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.