Trial Supports Further Development of Huntington Antisense Oligonucleotide Therapy

genetic code
genetic code
Antisense oligonucleotide drug HTTRx reduced the concentration of mutant huntingtin protein in the cerebrospinal fluid of persons with Huntington disease.

The following article is part of conference coverage from the 2019 American Academy of Neurology Annual Meeting (AAN 2019) in Philadelphia, PA. Neurology Advisor’s staff will be reporting breaking news associated with research conducted by leading experts in neurology. Check back for the latest news from AAN 2019.

PHILADELPHIA — IONIS-HTTRx (hereafter referred as HTTRx), an antisense oligonucleotide therapy designed to reduce concentrations of huntingtin (HTT) messenger RNA, delivered via intrathecal injection was well tolerated with no serious drug-related adverse events in patients with early Huntington disease, according to a study published in the New England Journal of Medicine.1 Findings from the study will also be presented at the 2019 American Academy of Neurology Annual Meeting, held May 4-10, 2019, in Philadelphia.

In this first-in-human, double-blind trial ( identifier: NCT02519036), 46 adults with early Huntington disease were randomly assigned in a 3:1 ratio to receive either HTTRx in increasing doses (10 mg, 30 mg, 60 mg, 90 mg, or 120 mg) or placebo at 9 centers in the United Kingdom, Germany, and Canada. Each patient received 4 bolus intrathecal injections of HTTRx or placebo every 4 weeks followed by a 4-month follow-up. An independent data and safety monitoring board authorized each dose escalation after unblinded review of safety data.

Primary end point was the safety of HTTRx treatment. Secondary end point was the characterization of the pharmacokinetics of HTTRx in cerebrospinal fluid (CSF). Exploratory end points included the concentration of mutant HTT protein in CSF.

Of the 46 patients, 34 were assigned to receive HTTRx and 12 were assigned to receive placebo. All patients received all scheduled doses and completed the trial. Adverse events were similar between both groups. Adverse events were reported in 98% of the patients, mostly mild (83%) or moderate (17%) in severity. There were no clinically relevant adverse changes in laboratory variables. In patients who received HTTRx, the most commonly reported adverse effect were procedural pain and post-dural-puncture headache, which occurred after approximately 10% of lumbar punctures.

Trough concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. In addition, there was a decrease in levels of mutant HTT protein in CSF. There was mean percentage change from baseline of -20%, -25%, -28%, -42%, and -38% in the 10 mg, 30 mg, 60 mg, 90 mg, and 120 mg dose groups, respectively. In the placebo group, the mean percentage change from baseline was an increase of 10% in the concentration of mutant HTT protein in CSF.

Currently, there is an open-label extension study ( identifier: NCT03342053), comprised of the participants who completed the phase 1/2a trial. This trial is evaluating the effect of HTTRx 120 mg either monthly or every other month and is expected to be completed in October 2019. In addition, a phase 3 trial ( identifier: NCT03761849) is now under way to determine whether HTTRx has a clinically meaningful effect. Researchers plan to enroll 660 patients worldwide for up to 2 years.

This phase 1/2a trial is “pathbreaking” and “strongly supports further development of HTTRx as a treatment for Huntington disease,” noted Fischbeck and Wexler in an editorial commentary.2 They stressed that “the ultimate challenge will be to bring safe, effective, and affordable treatment not only to patients in North America and Europe but also to patients with Huntington disease throughout the world.”

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Disclosure: This trial was sponsored by Ionis Pharmaceuticals, which provided the trial agent. Personnel from Ionis Pharmaceuticals designed the trial in conjunction with collaborators from F. Hoffmann–La Roche. Data were analyzed by personnel from the sponsor and interpreted by all the authors.

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  1. Tabrizi SJ, Leavitt BR, Bernhard Landwehrmeyer G, et al. Targeting huntingtin expression in patients with Huntington’s disease [published online May 6, 2019]. N Engl J Med. doi:10.1056/NEJMoa1900907
  2. Fischbeck KH, Wexler NS. Oligonucleotide treatment for Huntington’s disease [published online May 6, 2019]. N Engl J Med. doi:10.1056/NEJMe1904861