Last month, Ionis Pharmaceuticals announced the long-awaited results of a clinical trial designed to test the safety and tolerability of a gene-silencing drug called IONIS-HTTRx in people with Huntington’s disease (HD). While details are scant (the results haven’t yet been reported in a peer-reviewed journal), the announcement comes as extremely encouraging news: the treatment not only appears safe and well tolerated, but the preliminary evidence also suggests the drug works as intended to reduce levels of the toxic huntingtin (HTT) protein that damages the brains and other organs of HD sufferers.
The trial enrolled 46 men and women between the ages of 25 and 65 who had been diagnosed with the early manifestations of HD in Canada, the U.K., and Germany. Participants received spinal injections of IONIS-HTTRx at increasing doses or a placebo every four weeks for three months.
“We knew we had these agents that have the effect of lowering HTT expression in cells and animals,” says Jeff Carroll, an HD researcher at Western Washington University in Bellingham who has long consulted with Ionis and is himself a carrier of the HD mutation. “That’s a nice trick, but mice don’t have Huntington’s. There was no reason to think it wouldn’t work in human cells, but it’s a whole other thing to actually see a drug that might actually be approved one day working in humans.”
Now, a refresher: In people with HD, a single mutant copy of the HTT gene is enough to lead to a deadly array of problems as abnormal HTT protein accumulates in the brain and body. The disease is characterized most prominently by uncontrolled movements that can leave disease sufferers appearing as if drunk. Despite decades of research including the discovery more than 20 years ago of the responsible gene, there has been and still is no cure for HD. The only treatments available target disease symptoms only and therefore do nothing to slow disease progression. People with HD rarely live more than 20 years beyond the onset of symptoms, which often strike in the prime of life. (For more about HD, read “Hunt to Stop a Killer.”
IONIS-HTTRx is an antisense oligonucleotide (ASO) — a synthetic strand of DNA — specially designed to target the mutant HTT gene and reduce levels of the unwieldy and ultimately deadly protein that gene encodes. In the press release, C. Frank Bennett, senior vice president of research at Ionis Pharmaceuticals, noted that the results of this first trial “substantially exceeded” their expectations. That’s because, in addition to demonstrating safety and tolerability, the findings include an observed dose-dependent reduction in HTT protein.
In other words, as trial participants received higher drug doses, the concentration of mutant HTT in their cerebrospinal fluid (CSF) declined accordingly. That’s promising because it suggests that the drug is not only safe, but it might actually work. (There’s evidence that HTT levels in CSF reflect what’s happening in the brain. And, Carroll says, there’s already clear evidence in animals that lowering HTT leads to improvement in HD-like symptoms.)
Carroll says caution is warranted given that not all the data is available. It’s surely not yet clear whether IONIS-HTTRx will alleviate and prevent symptoms in HD sufferers or pre-symptomatic carriers of the mutant gene. That answer will have to wait for the results of a larger, longer clinical trial or trials designed to test the drug’s efficacy. Still, the findings do provide early evidence in humans that the treatment strategy reaches its target and lowers HTT in the hoped-for way.
For people who’ve studied and suffered with HD for decades, it’s a really big deal. In an HD Buzz post issued the day of the Ionis announcement, Carroll noted that it was “likely to stand as one of the biggest breakthroughs in Huntington’s disease since the discovery of the HD gene in 1993.”
The findings come on the heels of an announcement in November by Alnylam that its drug, patisiran, halted progression of a rare, life-threatening condition called hereditary ATTR amyloidosis in 90 percent of people who received it. Patisiran is designed to work in a similar manner to IONIS-HTTRx, silencing a gene to reduce production of an offending protein, only using RNA interference in place of the antisense DNA. Carroll says there have been efforts to develop RNAi drugs in the case of HD, too. He notes, however, that ASOs are more easily delivered to the brain.
The next step for IONIS-HTTRx is for researchers to find out whether the HTT-lowering drug can help people already suffering with HD. Many, including Carroll, also hope that the drug could soon be tested on people known to carry the mutant HTT even before any symptoms emerge. It’s too soon to say how long it might take before more results could be in. That will depend on whether and how quickly lowering HTT in people with HD symptoms leads to improvements.
Meanwhile, the findings have already attracted the attention of Roche. Ionis announced that Roche has “exercised its option to license” the drug for a $45 million fee. Roche will now be responsible for the drug’s future development, regulatory, and commercialization activities.
“I hope in 2018, we’ll have a lot more information about the next trial,” Carroll says. “I’m hopeful it will be structured in a way so as to be a definitive trial, but that’s hope and speculation at this point.” Once the details of that next trial are announced, he says a clearer timeline will emerge.