The first therapy to target the primary mechanism of the disease is safe and well tolerated, say study investigators.
An experimental drug safely lowered levels of the mutant protein associated with Huntington disease, reported a team of international researchers. Their findings were recently published in the New England Journal of Medicine.1
The drug, IONIS-HTTRx, inhibits expression of the huntingtin (HTT) gene and thereby reduces concentrations of huntingtin protein (HTT). This is the first therapy to target the primary mechanism of Huntington disease; currently available treatments address only symptoms.
“This is a tremendously exciting and promising result for patients and families affected by this devastating genetic brain disorder,” said study author Blair Leavitt, MD, Director of Research at the Centre for Huntington Disease, University of British Columbia, Vancouver, in a press statement. “For the first time, we have evidence that a treatment can not only decrease levels of the toxic disease-causing protein in patients, but that it is also safe and very well tolerated.”2
The phase 1/2a trial included 46 adults with early Huntington disease. Thirty-four patients received HTTRx in doses ranging from 10 to 120 mg, while 12 patients were given placebo. Each participant received a total of four bolus intrathecal injections, which were administered at 4-week intervals.
The researchers found dose-dependent reductions in the concentration of mutant HTT protein in the cerebrospinal fluid (CSF) of patients who received HTTRx. Specifically, there were reductions of 20%, 25%, 28%, 42%, and 38% in those given doses of 10 mg, 30 mg, 60 mg, 90 mg, and 120 mg, respectively. In contrast, patients who received placebo had an increase of 10% in CSF levels of mutant HTT.
No serious adverse events were reported in the patients who received HTTRx. Most of the events (83%) were mild, and the remainder were moderate in severity. The most common adverse events in those who received HTTRx were procedural pain and post–dural puncture headache.
After the study ended, participants were given the opportunity to enroll in a 15-month, open-label extension trial to assess the effects of intrathecal administration of 120 mg of HTTRx monthly or every other month.
Clinical benefits still unclear
Questions remain, however, about whether the reduction in CSF levels of mutant HTT will translate into clinical benefits. The researchers themselves noted the limitations of their trial: “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 HTTRx, regardless of the dose level.”1
“Larger studies of greater duration will be needed to determine whether HTTRx-mediated reduction of the concentration of mutant HTT in CSF is associated with a treatment effect on the disease course, which is typically slow, with changes on standard outcomes generally occurring over a period of years,” the authors concluded.
This article was originally published 6/20/19 and has since been updated.
This study was funded by Ionis Pharmaceuticals and F. Hoffmann–La Roche.
1. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting huntingtin expression in patients with Huntington’s disease. N Engl J Med. 2019;380:2307-2316. doi: 10.1056/NEJMoa1900907.
2. Fletcher T. Huntington drug successfully lowers levels of disease-causing protein [press release]. Vancouver, BC: University of British Columbia; May 6, 2019.