Results of an Open-Label, Escalating Dose Study To Assess the Safety, Tolerability, and Dose Range Finding of a Single Intrathecal Dose of ISIS-SMNRx in Patients with Spinal Muscular Atrophy (S36.002)

OBJECTIVE: This first-in-human study was conducted to evaluate the safety, tolerability, and pharmacokinetics of escalating single intrathecal doses of ISIS-SMN Rx (ISIS 396443) in patients with SMA. BACKGROUND: ISIS-SMN Rx is an antisense oligonucleotide (ASO) molecule designed to alter splicing of SMN2 mRNA to increase the amount of functional SMN protein produced. Results from experiments in SMA mouse models showed that ISIS-SMN Rx effectively altered SMN2 mRNA spicing and increased SMN protein in the spinal cord and had a significant effect on functional and histological measures of neuromuscular health, including survival, when delivered to the CNS. DESIGN/METHODS: A single dose of ISIS-SMN Rx was delivered by intrathecal injection to medically stable SMA patients 2-14 years of age. Four escalating dose levels (1, 3, 6, 9 mg) were examined in cohorts of 6-10 subjects (n=28). Subjects were followed for 29 days (cohorts 1, 2) or 85 days (cohorts 3, 4) post-dosing and monitored for drug safety and tolerability. Plasma drug levels were measured over the first 24 hours and CSF drug levels were assessed at 7 days post-dose. RESULTS: No serious adverse events or dose-limiting toxicities were reported. All adverse events were mild or moderate in severity and none were related to dose level of ISIS-SMN Rx . No drug-related changes in neurological exams, laboratory assessments (including CSF safety and cytokines), or systemic evaluations were reported. Intrathecal injections were well tolerated in SMA children. Analysis of drug pharmacokinetics in plasma and CSF indicate that drug levels in SMA patients were dose-dependent and consistent with levels predicted from pre-clinical animal studies. CONCLUSIONS: ISIS-SMN Rx is well tolerated when given as a single dose at the dose levels evaluated in this study; no safety concerns have been identified. Results from this study support continued development and further examination of ISIS-SMN Rx in a longer multiple-dose clinical study in SMA patients. Supported by: Isis Pharmaceuticals, Inc. Carlsbad, CA. Disclosure: Dr. Chiriboga has nothing to disclose. Dr. Swoboda has reeceived research support from BioMarin Pharmaceuticals and Orphamed. Dr. Darras has received personal compensation for activities with UpToDate, Inc., Isis Pharmaceuticals, Inc., and Athena Diagnostics. Dr. Darras has received research support from PTC Therapeutics, Inc. Dr. Iannaccone has nothing to disclose. Dr. Montes has received personal compensation for activities with ISIS Pharmaceuticals, Inc. as a consultant. Dr. Allen has nothing to disclose. Dr. Parad has nothing to disclose. Dr. Johnson has nothing to disclose. Dr. De Vivo has received personal compensation for activities with Isis Pharmaceuticals. Dr. Norris has received personal compensation for activities with Isis Pharmaceutical Corporation as an employee. Dr. Alexander has received personal compensation from Isis Pharmaceuticals as an employee. Dr. Alexander has received royalty or license fees or contractual rights payments from Isis Pharmaceuticals. Dr. Bennett has received personal compensation for activities with Isis Pharmaceuticals. Dr. Bennett has received (royalty or license fee or contractual rights) payments from Isis Pharmaceuticals. Dr. Bishop has received personal compensation for activities with Isis Pharmaceuticals as an employee.