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

Abstract

Objective To evaluate the safety, tolerability, and pharmacokinetics of an antisense oligonucleotide designed to inhibit SOD1 expression (ISIS 333611) following intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis (ALS). Background Mutations in SOD1 cause 13% of familial ALS. In animal studies, ISIS 333611 delivered to the cerebrospinal fluid (CSF) distributed to the brain and spinal cord, decreased SOD1 mRNA and protein levels in spinal cord tissue, and prolonged survival in the SOD1G93A rat ALS model. Methods In a randomized, placebo controlled Phase 1 trial, ISIS 333611 was delivered by intrathecal infusion using an external pump over 11.5 hours at increasing doses to four cohorts of eight SOD1 positive ALS subjects (randomized 6 drug: 2 placebo/cohort). Subjects were allowed to re-enroll in subsequent cohorts. Safety and tolerability assessments were made during the infusion and periodically over 28 days following the infusion. CSF and plasma drug levels were measured. Findings No dose-limiting toxicities were identified at doses up to 3.0 mg. No safety or tolerability concerns related to ISIS 333611 were identified. There were no serious adverse events (AEs) in ISIS 333611-treated subjects. Re-enrollment and re-dosing of subjects with ISIS 333611 was also well tolerated. Dose-dependent CSF and plasma concentrations were observed. Interpretation In this first clinical study to report intrathecal delivery of an antisense oligonucleotide, ISIS 333611 was well tolerated when administered as an intrathecal infusion in subjects with SOD1 familial ALS. CSF and plasma drug levels were consistent with levels predicted from preclinical studies. These results suggest that antisense oligonucleotide delivery to the central nervous system may be a feasible therapeutic strategy for neurological disorders. Source of funding ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…Study drug administration may be oral, intravenous, intramuscular, intramedullary, or intrathecal. Intrathecal delivery is used to target the central nervous system (CNS) when therapies cannot cross the blood-brain barrier, as is true of antisense oligonucleotides (ASOs) and, likely, stem cell therapies [1]. Some stem cell therapies are even being delivered directly into the spinal cord [2].…”

“…Their therapeutic potential was recently demonstrated by the phase I investigation of the intrathecal delivery of ASO ISIS 333611 in SOD1 patients with familial ALS [1]. Abnormal proteins in the CNS of individuals with ALS causative mutations may provide specific biomarkers in gene-targeted therapy.…”

Protein production is an early biomarker for RNA‐targeted therapies

“…ASOs are short, DNA‐like molecules that can be designed to selectively bind mRNA transcripts and cause the catalytic destruction of particular mRNAs 9. ASOs that lower mRNA levels and thus decrease translation of proteins prone to misfolding show great promise in preclinical models of tauopathy,10 ALS,11, 12, 13 and HD,14 and are relatively safe in humans 15. These promising data have led to the launch of multiple clinical trials for ASOs in neurodegenerative diseases (NCT03225846, NCT02623699, NCT02519036, NCT03186989).…”

RNA-targeted Therapeutics for ALS

“…Using this CSF delivery paradigm in SOD1G93A rats at onset, they demonstrated a slowing of disease progression by about 37%. These animal studies led to a successful phase 1 study in humans of intrathecally delivered ASOs against SOD1 that was well tolerated and had no significant adverse events [29]. They also established important first-in-human CSF pharmacokinetics for ASOs that will greatly aid in future ASO clinical trials.…”

“…Several issues regarding such genetic manipulation in humans still need to be addressed. First, while the first ASO clinical trial in the central nervous system (CNS) shows great promise from a safety/tolerability point of view [29], longer-term data in the next studies are needed to more fully assess tolerability. Whereas earlier ASOs tended to elicit immune responses, modifications in these ASOs now are better tolerated [18].…”