麻豆传媒

Deuterated tetrabenazine (Austedo) diminished abnormal involuntary movements in patients with tardive dyskinesia due to psychiatric drugs, researchers found.

In the phase III AIM-TD trial, patients taking 24 mg or 36 mg of deutetrabenazine daily had a significant decline in Abnormal Involuntary Movement Scale (AIMS) score compared with placebo over 12 weeks (-1.9 points, P=0.001, and -1.8 points, P=0.003, respectively), Karen Anderson, MD, of Georgetown University, and colleagues .

In April, the FDA approved the VMAT-2 inhibitor valbenazine (Ingrezza) for tardive dyskinesia (and FDA regulators for bringing it to market in the New England Journal of Medicine).

Two weeks earlier, FDA had approved deutetrabenazine for treating chorea in Huntington's disease. Its non-deuterated form, tetrabenazine (Xenaxine), has long been used to treat Huntington's chorea; deuterating the molecule allows for slower breakdown in the body.

Tetrabenazine has also been used off-label to treat tardive dyskinesia, though Anderson and colleagues noted concerns about "high peak concentrations and plasma fluctuations of this drug" and consequent adverse effects. Other strategies have included lowering the dose of the drug that's causing the problem, or switching to another drug. But with the positive findings on deutetrabenazine, clinicians may soon have two FDA-approved tardive dyskinesia drugs to choose from.

Deutetrabenazine was evaluated in two phase III trials: and . The researchers said that findings from ARM-TD informed the patient population used for the efficacy analysis in AIM-TD.

They enrolled 298 patients with tardive dyskinesia at 75 centers in the U.S. and Europe, who were randomized to placebo or to one of three doses of deutetrabenazine: 12, 24, or 36 mg/day in divided doses. A total of 222 patients with a baseline AIMS score of 6 or higher were evaluated in the modified intention-to-treat population for the primary efficacy sample.

Anderson and colleagues found that least-squares mean AIMS score improved by -3.3 points in the deutetrabenazine 36 mg/day group, by -3.2 points in the 24 mg/day group, and by -2.1 points in the 12 mg/day group, compared with -1.4 points in the placebo group.

Only the two higher doses performed significantly better than placebo.

The proportion of patients with an improvement of 50% or more in AIMS total score was significantly greater in the 36-mg and 24-mg groups (33% and 35% versus 12%). Odds ratios that patients on the two doses would achieve 50% AIMS improvement were 3.80 (95% CI 1.40-10.36) with 36 mg/day and 3.96 (95% CI 1.46-10.72) with 24 mg/day.

The frequency of adverse events was similar across groups, at 51%, 44%, 49%, and 47%, from the highest dose to placebo, the researchers said. There were two deaths, one in each of the 36-mg and 24-mg arms, but neither was deemed to be related to the study drug.

In an , Christoph Correll, MD, and Maren Carbon, MD, of Northwell Health in New York, noted that two-thirds of deutetrabenazine-treated patients were non-responders at week 12 in both the 36-mg and 24-mg groups.

But when a patient develops tardive dyskinesia "and stopping of the dopamine receptor antagonist, dose reduction, or switch to a lower-risk dopamine receptor antagonist is not feasible or ineffective, the only currently available, evidence-based treatments are deutetrabenazine or valbenazine."

They noted that many questions remain, such as what predicts a successful discontinuation after the resolution of tardive dyskinesia, and whether the drugs can prevent progression from early warning signs to more severe disease.

The availability of two new drugs should "stimulate research to answer these and related questions, as well as provide benefit to patients," the editorialists wrote.

FDA is expected to make its decision about deutetrabenazine for tardive dyskinesia by Aug. 30.