Megan Brooks

March 03, 2016

The first clinical trial of a second-generation antisense oligonucleotide that targets the cause of Huntington's disease is underway after promising results in animal testing.

A novel antisense oligonucleotide (ASO) that inhibits the production of mutant huntingtin protein, the cause of Huntington's disease (HD), has proven effective and safe in animal testing. The first test of the drug in people with the disease is underway.

"To say that the ASO approach is promising for the treatment of HD would be an understatement," George Yohrling, PhD, director of medical and scientific affairs at the Huntington's Disease Society of America, who is not involved in the research, told Medscape Medical News.

The drug is being developed by Ionis Pharmaceuticals and is now called IONIS-HTTRx. The results of animal testing, as well as details of the phase 1/2 study, were released February 26 and will be presented at the American Academy of Neurology (AAN) 68th Annual Meeting in Vancouver, British Columbia, Canada, in April.

HD is a rare, autosomal dominant neurodegenerative hereditary disease caused by a CAG repeat expansion in the huntingtin (HTT) gene. Current treatments target symptoms only; no treatments have been shown to successfully target the underlying cause of the disease and modify HD progression.

Studies in transgenic mouse models of HD showed that delivery of an ASO targeting HTT messenger RNA (mRNA) delays disease progression and results in sustained reversal of associated motor deficits.

Studies in monkeys showed dose-dependent reductions in HTT mRNA and huntingtin protein throughout the central nervous system after intrathecal administration of an ASO. Reduction of cortical huntingtin protein levels by 50% was readily achieved in monkeys and correlated with up to a 20% reduction in the caudate.

"In the monkeys, we've shown that you can lower huntingtin, the target of the drug, and there is no detectable adverse effects from lowering huntingtin," Frank Bennett, PhD, Ionis senior vice president of research and head of the company's HD program, told Medscape Medical News. "This was an important study to do because there were concerns that huntingtin might have a normal function and if you inhibited it there would be adverse effects."

The animal studies set the stage for design of a multicenter, randomized, double-blind, placebo-controlled phase 1/2 study assessing four ascending doses of intrathecally administered IONIS-HTTRx, a second-generation ASO.

The study has enrolled about 45 patients with early-manifest HD. The study endpoints, which include neuroimaging, electrophysiologic, clinical, and biochemical outcomes, serve both as safety/tolerability measures and as exploratory measures of potential pharmacodynamic effects. Initial results are expected in early in 2017, Dr Bennett said.

Exciting Times in HD Research

"It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease. Right now we only have treatments that work on the symptoms of the disease," principal investigator of the study, Blair R. Leavitt, MD, from the University of British Columbia, said in a conference statement.

Richard Bedlack, MD, PhD, Department of Neurology, Duke University School of Medicine, Durham, North Carolina, who isn't involved in the study, told Medscape Medical News that this approach "does sound incredibly exciting. It appears to have the potential to stop the disease. Unfortunately, though, it may be a few years off from being widely available for patients."

Dr Yohrling is equally excited about this potential therapeutic approach. "While there are drugs available to treat some of the symptoms associated with HD, currently there is nothing available to prevent or slow the progression of this devastating disease. Since the gene that causes HD was identified in 1993, HD families and researchers have dreamed of the day when technology would be available to lower the levels of the mutant protein in HD patients. The work of Isis [now Ionis] and their many collaborators around the world that is highlighted in this abstract, is a source of tremendous hope for HD patients and families around the world."

The preclinical studies were conducted by Ionis Pharmaceuticals. The ongoing clinical study is supported by Ionis Pharmaceuticals and is part of Ionis's collaboration with Roche to develop antisense drugs to treat HD. Several investigators disclosed financial relationships with Ionis.

To be presented at the 68th American Academy of Neurology (AAN) Annual Meeting, April 15-21, 2016. Abstract 2457.

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