The beginning of 2015 was a turning point for drug trials in HD—the end of one era, and the start of a new one. In 2014, two of the longest-running trials of drugs for HD ended in disappointment. But this year, five major clinical trials for HD drugs are either underway or almost ready to launch, including the first tests of a new wave of HD drugs. These new trials build upon what’s been learned about the disease. Most of them precisely target specific areas or processes in the brain, and some are using new sensitive measures that can indicate when a drug is working. One was even designed to directly counteract the mutant protein that causes HD.
Many HD researchers think that with this new knowledge, trials are more likely to succeed. “If there were no other trials, I’d be feeling down right now,” says Jeff Carroll PhD, an HD scientist at Western Washington University in the US, who is himself gene positive. Instead he is guardedly optimistic that these trials will either identify effective treatments or at least generate lots of valuable information that can lead the way towards an effective HD treatment. “It’s a new era in terms of the drugs being tested, and in terms of the quality of the data we can collect,” he says. The knowledge gained from each trial makes the subsequent ones more efficient. Improvements such as more sensitive tests and better designed trials that quickly recruit participants at the most appropriate stage of their disease should make it easier to find out faster whether a drug is working. That way, volunteers only have to stay in a study for six months or a year rather than for many years in a row.
“We know so much more now about HD biology,” says George Yohrling PhD, Senior Director of Mission and Scientific Affairs for the Huntington’s Disease Society of America. “Our understanding of the biology has progressed to where we’re testing better hypotheses.”
Good news and bad
CREST-E and 2CARE, the two long-running studies that ended in 2014, were both based on the idea that since HD seems to cause energy deficits in brain cells, helping cells produce more energy might improve symptoms. It’s a reasonable idea, and both compounds in these studies, coenzyme Q10 (or CoQ10) and creatine, are familiar dietary supplements that are thought to be fairly safe. But their influence on cells is very broad, rather than the kind of precise treatment that many researchers think will be necessary to make a big difference in HD, and neither of them helped. “They’re more generally like topping up the gas tank, as opposed to finding out where the leak is,” says Carroll. Some researchers weren’t convinced that either compound could actually penetrate the brain’s natural defenses and get inside brain cells to change how they function.
If there’s any good news it’s that at least both of these studies produced clear and definitive answers—they didn’t work. The much better news is that a number of other important drug trials also launched in 2014.
The more trials that are up and running, the more likely one is to succeed.
The LEGATO-HD study launched in November 2014 to test laquinimod, a drug that is intended to reduce the inflammation in brain cells that makes them function poorly and eventually die off. It is scheduled to enroll 400 people and finish in 2017. The Pride-HD trial, which enrolled its first volunteer in March 2014, is testing pridopidine, a drug that changes how brain cells use the neurochemical dopamine to communicate. In two previous studies pridopidine seemed to reduce movement symptoms in HD, and this study tests the drug at a higher dose to see if that has stronger effects. This study is expected to be finished collecting data by early 2016.
Also now underway are two trials in North America and Europe testing a phosphodiesterase (PDE10A) inhibitor that is designed to influence brain cell communication and prevent cells from dying. Data for one small trial of this drug has already been collected and is now being analyzed; a larger study is still recruiting participants in the US, Canada, UK, Poland and Germany. This year should also see the start of a European trial to test deep brain stimulation (DBS), a therapy that uses a tiny electrode surgically implanted into the brain to deliver a small electrical current that changes how brain cells function and may improve movement as well as mood and cognition. Although it sounds like science fiction, a similar therapy is used fairly routinely in Parkinson’s disease to help with movement control, and a previous small study in Germany had promising preliminary results for HD.
“We’re clearly at a phase where these trial announcements are going to come much faster than in the past,” says Carroll. And the more trials that are up and running, the more likely one is to succeed.
Still in the works is the official start of the Isis Pharmaceuticals study of antisense oligonucleotides (ASOs), a trial that many in the HD research community have been particularly eager to see. Expected to launch later in 2015, this study tests ASOs that are designed to reduce the amount of huntingtin protein (the product of the HD gene) in the brain. This would be the first test of so-called huntingtin-lowering therapies, an idea that has been discussed for a long time in the HD community and shown promise in mouse models, but has not yet been tested in people. Several other approaches to reducing huntingtin are already in advanced development. “We’re optimistic that it will be the first of many trials to lower huntingtin,” says Yohrling.
The best way to put it might be that 2014 combined set-backs with new horizons. In a blog post last November on the website HD Drug Works, patient advocate LaVonne Goodman, MD called 2014 a “yin-yang year,” since it brought both failures and the launch of promising new approaches. And 2015 may turn out to be not so different, calling for a mix of realism and optimism. “The HD community is pretty realistic,” says Goodman. “Disappointment is OK, if you can get up from it. And I do think the community will rebound.”
This story was originally published in the Spring 2015 issue of Enroll!