Deuteration offers alternative chorea treatment for Huntington disease patients

By Lucy Piper

Treatment with a deuterated form of tetrabenazine has resulted in improved motor signs among patients with Huntington disease, making it a potential treatment for chorea, trial findings show.

Deutetrabenazine, a vesicular monoamine transporter type 2 inhibitor, is structurally related to tetrabenazine and has the same pharmacological activity, but the deuterium chemistry alters the drug metabolism, improving the risk-benefit profile.

The half-life of deutetrabenazine is nearly twice that of tetrabenazine, allowing it to be administered twice rather than three times a day, and at lower doses, thus reducing peak concentration adverse effects while maintaining efficacy, the researchers explain.

Among 45 patients randomly assigned to receive the drug for 12 weeks, total maximal chorea scores decreased by an average of 4.4 points, from 12.1 to 7.7. This compared with a 1.9-point improvement, from 13.2 to 11.3, for the 45 placebo-treated patients, giving a significant absolute difference of 2.5 points.

They say that the clinical relevance of their findings, published in JAMA, is not definitive, however, as a minimal clinically important difference for change in total maximal chorea score has yet to be determined.

But the study authors, led by Samuel Frank (Harvard Medical School, Boston, Massachusetts, USA), believe that the difference in favour of deutetrabenazine is "notable" given the progressive decline in such symptoms normally associated with the disease.

They add that there is the suggestion of clinical relevance given that deutetrabenazine treatment was also associated with significantly superior improvements on three of the four secondary outcomes.

Significantly more deutetrabenazine- than placebo-treated patients were classed as "much" or "very much" improved on the Patient Global Impression of Change (51 vs 20%) and the Clinical Global Impression of Change (42 vs 13%) and there was a significant 4.3-point treatment effect on the 36-item Short Form physical functioning subscale compared with placebo.

Patient- and clinician-reported outcomes were consistent, the researchers note, providing further support for the improvement in motor signs and symptoms associated with deutetrabenazine being clinically important.

The Berg Balance Test was the only secondary outcome that failed to show a significantly greater improvement with deutetrabenazine than placebo.

Deutetrabenazine was started at a dose of 6 mg/day administered in two doses daily, approximately 10 hours apart, and increased weekly by 6 mg/day until chorea was adequately controlled or clinically significant adverse effects were experienced, up to a maximum allowed dose of 48 mg. The overall adherence rates were 95.1% for the deutetrabenazine group and 94.1% for the placebo group.

There was no significant difference between the two groups with regard to adverse events, which were generally mild to moderate and occurred at a similar frequency. Somnolence was the most common event among patients taking deutetrabenazine and generally resolved without dose reduction.

Just three patients from each group required dose reduction and serious adverse events occurred in one patient each - cholecystitis and agitated depression with deutetrabenazine and chronic obstructive pulmonary disease exacerbation with placebo. Treatment was suspended in these patients and the problems resolved.

In a related editorial, Michael Geschwind and Nick Paras, both from University of California, San Francisco, USA, describe the study as "well-done" and "clearly presented", and they now call for a head-to-head comparison of deutetrabenazine and tetrabenazine.

"Assuming deutetrabenazine is not priced to be significantly more expensive than tetrabenazine, the favorable profile of deutetrabenazine would offer an additional option for patients and clinicians, so physicians may consider prescribing deutetrabenazine over tetrabenazine, if and when the drug is approved", they comment.

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JAMA 2016; Advance online publication


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