Clinical development of valbenazine for tics associated with Tourette syndrome

Abstract

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.

Lack of Support for the Use of VMAT-2 Inhibitors for the Treatment of Tics in Tourette Syndrome

“…Valbenazine additionally failed to demonstrate efficacy in 2 phase 2, randomized, double-blind, placebo-controlled, fixed-dose studies of the treatment of Tourette syndrome: 1 in 120 adults (T-Forward) and 1 in adolescents and children (T-Force GREEN). 7 Furthermore, in the valbenazine studies, TEAEs were particularly frequent. For instance, in T-Forward (124 adults), 95.2% of the 80 mg valbenazine group and 73.8% of the 40 mg valbenazine group vs 52.5% of the placebo group reported TEAEs, most commonly somnolence, fatigue, akithesia, and headache.…”

Tourette Syndrome Treatment Updates: a Review and Discussion of the Current and Upcoming Literature

“…However, the phase 2/3 ARTIST1 and phase 3 ARTIST2 trials failed to reach the primary end point of tic reduction (NCT03567291, NCT03571256). The safety and tolerability of valbenazine for tics were established in the T-Force study but placebo-controlled trials in adults (T-Forward), pediatrics at fixed doses (T-Force green), and pediatrics at optimized doses (T-Force gold), as well as open-label extension studies (T-Fusion and T-Force gold +) failed to meet the primary endpoint [ 90 ]. As a result, this class of medications is often reserved for cases that have been refractory to other classes or in whom potential side effect profiles favor avoiding other classes.…”

A Comprehensive Review of Tic Disorders in Children

“…Although open-label studies suggested benefit of VMAT2 inhibitors for tics [ 320 , 321 , 322 ], controlled trials of two tetrabenazine derivatives in TS unfortunately failed to show efficacy. An open-label study of children and adolescents with TS failed to show benefit of valbenazine, which is a purified parent drug of the (+)-α-isomer of tetrabenazine [ 323 ]. The other trial failed to show significant benefit of deutetrabenazine, a deuterated from of tetrabenazine (ARTISTS1; NCT03452943) ( (accessed on 01 June 2021)).…”