A deuterated form of the vesicular monoamine transporter type 2 inhibitor tetrabenazine, called deutetrabenazine, modestly reduced chorea of Huntington disease over 12 weeks in a phase III, double-blind, randomized, placebo-controlled trial.
First author Samuel Frank, MD, of Beth Israel Deaconess Medical Center in Boston and his colleagues in the Huntington Study Group wrote that the observed treatment effect of 2.5 points on the primary end point of total maximal chorea score, “taken together with improvements in patient-centered end points, such as PGIC [Patient Global Impression of Change] and SF-36 [36-Item Short Form] physical functioning component scales, may be of clinical relevance, although this remains to be determined. The difference in total maximal chorea score associated with deutetrabenazine treatment that was observed in this study is notable given the progressive decline in total maximal chorea score and total motor score that has been previously described as part of the natural history of Huntington disease.”
The phase III trial is the first to use an active ingredient with deuterium substituted for hydrogen at key positions. The use of deuterium in the molecule, according to the investigators, prolongs “plasma half-life and reduce[s] metabolic variability, without changing target pharmacology,” and its “longer half-life and unique pharmacokinetic profile … may enable less frequent and lower daily doses, thus achieving similar systemic exposure with lower peak concentrations and simplified dosing, compared with tetrabenazine.”
Tetrabenazine (Xenazine) is used worldwide and is the only U.S. Food and Drug Administration–approved therapy for treating chorea associated with Huntington disease.
The trial enrolled 90 patients with genetically diagnosed Huntington disease across 34 centers in the United States and Canada. The patients had a baseline total maximal chorea score of 8 or higher (range 0-28) and were randomized on a 1:1 ratio to receive deuterated tetrabenazine (deutetrabenazine) or placebo. The deutetrabenazine group had a mean age of 55 years and 49% were male. The placebo group had a mean age of 52 years and 62% were men. Patients on the active drug were commenced at a total daily dose of 6 mg (divided into two doses) for the first week. Doses were then increased weekly by 6 mg daily until either chorea was adequately controlled or the maximum dose of 48 mg a day was reached. The final dose was maintained for an additional 4 weeks for a total of 12 weeks, followed by a 1-week washout (JAMA 2016;316:40-50. doi: 10.1001/jama.2016.8655 ).
The total maximal chorea score, in which higher scores represent worse chorea, that was measured from baseline to an average across the maintenance period during weeks 9 through 12 of therapy declined by a statistically significant 4.4 points – from a mean of 12.1 to 7.7 – in the deutetrabenazine group, compared with a decline of 1.9 points – from a mean of 13.2 to 11.3 – in the placebo group.
Improvements in secondary endpoints such as PGIC and SF-36 physical functioning component scales were also seen in the treatment group, although no improvement was seen in the Berg Balance Test.
Adverse events were similar between the deutetrabenazine and placebo groups, including depression, anxiety, and akathisia.
“Further research is needed to assess the clinical importance of the effect size, and to determine longer-term efficacy and safety,” the study authors concluded.
The study was supported by Auspex Pharmaceuticals, a wholly owned subsidiary of Teva Pharmaceutical Industries. Dr. Frank reported receiving grants from the Huntington Study Group, and many other authors in the group reported financial ties to pharmaceutical companies, including Auspex and Teva. Several authors are employees of Auspex.