Medscape: Novel 'Gene Silencer' Shows Promise in Huntington's
Even Medscape is writing about IONIS-HTTRx!!!! Sorry, they didn't include a
link to Abstract 2457. Another article this, in the news the other day, was
First drug for Huntington's disease proves safe and effective in mice and
monkeys
and-effective-in-mice-and-monkeys Human trials have begun 3 MAR 2016
Jean Miller
Novel 'Gene Silencer' Shows Promise in Huntington's
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 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."
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.
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.