Valbenazine improves tardive dyskinesia in schizophrenia
The novel VMAT2* inhibitor valbenazine (NBI-98854) significantly improved tardive dyskinesia in individuals with schizoaffective disorder, schizophrenia, or mood disorder, and was generally well tolerated with maintenance of psychiatric stability, according to the KINECT 3** study.
Tardive dyskinesia can be a disabling, and often, persistent condition, which results from long-term exposure to dopamine receptor blockers. Hallmark symptoms include involuntary movements such as lip pursing, lip smacking, and tongue movements.
“One approach to managing tardive dyskinesia is to discontinue antipsychotic treatment or reduce the dosage, but these options are not always feasible, because withdrawal can exacerbate tardive dyskinesia symptoms or have a negative impact on psychiatric status,” said the researchers. “Moreover, tardive dyskinesia symptoms often persist even after discontinuation or dosage reduction.”
Valbenazine is the first drug approved for tardive dyskinesia by the FDA recently, more than 50 years after the condition was first identified.
After 6 weeks, participants treated with valbenazine 80 mg/day saw a significantly greater reduction from baseline in dyskinesia score assessed on Abnormal Involuntary Movement Scale (AIMS) compared with placebo (-3.2 vs -0.1; p<0.001). This observation in the intent-to-treat group was further supported by similar result in the per-protocol analysis (-3.7 vs -0.1; p<0.001). [Am J Psychiatry 2017;174:476-484]
Similarly, valbenazine 40 mg/day treatment also improved AIMS dyskinesia score more than placebo at week 6 (-1.9 vs -0.1; p=0.002), with supporting results in favour of valbenazine in the per-protocol analysis (-2.3 vs -0.1; p<0.001).
“Differences in AIMS dyskinesia score change from baseline were evident in both of the valbenazine treatment groups compared with placebo at [as early as] week 2 ([the] first on-treatment study visit),” observed the researchers.
Although the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) score at week 6 was not significantly different between valbenazine (at either dosage) and placebo in the intent-to-treat group, the per-protocol population, which excluded those (assigned to the valbenazine group) with undetectable plasma level of valbenazine at week 6 (n=17), showed significant improvements in favour of valbenazine (p=0.011 for both valbenadine dosages vs placebo).
“Such results underscore the importance of including prespecified, objective measures to quantify the impact of nonadherence in clinical trials,” said the researchers.
The most frequent treatment-emergent adverse events (TEAEs) for valbenazine (both dosages) vs placebo were somnolence (5.3 percent vs 3.9 percent), dry mouth (3.3 percent vs 1.3 percent), and akathisia (3.3 percent vs 1.3 percent), while suicidal ideation occurred more commonly in the placebo group (5.3 percent vs 2.6 percent in the valbenazine groups combined).
Of the serious TEAEs reported in 13 participants, all were considered to be “not related” or “unlikely to be related” to the study drug, except one viral hepatitis reactivation case in the valbenazine 80 mg/day group which was deemed “possibly related” to the drug. There were no psychiatric stability-related safety signals from any treatment group.
The double-bind phase III trial randomized 225 participants with schizoaffective disorder, schizophrenia, or mood disorder, who also had moderate or severe tardive dyskinesia, to once-daily valbenazine (80 mg/day or 40 mg/day) or placebo in a 1:1:1 ratio for 6 weeks.
“Both valbenazine dosages were generally well tolerated, even as participants were taking a wide range of concomitant medications,” said the researchers, noting that 85.5 percent of the participants were on concomitant antipsychotics.
Due to the short study duration, the long-term efficacy and safety of the drug remained unclear, but follow-up study with a 42-week extension and an ongoing 52-week study in KINECT 4 would be expected to inform about the long-term effects, according to the authors.