Novel Therapy May Improve Symptoms in Early Huntington Disease

DNA Strands
DNA Strands
Researchers found that high doses of the novel antisense oligonucleotide were associated with lower concentrations of mutant huntingtin protein in the cerebrospinal fluid and brain.
The following article is part of conference coverage from the 2018 American Academy of Neurology Annual Meeting in Los Angeles, California. 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 2018.

LOS ANGELES — A novel antisense oligonucleotide, IONIS-HTTRx, has shown promise as a potential disease-modifying therapy for Huntington disease (HD). Results of the phase 1/2a trial were presented at the 2018 American Academy of Neurology Annual Meeting, April 21-27 in Los Angeles.

Sarah Tabrizi, MD, PhD, FRCP, FMedSci, of University College London, and colleagues sought to characterize the safety, tolerability, and pharmacodynamics of IONIS-HTTRx, which targets huntingtin mRNA and suppresses mutant huntingtin production. The trial was a first-in-human, multicenter, double-blind study that included 46 patients randomly assigned to receive 4 doses of IONIS-HTTRx or placebo via monthly intrathecal injection. The trial utilized an ascending-dose design to effectively evaluate safety prior to dose escalation.

Overall, IONIS-HTTRx was found to be safe and well tolerated, with 100% of enrolled patients completing the trial. The highest doses of IONIS-HTTRx were associated with a significant 40% to 60% decrease in CSF mutant huntingtin protein, which correlates to 55% to 85% decrease of the protein in the brain, based on concentrations determined in preclinical studies.

Adverse events were mostly mild and unrelated to the study drug, with the most common adverse event cited being headache as a result of the lumbar puncture. There were no dose-related toxicity and no drug-related adverse events observed during the 4-month follow-up.

While the study focused on safety parameters, exploratory analyses showed a link between lowering of mutant huntingtin protein in CSF with improvement in total motor score and the Symbol Digit Modality test.

Related Articles

“The results are exploratory and require follow-up and replication in long and larger studies, but they are encouraging,” Dr Tabrizi said during a press conference. “This is an important first step; now we have to … see whether lowering CSF mutant huntingtin with the [antisense oligonucleotide] slows the progression of this devastating disease.”

Disclosure: This study was supported by Ionis Pharmaceuticals. Several authors are employed by Ionis Pharmaceuticals and F. Hoffmann-La Roche Ltd.

For more coverage of AAN 2018, click here.


Tabrizi S, Leavitt B, Kordaseiwicz H, et al. Effects of IONIS-HTTRx in patients with early Huntington’s disease: results of the first HTT-lowering drug trial. Presented at: 2018 American Academy of Neurology Annual Meeting. April 21-27, 2018; Los Angeles, CA.