Promising Results for Huntington's Disease Chorea Drug

Pauline Anderson

July 05, 2016

A deuterated form of the drug tetrabenazine significantly reduces chorea, increases weight, and improves quality of life compared with placebo in patients with Huntington's disease, a new study suggests.

"We expected that deutetrabenazine would reduce chorea, and it did, but I think the most surprising or interesting finding was the tolerability and the safety profile," lead investigator Samuel Frank, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, and member of the Huntington Study Group (HSG), told Medscape Medical News.

"We have decades of experience and data to support its use of tetrabenazine, but there are some limitations with it, and that's where deutetrabenazine may play a role," he added.

Dr Samuel Frank

Such limitations include having to take the drug 3 times daily and side effects such as depression.

The study was published online July 5 in JAMA.

Only FDA-Approved Treatment

Tetrabenazine (Xenazine, Lundbeck Inc) is a vesicular monoamine transporter type 2 inhibitor that depletes monoamines, including dopamine, in the central nervous system. It is the only therapy to treat chorea associated with Huntington's disease that is approved by the US Food and Drug Administration (FDA).

To develop the new drug, deutetrabenazine (Teva Pharmaceutical Industries Ltd), certain hydrogen atoms in tetrabenazine were exchanged for the heavier hydrogen isotype deuterium. This structural change resulted in a drug that doesn't break down as fast or have the same peaks in terms of the concentration, enabling less frequent dosing, said Dr Frank.

The double-blind study included 90 patients at 34 centers in the United States and Canada. Of these participants, 45 were randomly assigned to deutetrabenazine and 45 to placebo.

The two groups were similar in terms of Huntington's disease characteristics, including stage of disease, although the deutetrabenazine group had a higher baseline Berg Balance Test score (mean, 51.3 vs 48.4).

Patients were titrated to an optimal drug dose over 8 weeks, followed by 4 weeks of maintenance therapy. The study drug was administered in 2 doses daily, approximately 10 hours apart.

For the primary analysis, researchers used the Unified Huntington's Disease Rating Scale (UHDRS) total maximal chorea score, which ranges from 0 to 28, with a lower score indicating less chorea. The score is the sum of maximal chorea scores for seven body regions (face, buccal-oral-lingual region, trunk, and four extremities), each of which is scored on a scale from 0 to 4.

The investigators found that patients in the deutetrabenazine group had a mean –4.4 (95% confidence interval [CI], –5.3 to –3.6) improvement in total maximal chorea score, compared with the placebo group, which improved by –1.9 (95% CI, –2.8 to –1.1), with a treatment difference of –2.5 (95% CI, –3.7 to –1.3; P < .001).

Although there is no well-accepted minimal clinically important difference for total maximal chorea score, the authors noted that the improvement in the current study is in line with that of the pivotal trial of tetrabenazine (published in 2006).

As for secondary endpoints, the 36-Item Short Form Health Survey physical functioning subscale score improved by 0.7 (95% CI, –2.0 to 3.4) in the deutetrabenazine group and worsened by –3.6 (95% CI, –6.4 to –0.8) in the placebo group, for a treatment difference of 4.34 (95% CI, 0.4 to 8.3; P = .03).

More patients in the treatment than in the placebo group improved on the Patient Global Impression of Change and on the Clinical Global Impression of Change scales, which were rated on a 7-point Likert scale ranging from "very much improved" to "very much worse." The difference on both of these scales was statistically significant compared with placebo.

There was no significant difference in improvement in Berg Balance Test.

The UHDRS total motor score improved by –7.4 (95% CI, –9.1 to –5.6) in the deutetrabenazine group vs a change of –3.4 (95% CI, –5.1 to –1.6) in the placebo group, for a mean between-group difference of –4.0 points (95% CI, –6.5 to –1.5; P = .002).

Changes from baseline were not significantly different for the Montreal Cognitive Assessment or the UHDRS cognitive, behavioral, or functional measures.

The number of patients experiencing adverse events overall was similar in the two groups. These adverse events were generally mild to moderate. Serious adverse events occurred in 1 patient (2.2%) per group.

The treatment group appeared to experience less depression, noted Dr Frank. Two of these patients (4.4%) had depression or agitated depression compared with 3 patients (6.7%) in the placebo group.

