Authors:
Dr Timothy M Miller MD, Prof Alan Pestronk MD, William David MD, Prof Jeffrey Rothstein MD, Ericka Simpson MD, Prof Stanley H Appel MD, Patricia L Andres MS, Katy Mahoney BA, Peggy Allred DPT, Katie Alexander BA, Lyle W Ostrow MD, Prof David Schoenfeld PhD, Eric A Macklin PhD, Daniel A Norris PhD, Georgios Manousakis MD, Matthew Crisp BS, Richard Smith MD, C Frank Bennett PhD, Kathie M Bishop PhD, & Prof Merit E Cudkowicz MD
Summary:
Background - Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis.
Methods - In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11•5 h at increasing doses (0•15 mg, 0•50 mg, 1•50 mg, 3•00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion.
Findings - Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated.
Interpretation - This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders.
Source:
The Lancet Neurology; Vol. 12, Issue 5, 435-442 (05/2013)