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LOS ANGELES -- The first human trial of an antisense oligonucleotide (ASO) for Huntington's disease in cerebrospinal fluid (CSF) by 40% to 60%, researchers reported here.

"The ASO was well tolerated at all doses tested," said Sarah Tabrizi, MBChB, PhD, of University College London in the U.K., at the annual meeting. "We found significant and dose-dependent reductions of our target, mutant huntingtin, in CSF."

The magnitude of this reduction exceeds the amount needed for phenotypic reversal in animal models of Huntington's disease, Tabrizi noted. And data so far suggest that longer-term dosing with the antisense drug could result in even greater reductions of mutant huntingtin: "We don't believe we reached maximum reduction during this study," she said.

Huntington's disease is caused by cytosine-adenine-guanine (CAG) repeat expansion in the HTT gene. In rodent models, suppressing HTT production delays disease progression and reverses disease phenotype.

The antisense drug, known as IONIS-HTT_Rx, is designed to bind to the huntingtin mRNA in a specific sequence that leads to its degradation, resulting in less mutant huntingtin protein being made.

Tabrizi and colleagues evaluated the drug in a double-blind phase I/IIa trial of 46 patients with early Huntington's disease, randomizing them 3:1 to placebo. They tested five ascending doses ranging from 10 mg to 120 mg a day, administering the drug through intrathecal bolus injection. Study participants each had four IONIS-HTT_Rx doses -- at day 1, 29, 57, and 85 -- over a 3-month period and were followed up for 4 more months.

The trial's primary objective was to evaluate the safety and tolerability of the drug; a key exploratory objective was to measure CSF mutant huntingtin.

"We had no participants discontinue, which is impressive for a first-in-man study," said Tabrizi. Most adverse effects were mild and unrelated to the study drug. About 10% of participants reported post lumbar-puncture headaches.

The antisense drug produced dose-dependent reductions in CSF mutant huntingtin. "There is a very clear dose-response relationship, and at the higher doses of 90 and 120 mg, we got between 40% and 60% lowering of CSF mutant huntingtin," Tabrizi said.

Based on previous animal data, the CSF findings should correspond to a 55% to 85% drop in cortical huntingtin and a caudate tissue reduction of 20% to 50%. In animal models of Huntington's disease, researchers saw a clinical benefit at cortical reductions of 30% to 50%.

The researchers found no significant group-wise findings of any exploratory clinical measures, but noted they didn't expect clinical change in a small study over 7 months. They did observe, though, that CSF mutant huntingtin lowering was associated with positive trends of several exploratory clinical measures in a post-hoc analysis.

An open-label extension study to investigate the effects of sustained long-term mutant huntingtin lowering is currently underway.