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Antisense Oligonucleotide Lowers HTT Protein in CSF of Huntington's Disease Patients

Article In Brief

In a phase 1 study, scientists reported a 40 percent average reduction of the HTT protein in the CSF of patients with Huntington's disease who received the two highest doses (90-mg and 120-mg) of an antisense oligonucleotide, HTTRx.

An antisense oligonucleotide (ASO) directed at huntingtin gene (HTT) messenger-RNA led to a dramatic reduction of the mutant huntingtin protein in the cerebrospinal fluid of 46 patients in the early symptomatic stages of Huntington's disease (HD), researchers reported in the May 6 online issue of The New England Journal of Medicine.

The phase 1 study of IONIS-HTTRx was found to be safe over four monthly doses. All study patients continued on in a 15-month open label study of the drug, which is delivered intrathecally.

The hope is that the reductions of the toxic form of the huntingtin protein in the CSF mean that the treatment is suppressing the protein's activity in the brain.

The study was led by Sarah Tabrizi, FRCP, PhD, FMedSci, a professor of neurology at University College London and director of the UCL Huntington's Disease Centre. IONIS-HTTRx is now being tested in a much larger sample (660 patients) in a 25-month placebo controlled double blind dosing phase 3 multi-center study. Huntington's disease is caused by a CAG repeat expansion in exon 1 of the HTT gene. Patients have one copy of the mutant gene and one copy of the normal gene. ASOs work by binding to the messenger RNA and inducing degradation of the transcript, preventing synthesis of the relevant protein. This drug is a non-selective HTT-lowering drug, meaning that it lowers both the normal and the mutant protein. It was developed by Ionis Pharmaceuticals in partnership with F. Hoffman-Roche.

Study Methods, Findings

The phase 1 randomized, double-blind study was conducted at nine sites in the UK, Germany and Canada. Forty-six HD patients in the early stages were enrolled, and 34 were randomly assigned to receive intrathecal injections of ascending doses of HTTRx (10 to 120 mg), and the rest received an intrathecal administration of placebo.

The researchers monitored the patients for an additional four months after the last treatment. Scientists collected blood and CSF to measure a number of biomarkers, and patients completed cognitive and behavioral tests throughout the study. Brain scans and electrocardiograms were also performed at baseline and at the end of the study.

The scientists reported a 40 percent average reduction of the HTT protein in the CSF of patients who received the two highest doses (90-mg and 120-mg).

One patient on the highest dose had a 63 percent reduction in mutant huntingtin. (If animal models can predict what might be going on in humans, a 40 percent reduction in Htt protein in CSF may correspond to a 55 to 70 percent reduction in some regions of the brain.)

“That we found a significant reduction of the Huntingtin protein in CSF validates that we are on the right track in developing a therapy for Huntington's disease,” said study co-author C. Frank Bennett, PhD, senior vice president for research at Ionis Pharmaceuticals and one of the founding members of the company.

Driving down normal HTT did not cause any severe safety concerns in patients treated with IONIS-HTTRx, the study authors said. While many patients had minor complaints, mostly transient irritation or pain at the injection site and headache, there were no serious adverse events reported, and no one dropped out. There were also no problematic changes in the standard safety laboratory values, said Dr. Bennett.

The scientists did identify a puzzling transient increase in CSF neurofilament light chain protein, which is thought to be a marker of cell injury. These levels were observed at the maximum peak of the CSF mutant HTT reduction towards the end of the study, after the drug injections were completed and then returned to baseline values.

They also reported a dose-dependent increase in the brain's ventricular volume, which could reflect subtle decreases in whole brain volume. There were no clinical findings associated with these changes, said Dr. Bennett. He said that these types of changes are associated with Huntington's disease, and that the team is continuing to measure and study these biomarker changes.

Roche is also conducting a natural history study to understand the clinical progression and whether it changes with ASOs on board.

While the study duration was short, they did look for functional, cognitive, psychiatric and neurological changes between those on active medication and those on placebo. As expected, they didn't find any overall significant differences, said Dr. Bennett. But they also conducted a post-hoc assessment and looked for correlation of clinical changes associated with the actual reductions in Htt levels. Here, they did find some signals worth noting, although Dr. Bennett cautioned that “it is a small study of short duration and we would not expect to find any clinical changes.”

Still, the scientists reported that the total motor score went down as the Htt in CSF decreased (p=.007) and the symbol digit modalities score got higher when the mutant Htt protein in CSF continued to decline (.044). Neither the Stroop test nor the total functional capacity seemed to change in a positive direction with the reductions of Htt protein in CSF, the authors reported. The phase 3 study is powered to answer these clinical questions.

Expert Commentary

“I was blown away by the strength of their data,” said Nancy Wexler, PhD, the Higgins professor of neuropsychology at Columbia University and the president of the Hereditary Disease Foundation. “They looked at safety, tolerability, and efficacy. The treatment doses lowered the mutant huntingtin protein and they performed a whole series of tests, and these measures improved over time, suggesting a signal of efficacy. I am extremely enthusiastic. You can see the mutant protein go down.”


“I am extremely enthusiastic. You can see the mutant protein go down.”



“That we found a significant reduction of the Huntingtin protein in CSF validates that we are on the right track in developing a therapy for Huntington's disease.”


Dr. Wexler and Kenneth H. Fischbeck, MD, FAAN, a senior investigator in the neurogenetics branch at the National Institute for Neurological Disorders and Stroke, wrote an accompanying editorial in the NEJM.

“This is a pathbreaking trial that strongly supports further development of HTTRx as a treatment for Huntington's disease,” they wrote. “The next step is to determine whether HTTRx has a clinical effect in a larger number of patients followed over a longer period of time. The current trial was of insufficient size and duration to show a significant difference in clinical measures between patients given the active agent and those who received placebo.”

“The fact that you can lower mutant huntingtin in CSF of patients (and hopefully this is a measure of what is happening in the brain) is remarkable,” said Christopher Ross, MD, PhD, professor of psychiatry, neurology, neuroscience and pharmacology at Johns Hopkins University School of Medicine. “And a post-hoc analysis suggested a clinical benefit in a short period of time. The extent to which the drug can penetrate deep into the brain to reach the striatum is still an issue, but the data, while early, are very impressive. This is a highly significant paper.”

“These results are a useful first step but there is still some way to go before we know whether this therapy really helps patients with HD,” added Roger A. Barker, PhD, professor in the department of clinical neurosciences at Cambridge Neuroscience, part of the University of Cambridge in the United Kingdom. “In particular, it will be critical to know whether this agent can be given chronically via repeated lumbar punctures for years on end without producing problems. Also we need to see whether the reductions in CSF huntingtin reported to date translate into meaningful sustained clinical effects across those domains most affected by the disease process.”


Dr. Bennett is an employee and holds stock options in Ionis Pharmaceuticals.

Link Up for More Information

•. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting huntingtin expression in patients with Huntington's disease N Engl J Med 2019; Epub 2019 May 6.
    •. Fischbeck KH, Wexler NS. Oligonucleotide treatment for Huntington's disease N Engl J Med 2019; Epub 2019 May 6.