G.O.17: Results of a phase 2 open-label study of ISIS-SMNRx in patients with infantile (Type 1) spinal muscular atrophy

Abstract

This study was conducted to evaluate the safety, tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of ISIS-SMNRx (ISIS 396443) in patients with infantile-onset spinal muscular atrophy (SMA type 1). ISIS-SMNRx is an antisense oligonucleotide (ASO) drug designed to alter splicing of SMN2 mRNA, increasing the amount of functional SMN protein produced. Results from experiments in SMA mouse models showed that ISIS-SMNRx effectively altered SMN2 mRNA splicing, increased SMN protein in the spinal cord, and had significant effects on functional and histological measures of neuromuscular health, including survival, when delivered to the CNS. A single-dose, dose-ascending clinical study of ISIS-SMNRx in children with Type 2/Type 3 SMA has previously been completed. Multiple doses of ISIS-SMNRx were delivered by intrathecal injection to infants with genetically confirmed SMA who were 7 months of age or less at study enrollment. Four subjects were administered multiple 6 mg equivalent doses of ISIS-SMNRx and up to 16 subjects will be administered multiple 12 mg equivalent doses. Subjects are being monitored for drug safety and tolerability. Plasma drug levels are measured over the first 24 h and CSF drug levels are assessed prior to each dose administration. Preliminary measures of clinical efficacy include the CHOP-INTEND infant motor exam, Hammersmith infant neurologic exam, CMAP, growth measurements, ventilator use, and survival. Enrollment of the lower dose cohort has been completed and no safety concerns related to ISIS-SMNRx have been identified to date; enrollment of the higher dose cohort is ongoing. Available safety, tolerability, pharmacokinetic, and clinical data will be presented. Results from this study will inform the design and conduct of a Phase 3 clinical study of ISIS-SMNRx in infants with SMA.