(#53) Once-Daily Valbenazine Demonstrates Greater and More Predictable Exposure Than Deutetrabenazine Extended-Release: Results From a Positron Emission Tomography Study in Healthy Male Adults

Abstract: Responses from patient and clinician surveys indicate that individuals with tardive dyskinesia (TD) would benefit from a simple, predictable, and clinically effective treatment option for their TD. Vesicular monoamine transporter 2 (VMAT2) inhibition is the proven target for successfully treating TD. A relationship between VMAT2 target occupancy (TO) and clinical efficacy (Abnormal Involuntary Movement Scale [AIMS] response) has been predicted in analyses that link ~70-80% TO with clinically meaningful efficacy in TD. This crossover study was conducted to measure VMAT2 TO after single doses of two VMAT2 inhibitors: valbenazine (VBZ), a once-daily medication; and deutetrabenazine extended-release (DTBZ XR), a once-daily formulation of DTBZ with no published clinical safety/efficacy data. Healthy male participants (N=8) received VBZ (40 or 80 mg) followed by ≥7-day washout and then DTBZ XR (24 or 48 mg), or vice-versa. Positron emission tomography (PET) scans were conducted when plasma concentrations for the active dihydrotetrabenazine (HTBZ) metabolites were expected to be maximal. A linear mixed-effects model yielded a least-squares mean VMAT2 TO of 76.5% for VBZ doses and 38.3% for DTBZ XR doses (P=0.0002). Predicted steady-state VMAT2 TO levels were higher for VBZ at every dose than any dose of DTBZ XR. Exposure-occupancy and plasma concentration analyses of HTBZ metabolites indicated greater inter-individual variability with DTBZ XR and a more consistent, dose-dependent pattern with VBZ, suggesting more predictable inter-individual exposure and response with a once-daily medication (VBZ) than with a once-daily formulation (DTBZ XR).

Short Description: Patient and clinician surveys indicate that patients with tardive dyskinesia (TD) would benefit from a simple, predictable, clinically effective treatment. VMAT2 inhibition is proven to treat TD, and analyses suggest a relationship between VMAT2 target occupancy and clinical efficacy. VMAT2 target occupancy and drug metabolite plasma concentration results after single-dose administration of VMAT2 inhibitors suggest higher, clinically meaningful potency and more predictable exposure with a once-daily medication (valbenazine) than with a once-daily formulation (deutetrabenazine extended-release).

Name of Sponsoring Organization(s): Neurocrine Biosciences, Inc.