Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by a trinucleotide repeat (CAG) expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce levels of mutant huntingtin.

Methods We conducted a randomized, double-blind, multiple-ascending-dose, phase 1/2a study in adult persons with early-manifest Huntington’s disease. Participants received IONIS-HTTRx or placebo (3:1) via bolus intrathecal administration every 4 weeks for 4 doses. Dose selection was guided by a preclinical model in mouse and monkey relating dose level to reduction in huntingtin. The primary endpoint was safety. The secondary endpoint was IONIS-HTTRx pharmacokinetics in cerebrospinal fluid. Prespecified exploratory outcomes included the concentration of mutant huntingtin in cerebrospinal fluid. Results Of the 46 patients who enrolled in the study, 34 were randomized to receive IONIS-HTTRx (10 to 120 mg) and 12 were randomized to receive placebo; each participant received all 4 doses and completed the study. Adverse events were reported in 98% of patients with all being grade 1 or 2; no serious adverse events were seen in drug-treated patients. There were no clinically-relevant adverse laboratory parameter changes. Pre-dose (trough) cerebrospinal fluid concentrations of IONIS-HTTRx exhibited dose-dependence up to doses of 60 mg. IONIS-HTTRx treatment resulted in dose-dependent reduction in cerebrospinal fluid mutant huntingtin (mean changes from baseline to endpoint of +9.8%, 19.9%, 25.0%, 27.5%, 42.4% and 37.7% for placebo, 10-, 30-, 60-, 90- and 120-mg dose groups, respectively).
Conclusions Intrathecal administration of IONIS-HTTRx to early HD patients was not accompanied by serious adverse events. We observed dose-dependent reductions in levels of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche Ltd; ClinicalTrials.gov NCT02519036)