LOS ANGELES — The novel antisense oligonucleotide (ASO) known as IONIS-HTTRx (Ionis Pharmaceuticals) is safe and well tolerated in patients with early Huntington's disease (HD) and "has the potential to provide disease-modifying benefits," new research suggests.
Following the release last winter of top-line results for a phase 1/2a first-in-human trial of the drug, further trial findings were presented here at the American Academy of Neurology (AAN) 2018 Annual Meeting.
Among 46 patients with early-stage HD, those who received four doses of IONIS-HTTRx via monthly bolus intrathecal injections showed significant lowering in the level of mutant huntingtin (mHTT) protein after 7 months, as measured in cerebrospinal fluid (CSF). At the highest doses, 90 mg and 120 mg, levels of mHTT protein were reduced by 40% to 60%.
"This correlates to a 55% to 80% lowering of mutant huntingtin in the brain, based on [previous] preclinical animal work," Sarah J. Tabrizi, MD, University College London, United Kingdom, said during a press conference ahead of her meeting presentation.
In addition, the drug was also well tolerated at all doses tested, with 100% of the participants completing the study.
Although replication in larger studies is now needed, "this is an important first step in an early-phase study," said Tabrizi.
Session moderator and chair of the meeting's scientific committee, Natalia S. Rost, MD, MPH, director of the Acute Stroke Service at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School, Boston, told Medscape Medical News she agrees wholeheartedly with that statement.
"I'd say I have cautious optimism with this one," said Rost.
HD is caused by CAG repeat expansion in the HTT gene that results in polyglutamine expansion in the mHTT with "a toxic gain-of-function disease mechanism," write the investigators.
They add that no disease-modifying treatments are currently available. However, disease progression has been delayed in transgenic rodent models when HTT production is suppressed.
Because of this, "a comprehensive drug discovery effort…was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA [messenger RNA] that potently suppresses HTT production," the researchers write.
"An ASO is a single strand of chemically modified DNA that has been designed to sensitively bind to the Huntington message and switch it off. That means you get less of the toxic [mHTT] protein being made," noted Tabrizi.
She added that HD has a prevalence of 1 in 8000. "That means that in the US, there are 30,000 affected individuals."
In the current study, 46 patients with early HD were enrolled at nine centers in the United Kingdom, Canada, and Germany. All were randomly assigned to four doses of the ASO by monthly injection or matching placebo for 3 months, followed by an untreated follow-up period lasting 4 months.
The novel drug was given into spinal fluid "so we could reach the brain," Tabrizi reported. During the active treatment phase, the dose of study drug was increased several times as part of the dose-ascending design.
There were five cohorts in total, with ascending doses ranging from 10 mg to 120 mg. The four doses of study drug were given on days 1, 29, 57, and 85.
Adverse events (AEs) reported were mostly mild and unrelated to the study drug, with no adverse trends found in any laboratory parameter, noted Tabrizi. Headache after lumbar puncture was the most commonly reported AE (10% of patients).
In the efficacy analysis, "significant, dose-dependent reductions were observed" in mHTT levels, said Tabrizi.
She added that exploratory analyses also showed a link between the lowering of CSF mHTT and improvement in total motor scores, "which is a measure of neurological function," and improvement in cognitive function, as measured by symbol digit modalities testing.
"This requires follow-up and replication in longer, larger studies, but the results are encouraging," said Tabrizi.
Asked after the presentation if she'd describe this study as the first hope for treating HD, she said, "Yes, it's the first huntingtin-lowering trial and it's the first technology targeting the known cause" of the disease.
Tabrizi reported that all of the participants are now part of an open-label extension study, with each one now receiving the active treatment. "That will allow us to follow up long term in subjects who are getting frequent dosing of the ASO and will give additional critical information in addition to the planned phase 3 study," which is still under discussion but should begin recruitment next year, she said.
This new study will fall under the leadership of Ionis' development partner, Roche. The treatment has been granted orphan drug designation by the US Food and Drug Administration.
"Is there any consideration to use this as a preventive therapy?" asked one audience member. "Yes," Tabrizi replied. "I think our future goal is to treat people with symptomatic Huntington's disease."
"If that's successful, we will then move to prevention trials in people who carry the gene but are still well," Tabrizi said. "That's the hope: that one day we may be able to prevent this disease completely by delaying its onset."
Rost noted after the press conference that although it's still early days, she chose this as one of the top studies to be presented at the meeting, especially because there have been so few options for patients with HD.
In the past, several neurologic disorders fell almost into the "diagnose and adios" category, she said. "Huntington's was one of these terrible disorders. In addition to neurological disability, patients often have a severe psychiatric disease that is often accompanied by profound, untreatable depression, and many of them commit suicide," Rost added.
"Having any breakthroughs in this area is exciting to me as a neurologist. Any time you look someone in the eye and they say, 'Help me,' but you have nothing to offer, obviously there are some problems."
That said, she noted several concerns with this new treatment. "A, It's very early stages; B, It's awkwardly administered through intrathecal injection; and C, It's going to be very expensive," said Rost.
"We are facing the era of very high drug prices. We're anticipating a scientific breakthrough, but we need to be careful with what we're asking for. We're on the verge of healthcare system overload with all of these breakthroughs that are going to cost us millions of dollars," she said.
"I think we'll find a way to work it out as a profession and as a society, but making a step toward a cure is the most important step right now," concluded Rost.
The study was funded by Ionis Pharmaceuticals. Tabrizi has disclosed no relevant financial relationships. Rost has received personal compensation for consulting, serving on a scientific board, speaking, or other activities from Broadview Ventures, Covance Inc, Merck and Co, Omniox, and Sanofi Genzyme and has received personal compensation in an editorial capacity for UpToDate and Current Treatment Options in Cardiovascular Medicine.
American Academy of Neurology (AAN) 2018 Annual Meeting. Clinical Trials Plenary Session, Abstract 002. Presented April 24, 2018.
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Cite this: More Positive Results Released for Novel Huntington's Drug - Medscape - May 01, 2018.