According to Dr Frank, the original 2006 tetrabenazine study showed depression in almost 20% of patients taking that drug.

"This is concerning in someone with Huntington disease because 50% of them have depression, anxiety, or both anyway."

While all participants in the current study started off with "normal" swallowing, those in the deutetrabenazine group had some improvement, while the placebo group remained about the same, said Dr Frank. But he cautioned about making too much of this finding.

"Those on deutetrabenazine had improvement, but it was from normal to more normal."

Unexpected Findings

But a more striking finding was that the treatment group had a gain in body mass index (BMI) of 0.6 while the placebo group lost 0.1 BMI. The mean between-group difference was 0.7 (95% CI, 0.3 - 1.2; P = .002).

"There has been very little that has been shown to increase weight in Huntington disease, so this is a very exciting finding," said Dr Frank.

While this weight gain may not seem that impressive, Dr Frank stressed that "it's in the right direction" and that patients with Huntington's disease typically lose weight.

"And remember that this was only after 12 weeks of exposure to the drug," he said.

Another somewhat unexpected benefit of deutetrabenazine was improvement in dystonia. Researchers don't know why it improved, but a possibility is that because of the tolerability profile, patients were able to take a high enough dose to affect dystonia, said Dr Frank.

While 8.9% of the treatment group reported diarrhea, none in the placebo group did. But Dr Frank pointed out that gastrointestinal issues are "remarkably common" in patients with Huntington's disease.

Dr Frank believes there's a need for another drug to treat chorea in these patients.

"It's important to note that we saw overall benefit, not just in chorea," he said. "We saw an improvement in the quality of life as well as on measures such as weight, and those are important considerations when choosing the best medication for our patients."

The company is developing the drug for other hyperkinetic movements disorders, including tics and tardive dyskinesia, said Dr Frank.

Limitations and Caveats

In an accompanying editorial, Michael D. Geschwind, MD, PhD, and Nick Paras, PhD, University of California, San Francisco, called the study "well-done" and "clearly presented."

However, they noted that it's not possible from this study to determine how this drug holds up to tetrabenazine.

While a comparison of the current trial with the prior tetrabenazine trial is limited by several important factors, including the fact that patients in the deutetrabenazine trial overall had worse motor symptoms, the editorialists note that the results of the two studies appear similar in terms of efficacy.

In the tetrabenazine study, there was a 3.5-unit improvement (23.5% reduction) in the total maximal chorea score compared with 2.5-unit improvement (21% reduction) in the current deutetrabenazine trial.

In addition to deutetrabenazine's more favorable adverse effect profile, its twice-daily dosing is preferable to the three-times-daily dosing generally required for tetrabenazine, Dr Geschwind and Dr Paras point out.

"This is particularly true for patients with Huntington disease who might have difficulty with medication adherence due to cognitive impairment, swallowing problems, and behavioral issues."

From a clinician's standpoint, an ideal trial might compare deutetrabenazine, tetrabenazine, and placebo and also compare deutetrabenazine head-to-head with tetrabenazine.

Noninferiority trials, however, require much larger sample sizes, are more costly, and have a higher likelihood of an inconclusive result, note the editorialists.

The current study should be interpreted in light of "several caveats and limitations."

Because the trial was relatively short — consisting of only 12 weeks of therapy — the sustainability of benefit over a period is not known, they note.

Other remaining issues include understanding why deutetrabenazine had a slight benefit in dystonia and was associated with increased diarrhea, "both of which were not observed in the tetrabenazine trial."

It is hoped that data from the ongoing Alternatives for Reducing Chorea in Huntington Disease study will support the preliminary findings from this new trial and that "additional research will validate the potential approach of deuterating certain compounds to make safer, longer-lasting drugs," the editorialists conclude.

Dr Frank reports receiving grants from the Huntington Study Group (HSG). Dr Geschwind reports receiving research grants from National Institute on Aging, Quest Diagnostics Inc,?Tau Consortium, and CurePSP; has served as a consultant for Lundbeck Inc and other groups; and has received travel support from Teva Pharmaceuticals. Dr Paras reports research support from Daiichi-Sankyo, US Department of Defense, and the Tau Consortium.

JAMA. Published online July 5, 2016. Abstract Editorial

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