New Drug Improves Chorea Movements in Huntington Disease

Christin L. Melton, ELS

Washington, DC—Results from First-HD: A Huntington Disease Research Trial showed that the novel drug SD-809 significantly reduced the symptoms of chorea, an involuntary movement disorder, in people with Huntington disease (HD) and was well tolerated. SD-809 is a novel deuterated form of tetrabenazine, which is the only drug currently approved in the United States to treat chorea in patients with HD. It is being developed by Auspex Pharmaceuticals and the Huntington Study Group.  Samuel Frank, MD, associate professor of neurology at Boston University School of Medicine in Massachusetts and lead investigator for the First-HD study, presented the results on behalf of the Huntington Study Group during an oral session at the 67th Annual Meeting of the American Academy of Neurology in Washington, DC.

The phase 3, double-blind trial enrolled 90 patients with HD (mean age, 53.7 years) to SD-809 (n = 45) or placebo (n = 45). Eligible participants were required to have had no exposure to tetrabenazine or any agent that would have suppressed their chorea within the 6 months prior to enrollment. In an interview with Rare Disease Report, Dr Frank said participants were titrated over 8 weeks and maintained on treatment for 4 weeks. “We saw a statistically significant reduction in their chorea over that time,” he reported.

Mean improvement from baseline in the Total Maximum Chorea score was 2.5 points (21%) greater for people treated with SD-809 than for those given placebo (P <.0001). Mean improvement in total motor score was 4 points higher in the SD-809 arm than in the placebo arm, which also represented a statistically significant difference (P = .002).

“We also looked into whether SD-809 would provide meaningful change according to the people who participated. The Patient Global Impression of Change and quality of life, which are patient-reported outcomes, were both statistically improved for people taking SD-809,” said Dr Frank.

Although SD-809 has the same pharmacological mechanism as tetrabenazine, it contains atoms of deuterium, a heavier hydrogen isotope, at 6 locations where tetrabenazine contains regular hydrogen atoms. “Deuterium is a naturally occurring, nonradioactive form of hydrogen, with an extra neutron in the nucleus. It provides a much stronger bond—it’s like using industrial epoxy glue instead of hobby Elmer’s glue,” Dr Frank said.

Because of the tighter molecular bonds, the body takes longer to break SD-809 down into its active metabolites. Dr Frank said this allows SD-809 to deliver the same amount of drug but over a longer time and with lower peak plasma concentrations. SD-809 is taken twice a day, whereas tetrabenazine must be taken 3 or even 4 times a day. Prior studies have shown that SD-809 achieves a similar area under the curve as tetrabenazine, but at half the dose. The maximum plasma concentration is also about half as high with SD-809 as it is with tetrabenazine.

“When we started [investigating SD-809], we theorized it would reduce the side effects people have with peak concentrations while maintaining efficacy, which is what we saw in First-HD,” Dr Frank said. More common adverse events included irritability, somnolence, dry mouth, and dizziness (see Table). “We really saw few cases of anticipated adverse events, such as depression, akathisia, and anxiety,” he said. In the abstract, the investigators noted that these adverse events actually occurred with greater frequency in the placebo arm.

Table. Common Adverse Events in First-HD

 Adverse Event, % SD-809 Placebo
 Dizziness 4.4 8.9
 Dry Mouth 8.9 6.7
 Irritability 6.7 13.3
 Somnolence 11.1 4.4
Dr Frank presented some unexpected findings at the meeting, including that significantly more patients in the SD-809 arm reported improved swallowing ability, and significantly more experienced weight gain than in the placebo arm. “People taking SD-809 had a 1.8-kg increase in weight versus a 0.3-kg loss in weight for people taking placebo, which is a really important improvement for people with HD. We’re not quite sure why the weight gain occurred, but it is probably due to a combination of factors, including the improvements in swallowing and chorea with SD-809,” said Dr Frank. In addition, once the data were unblinded, the researchers observed that participants with a CYP2D6 polymorphism had typically not required dose adjustments.

The First-HD trial is finished, but an open-label extension phase is ongoing. The ongoing Alternatives for Reducing Chorea in Huntington Disease (ARC-HD) trial, which has completed enrollment, is looking at the effects of switching people with HD who are taking tetrabenazine over to SD-809. “Results from ARC-HD will be presented at the International Parkinson and Movement Disorder Society meeting in June 2015,” Dr Frank said.


Frank SA; First-HD Investigators of the Huntington Study Group. First time use of SD-809 in Huntington Disease (First-HD). Paper presented at: 67th Annual Meeting of the American Academy of Neurology; April 18-25, 2015; Washington, DC.

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