaving the study facility. The study center will monitor the subject’s condition through telephone contact on Study Days 15, 30 (Cohorts 1 and 2 only), 57, 86, 127 and 211. Safety monitoring visits will occur on Days 8, 36, 92, 169, and 253 (through 24 weeks after the last dose of ISIS 396443). A CSF sample will be taken pre-dose on each injection day for safety and PK analyses. If a subject terminates early from the study, they will be encouraged to complete safety assessments per the Day 92 visit. Subjects who participated in ISIS 396443-CS1 Cohort 1 (Single-dose of 1 mg ISIS 396443) may enroll. Subjects who are being re-enrolled must repeat all screening assessments, except the Brain and Spinal Cord MRI which does not have to be repeated if they have had a study-specific MRI at screening in ISIS 396443-CS1.