Novel genetic therapy reduces key protein in Huntington’s disease

In a trial of a novel gene-silencing therapy, patients with early Huntington’s disease had dose-dependent reductions of the mutant protein characteristic of their disease and no serious adverse events, according to a study published in the New England Journal of Medicine.

Huntington’s disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. No disease-modifying treatment currently exists. The experimental therapy tested in this trial, developed by Ionis Pharmaceuticals and licensed to Roche as HTT_Rx, is an antisense oligonucleotide that inhibits HTT messenger RNA signaling specific to the production of the mutant huntingtin protein implicated in Huntington’s disease. Whether HTT_Rx, which is delivered intrathecally, can produce functional or cognitive improvement is yet unclear, as this randomized, double-blinded, multiple-ascending-dose, placebo-controlled trial, which enrolled 46 patients in Canada, Germany, and the United Kingdom, was primarily a safety study.

For the phase 1-2a trial, lead author Sarah J. Tabrizi, MB, ChB, PhD, of University College London and colleagues assigned patients with early Huntington’s disease to monthly intrathecal injections of one of five different doses of HTT_Rx (10, 30, 60, 90 or 120 mg), or placebo. Most patients (n = 34) received active drug. After the 85-day treatment period, in which four doses were delivered, patients were followed for 4 months.

The treatment groups saw a mean dose-dependent reduction from baseline in the concentration of CSF mutant huntingtin of between –20% and –42% at 28 days post dosing, while the placebo arm saw an increase of a mean 10%. The most common adverse events seen in the trial were procedure-related pain and headache following spinal puncture.

Other endpoints in the study included concentrations of mutant huntingtin in plasma, the effect of treatment on other neurodegenerative biomarkers, and cognitive scores.

The median peak plasma concentrations of HTT_Rx were reached within 4 hours after the bolus intrathecal administration and declined to less than 30% of the peak concentration by 24 hours after administration. There was no evidence of accumulation of concentration in plasma 24 hours after dose administration.

Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received active treatment, regardless of the dose level.

An open-label, follow-up study in the same group of patients, all of whom have been assigned to the 120-mg dose monthly or every other month, is expected to end in October 2019. While the extension study is also mainly a safety study, it will also look at biomarkers and cognitive scores over a longer treatment period.

The study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche, and most of the authors, including Dr. Tabrizi, reported financial relationships with one or both entities.

SOURCE: Tabrizi SJ et al. N Eng J Med. 2019:380;2307-16.