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.
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. This study was registered with Clinicaltrials.gov,
number NCT01041222.
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.
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.
The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.
Copyright © 2013 Elsevier Ltd. All rights reserved.