Objective Evaluate the efficacy, safety and tolerability of deutetrabenazine for chorea in Huntington’s disease (HD).
Background Deutetrabenazine (SD-809) is a novel deuterium containing VMAT2 inhibitor. When deuterium, a naturally occurring form of hydrogen, is at specific sites, in this case CYP2D6 enzymatic targets on the tetrabenazine (TBZ) molecule, it prolongs active metabolite half-lives and reduces metabolic variability, without changing target pharmacology. Deutetrabenazine achieves comparable area under the curve (AUC) with lower total daily dose and dose frequency than TBZ.
Methods First-HD was a randomised, double-blind, placebo-controlled trial with 8 weeks of titration to adequate chorea control plus a 4-week maintenance. The ongoing open-label ARC-HD has 2 groups: First-HD participants now in a long-term safety study; and patients switched overnight from TBZ to an AUC-matched deutetrabenazine dose with optional dose adjustments after 1 week.
Results 90 subjects (45:45) enrolled in First-HD (44% female, mean age = 53.7). The total maximal chorea (TMC) score on deutetrabenazine improved by 2.5 points (21%) over placebo from baseline to end maintenance (p < 0.0001). Significantly improved secondary endpoints were patient and clinical global impressions of change (each p = 0.002) and SF-36 physical functioning scale (p = 0.03). The deutetrabenazine group had a mean BMI gain of 0.6 (0.2) kg/m2, compared with a loss in the placebo group of 0.1 (P = 0.002). Mean deutetrabenazine daily dose at end treatment was ~40 mg. Three subjects terminated early, 2 on placebo. In First-HD, the most common AEs in all subjects were irritability (deutetrabenazine 6.7% vs. placebo 13.3%), somnolence (11.1% vs. 4.4%), dry mouth (8.9% vs. 6.7%) and dizziness (4.4% vs. 8.9%). Depression, anxiety, akathisia and parkinsonism were reported at same or lower rates for deutetrabenazine vs placebo.
36 HD patients (60% male, mean age 52.4) with adequately controlled chorea on stable TBZ doses for at least 8 weeks enrolled in ARC-HD. Mean TMC change from baseline was −0.8 at both week 1 and 4. The mean TBZ dose was 41 mg; mean deutetrabenazine dose weeks 1 and 4 was 20 mg and 29 mg. 21 patients at week 8 had an improvement of −1.9 (SE 0.8) in TMC, with mean deutetrabenazine dose 33 mg.
Conclusions Deutetrabenazine can effectively and safely reduce chorea in HD. Improved functional and quality of life measures suggest effective chorea treatment with good tolerability and twice-daily dosing can provide clinically meaningful benefit. HD patients can safely and rapidly convert from TBZ to open-label deutetrabenazine.
- quality of life