Targeting Huntingtin Expression in Patients with Huntington's Disease.

Abstract

Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in <i>HTT</i>, resulting in a mutant huntingtin protein. IONIS-HTT_Rx (hereafter, HTT_Rx) is an antisense oligonucleotide designed to inhibit <i>HTT</i> messenger RNA and thereby reduce concentrations of mutant huntingtin. We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTT_Rx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTT_Rx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTT_Rx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTT_Rx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTT_Rx in CSF showed dose dependence up to doses of 60 mg. HTT_Rx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTT_Rx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). Intrathecal administration of HTT_Rx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).