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.
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