Several clinical trials have tested the efficacy and safety of valbenazine and deutetrabenazine in patients with TD.
VMAT2 inhibitors have shown promise in clinical trials for treating tardive dyskinesia (TD), according to an article recently published in Tremor and Other Hyperkinetic Movements.
Lead author Mohadese Golsorkhi, MD, and colleagues conducted a systematic review to analyze the efficacy and safety of deutetrabenazine and valbenazine for patients with TD.
“The prevalence of TD for lifetime exposure is 13.1% for second-generation antipsychotics and 32.4% for first-generation antipsychotics. Moreover, around 20%-35% of people who have been prescribed antipsychotics for a minimum of three months encounter TD,” Dr. Golsorkhi and colleagues wrote. “TD symptoms can significantly affect a patient’s quality of life and lead to significant physical disability in severe cases.”
Using PubMed, Cochrane Library, Embase, and clinicaltrials.gov, the authors identified relevant articles published between January 2017 and October 2023. A total of 230 articles populated in the initial search, out of which four randomized, double-blind clinical trials met the authors’ inclusion criteria.
Valbenazine Demonstrates Efficacy
Two of the four clinical trials tested valbenazine: the KINECT-3 study, conducted with 205 patients across North America; and J-KINECT, which included 259 patients from Japan.
Patients in the KINECT study received placebo, valbenazine 40 mg/day, or valbenazine 80 mg/day for six weeks. Valbenazine produced significant decreases in AIMS scores at six weeks (-3.2 valbenazine 80 mg vs. -0.1 placebo, P<0.001) and 52 weeks (-4.8 valbenazine 80 mg vs. -3.0 valbenazine 40 mg, P<0.001).
At week six, there were no significant differences in CGI-TD and PGI-TD scores between the valbenazine and placebo groups. Researchers noted, however, that patients achieved clinically meaningful improvements in both scales during long-term treatment.
In the J-KINECT study, patients were randomly assigned to receive placebo, valbenazine 40 mg/day, or valbenazine 80 mg/day. Then, after six weeks, those who started on placebo were reassigned to receive 40-mg or 80-mg valbenazine for 42 more weeks.
“Patients receiving either 40 or 80 mg/day of [valbenazine] consistently showed decreased AIMS scores throughout the study. Those who transitioned from placebo to [valbenazine] also experienced a significant change,” Dr. Golsorkhi and team wrote.
Both groups receiving valbenazine sustained improvements in AIMS scores through week 48. In addition, at week six, least-squares (LS) mean CGI-TD scores improved in both the lower dose (2.8, P=0.021) and higher dose (3.0, P<0.001) valbenazine groups as compared to placebo (3.4).
Deutetrabenazine Improves Function
Both deutetrabenazine trials included in the review included patients in the U.S. and Europe.
In the ARM-TD study, researchers evaluated deutetrabenazine versus placebo in 117 patients with moderate-to-severe TD. Patients received 6 mg of deutetrabenazine twice daily, and then investigators titrated doses by 6 mg/week for six weeks until patients achieved adequate TD control, experienced a significant AE, or reached the maximum allowable dose of 48 mg/day.
At week four, AIMS scores decreased by 2.6 in the deutetrabenazine group compared to 0.4 in the placebo group (95% CI, P=0.007). Deutetrabenazine also demonstrated significantly greater reductions in AIMS scores at week 12 (LS mean [standard error (SE)]: -3.0 [0.45] vs. -1.6 [0.46], P=0.019; treatment difference -1.4 [0.60], 95% CI -2.6 to -0.2).
“Although [the deutetrabenazine] group showed higher treatment success rates on the CGIC (48.2% vs. 40.4%), PGIC (42.9% vs. 29.8%), mCDQ-24 compared to placebo, these differences were not statistically significant,” Dr. Golsorkhi and colleagues wrote.
Meanwhile, in the AIM-TD study, 293 patients received placebo or deutetrabenazine in daily doses of 12 mg, 24 mg, or 36 mg. All patients started at 12 mg/day and then increased until they reached the dosage goal for their assigned group. Authors reported that “the LS mean AIMS score improved by -3.3 points (SE 0.42) in the 36 mg/day group, -3.2 points (SE 0.45) in the 24 mg/day group, and -2.1 points (SE 0.42) in the 12 mg/day group.”
From highest dosage to lowest, the treatment difference in each group was -1.9 points (SE 0.58, P=0.001), -1.8 points (0.60, P=0.003), and -0.7 points (0.57, P=0.217), compared to -1.4 points (0.41) for placebo.
“Patients receiving [deutetrabenazine] at doses of 24 and 36 mg/day had higher chances of achieving treatment success on the CGIC score than placebo (P=0.002 and P=0.011, respectively). [Deutetrabenazine] also showed a slightly better response on PGIC and mCDQ24 scores, but the difference was not statistically significant,” researchers wrote.
Safety Considerations & Clinical Significance
Treatment-related AEs occurred with both medications, with rates ranging from 19%-48.3% for deutetrabenazine and 45.7%-71.6% in studies of valbenazine. Only 5% of patients receiving VMAT2 inhibitors experienced serious AEs, and 1 in 10 patients required a dose reduction or discontinued treatment.
“The most common AEs for [deutetrabenazine] were headache (5%), somnolence (4%), diarrhea (4%), fatigue (3.5%), anxiety (3.5%), and nasopharyngitis (3.2%),” researchers noted. “The occurrence of side effects was comparable between [valbenazine] and placebo, with the most frequently reported being somnolence (12%), akathisia (4%), nasopharyngitis (3.1%), and insomnia (3.1%).”
Dr. Golsorkhi and coauthors concluded that valbenazine and deutetrabenazine were well-tolerated and efficacious for patients with TD. These agents offer significant advantages over tetrabenazine such as longer half-life, better tolerability, and fewer side effects, researchers wrote.
“The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations,” the authors said, adding that these agents offer “new hope for individuals affected by this challenging condition.”
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