Targeting Huntingtin Expression in Patients with Huntington’s Disease

BACKGROUNDHuntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein.IONIS-HTT Rx (hereafter, HTT Rx ) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. METHODSWe 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. RESULTSOf 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). CONCLUSIONSIntrathecal 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.