June 11, 2012

A Phase 1, Double-Blind, Placebo-Controlled, Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of ISIS 333611 Administered Intrathecally to Patients with Familial Amyotrophic Lateral Sclerosis Due to Superoxide Dismutase 1 Gene Mutation

The purpose of this study was to test the safety, tolerability, and pharmacokinetics of
single doses of ISIS 333611 administered as 12-hour infusions into the spinal fluid.
Four dose levels were evaluated sequentially. Each dose level was studied in a
cohort of 8 patients where 6 were randomized to active treatment with ISIS 333611
and 2 were randomized to placebo.

A total of 32 doses were given to 21 individuals with SOD1 ALS (7 subjects were
dosed 2 times and 2 subjects were dosed 3 times). Results indicate that ISIS 333611
was well tolerated. No safety or tolerability concerns related to ISIS 333611 were
identified. Drug levels in the spinal fluid and blood corresponded well with the
predicted levels based on preclinical testing.