An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study

Abstract

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. This study was registered with Clinicaltrials.gov, number NCT01041222.

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.

Funding: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Fig. 1. Subject Disposition

The subject disposition among the 26 subjects assessed is detailed above. One enrolled subject was not treated because of failed intrathecal catheter placement. Some subjects were enrolled in more than cohort.

Fig. 2. CSF and Plasma Concentrations of ISIS 3336111

A. CSF was drawn immediately after the end of the intrathecal infusion (11hours, 22 minutes) one level above or below the infusion site. Measured ISIS333611 concentrations and predicted values are shown. B. Plasma was drawn at each of the indicated time points for all 4 cohorts and ISIS333611 measured by ELISA. As anticipated, plasma levels for cohorts 1 and 2 were below the limit of detection of the assay. (N=6 +/− SE)

Fig. 3. SOD1 Protein Levels in CSF

SOD1 protein levels in the CSF were measured by ELISA assay in those subjects that were enrolled in more than one cohort and plotted vs. months since previous cohort. SOD1 Mutation and cohort number are indicated for individual subjects; * denotes placebo for that cohort.