Clinical development of valbenazine for tics associated with Tourette syndrome.

Introduction: Significant need exists for effective, well-tolerated pharmacologic treatments for Tourette syndrome (TS). Medications that inhibit vesicular monoamine transporters (i.e. VMAT2 inhibitors) downregulate presynaptic packaging and release of dopamine into the neuronal synapse and are effective in treating hyperkinetic movement disorders such as Huntington's chorea and tardive dyskinesia (TD); thus, they may be useful in treating TS.Areas covered: This review describes the clinical program evaluating the safety and efficacy of valbenazine in the treatment of involuntary tics associated with TS in adult and pediatric subjects. While there was a trend in the 6 completed trials toward greater improvement in valbenazine-treated versus placebo subjects on the primary efficacy endpoint (Yale Global Tic Severity Scale Total Tic Score), this difference did not reach statistical significance. Valbenazine was generally well-tolerated in the studies, and treatment-emergent adverse events were consistent with valbenazine studies in TD.Expert opinion: Due to the failure to meet the primary endpoint in these trials, further investigation of valbenazine for TS is unlikely. Given the need for safe and effective TS therapies and the key role of VMAT2 in modulating dopaminergic activity, it is reasonable for future studies to investigate other VMAT2 inhibitors as potential treatments for TS.

Cardiovascular Profile of Valbenazine: Analysis of Pooled Data from Three Randomized, Double-Blind, Placebo-Controlled Trials.

INTRODUCTION: Valbenazine is a novel vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. OBJECTIVE: Using data from double-blind, placebo-controlled trials, analyses were conducted to evaluate the cardiovascular effects of once-daily valbenazine in patients with a psychiatric disorder who developed tardive dyskinesia after exposure to a dopamine-blocking medication. METHODS: Data were pooled from three 6-week, double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Data from the 42-week valbenazine extension period of KINECT 3 were also analyzed. Outcomes of interest included cardiovascular-related treatment-emergent adverse events, vital sign measurements, and electrocardiogram parameters. RESULTS: The pooled safety population included 400 participants (placebo, n = 178; valbenazine 40 mg/day, n = 110; valbenazine 80 mg/day, n = 112). A history of cardiac disorders was present in 11.8% of participants, and 74.3% were taking a concomitant medication with known potential for QT prolongation. Mean changes from baseline to week 6 in supine vital signs and QTcF (Fridericia correction) were as follows for placebo, valbenazine 40 mg/day, and valbenazine 80 mg/day, respectively: systolic blood pressure (0.2, - 2.1, - 1.8 mmHg), diastolic blood pressure (- 0.1, - 1.6, - 1.2 mmHg), heart rate (- 1.7, - 2.2, - 1.7 bpm), QTcF interval (1.2, 1.1, 2.1 ms); all p > 0.05 for valbenazine vs. placebo. No statistically significant differences were observed between placebo and valbenazine in cardiovascular-related, treatment-emergent adverse events. No notable additional effects on cardiovascular outcomes were found with up to 48 weeks of valbenazine treatment. CONCLUSIONS: Results from double-blind, placebo-controlled trials showed no apparent difference between valbenazine and placebo on cardiovascular outcomes. No additional cardiovascular risk was detected during a longer extension study with valbenazine.