Tabrizi SJ, et al. - As CAG trinucleotide repeat expansion in HTT causes Huntington’s disease, resulting in a mutant huntingtin protein, researchers designed IONIS-HTT_Rx (HTT_Rx), an antisense oligonucleotide, to impede HTT messenger RNA and consequently reduce concentrations of mutant huntingtin. Its safety in adults with early Huntington’s disease was evaluated in this study. Outcomes revealed no serious adverse events after intrathecal administration of HTT_Rx to patients with early Huntington’s disease. Concentrations of mutant huntingtin were lowered in a dose-dependent manner.

Methods

• With adults who had early Huntington’s disease, a randomized, double-blind, multiple-ascending-dose, phase 1–2a trial was conducted.
• In a 3:1 ratio, researchers randomized patients to receive HTT_Rx or placebo as a bolus intrathecal administration every 4 weeks for four doses.
• A preclinical model in mice and nonhuman primates guided the dose selection that related dose level to reduction in the concentration of huntingtin.
• Safety was assessed as the primary end point; HTT_Rx pharmacokinetics in cerebrospinal fluid (CSF) was assessed as the secondary end point.
• The concentration of mutant huntingtin in CSF was one of the prespecified exploratory end points.

Results

• The trial included 46 patients; HTT_Rx (at ascending dose levels of 10 to 120 mg) was administered to 34 patients and placebo to 12 patients randomly.
• All four doses were received by every patient and the trial was completed by all participants.
• Ninety-eight percent of patients experienced adverse events, all of which were grade 1 or 2; HTT_Rx-treated patients experienced no serious adverse events.
• Laboratory variables displayed no clinically relevant adverse changes.
• In CSF, predose (trough) concentrations of HTT_Rx indicated dose dependence up to doses of 60 mg.
• The concentration of mutant huntingtin in CSF was lowered in a dose-dependent manner with HTT_Rx treatment (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).