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‘Pathbreaking’ Ionis trial offers way forward in Huntington’s disease

An experimental drug developed by Ionis Pharmaceuticals and Roche could offer a way forward to treat Huntington’s disease, nearly three decades after researchers first pinpointed the gene behind the hereditary neurodegenerative disorder. 

Despite that known genetic link, no drugs currently exist to treat the underlying causes of the condition, which usually appears in a person’s 30s or 40s. Over time, Huntington’s leads to involuntary movements known as chorea, as well as cognitive and behavioral changes. 

Those symptoms, which become increasingly pronounced as the disease progresses, stem from extra genetic code tacked onto a gene called HTT. These so-called repeats result in the production of an elongated huntingtin protein that builds up in neurons, causing dysfunction and neuronal death. 

Ionis and Roche’s drug, known as RG6042, aims to stop that toxic protein from being made, which in theory would change the disease course. 

Data published in the New England Journal of Medicine on Monday suggest it could do just that. The Phase 1/2a study, which enrolled 46 patients with early Huntington’s, showed treatment with RG6042 was safe and led to dose-dependent reductions in the concentration of mutant huntingtin protein in the cerebrospinal fluid. 

While such reductions aren’t guaranteed to yield clinical benefits, the study is the first time that a targeted huntingtin-lowering agent has been shown to lower mutant protein levels. Ionis and Roche first disclosed topline results from the trial last spring. 

“This is a pathbreaking trial that strongly supports further development of [RG6042] as a treatment for Huntington’s disease,” wrote Kenneth Fischbeck of the National Institutes of Health and Nancy Wexler, a professor at Columbia University best known for her involvement in the discovery of the Huntington’s gene, in an editorial published in NEJM Monday.

Patients in the study were either given placebo or one of five dose levels of RG6042, injected intrathecally four times over the course of the study. Trial investigators took cerebrospinal fluid samples to gauge the concentration of mutant protein.

Measured against baseline levels, results found average reductions of 20%, 25%, 28%, 42% and 38% in huntingtin protein across the five increasing doses, respectively. The 12 patients given placebo, meanwhile, experienced an increase of 10%.

“The news we can lower mutant huntingtin protein in the cerebrospinal fluid is the best piece of news that’s emerged from any clinical trial in Huntington’s disease,” said Edward Wild, an author on the NEJM paper and a neurologist at University College London, in an interview. Wild has received financial support from both Roche and Ionis in his work at UCL.

Wild noted that the study results, however, still leave questions about the ultimate effect Roche and Ionis’ drug might have.

“Lowering mutant huntingtin protein doesn’t guarantee clinical efficacy,” he said. “We might see disease slowing, while the prospect of reversal is much more difficult to contemplate.” 

Wild and his colleagues noted such limitations in the NEJM publication: 

“Functional, cognitive, psychiatric, and neurologic clinical outcomes were generally unchanged at the dose-group level during the trial, and no meaningful differences were observed between patients who received placebo and patients who received [RG6042], regardless of the dose level.”

Researchers did conduct a post-hoc analysis, finding that protein reduction correlated to improvement on a disease rating scale. But such testing was exploratory and the study authors cautioned against reading too much into the correlation.

The reductions on the higher doses fell within the range of 30% to 50% that Roche had hoped to see, according to Scott Schobel, an associate group medical director at Roche. Animal models have suggested that lowering of those levels in the cerebrospinal fluid would achieve the necessary reductions in tissue to result in a therapeutic benefit, Schobel said in an interview. 

Most importantly for an early study, RG6042 was safe. No severe adverse events were reported and no patients discontinued or delayed treatment. Roughly 10% of patients who received the drug reported post lumbar puncture headaches, but researchers found no evidence that side effect was tied to trial duration or dose. 

RG6042 is a type of antisense oligonucleotide, designed to degrade the cellular messages that convey instructions for building proteins. The technology promises an “upstream” effect of how most drugs work currently, suppressing protein production rather than targeting the proteins themselves. 

Similar Ionis-developed drugs targeting spinal muscular atrophy and TTR amyloidosis are approved, and this initial success in Huntington’s gives further support to the biotech’s RNA-based approach. 

“[The results] bode well for Huntington’s disease, but also for other neurodegenerative diseases, particularly ones with similar types of mutations,” NIH’s Fischbeck said in an interview. 

Unlike gene therapy, antisense therapeutics would likely need to be given chronically for life. Disease progression in Huntington’s typically happens over the course of 15 to 20 years after diagnosis.