G.O.18: Results of a phase 2 study of ISIS-SMNRx in children with spinal muscular atrophy

Abstract

This open-label, multiple ascending-dose study was conducted to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of ISIS-SMNRx (ISIS 396443) in children with Types 2 and 3 SMA. ISIS-SMNRx is an antisense oligonucleotide designed to alter splicing of SMN2 mRNA to increase the amount of functional SMN protein. Results from SMA mouse models indicate ISIS-SMNRx had a significant effect on functional and histological measures of neuromuscular health when delivered to the CNS. A Phase 1 single ascending-dose study in children with SMA had previously been completed, showing acceptable safety/tolerability. Multiple doses of ISIS-SMNRx (3 dose levels) were delivered by intrathecal injection to medically stable SMA patients 2–15 years of age (n = 25). Subjects were dosed 2–3 times over 3 months and then followed for 6 months post-dosing and monitored for drug safety and tolerability, CSF and plasma pharmacokinetics, CSF SMN protein levels, and clinical outcome measures. Overall, no safety or tolerability concerns related to ISIS-SMNRx were identified; the majority of adverse events were mild or moderate in severity and none were related to dose level of ISIS-SMNRx. No drug-related changes in neurological exams, laboratory assessments (including CSF safety), or systemic evaluations were reported. Repeated intrathecal injections were well tolerated in SMA children. CSF and plasma drug levels were dose-dependent predictable, and consistent with expected levels. HFMSE scores indicated an improvement in motor function at all doses levels, with a time and dose dependency. 6MWT and ULM functional tests also indicated improvement, although with limited data. Measurement of SMN protein levels in CSF indicated a significant increase at the highest dose (p = 0.004), indicating biological activity of ISIS-SMNRx in SMA patients. Results from this study support continued development and further examination of ISIS-SMNRx in a Phase 2/3 controlled study.