The data behind the promising trial of a drug that blocks the production of a mutant protein that causes brain damage in people with Huntington disease—an inherited and ultimately fatal neurological disorder—were published today in The New England Journal of Medicine, giving an official imprimatur to news that first electrified the community of patients with the disease 17 months ago.
The results, originally announced in December 2017, were published alongside an editorial that called the trial “pathbreaking.” The new paper reports that the drug, a short stretch of synthetic DNA called HTTRx that blocks the production of the mutant protein huntingtin, is safe in humans; no serious adverse events were reported by the 46 people who participated in the trial. (Last summer, Science wrote in depth about the first participant, Michelle Dardengo.)
The results also provide details behind the source of excitement about the trial: that HTTRx reduced levels of huntingtin in the cerebrospinal fluid (CSF) that bathes the spinal cord—a proxy, it is hoped, for what is happening in the brain—by amounts that had reversed Huntington-like motor and cognitive symptoms in mice. And the reductions in the mutant protein in the CSF of patients were dose-dependent: Through a range of dosing levels, the bigger the dose, the more the reduction of the mutant protein.
The authors report, however, that symptoms of the disease were generally unchanged when the data were considered for each of five patient groups that received different doses, and “no meaningful differences were observed between patients who received placebo and patients who received HTTRx, regardless of the dose level.”
Now, all eyes are on a pivotal clinical trial that aims to enroll 660 people with Huntington disease. The first patient was enrolled in January, and the last patient data are expected to be collected in March 2022. Large enough and long enough to allow scientists to measure the drug’s impact on symptoms of the slowly progressive disease, the study should show whether the drug can deliver on its promise of slowing or stopping the course of the devastating disease.
Running the key trial is Roche of Basel, Switzerland, which licensed HTTRx from its developer, Ionis Pharmaceuticals of Carlsbad, California, in December 2017, and renamed it RG6042.