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T81

A HEAD-TO-HEAD ASSESSMENT OF VMAT2 TARGET OCCUPANCY OF ONCE-DAILY VALBENAZINE COMPARED TO DEUTETRABENAZINE EXTENDED RELEASE

Daniel Albrecht — Satjit Brar1, Wei Hou1, Hui Zhang1, Gena Riggs1, Shannon Ingersoll1, Jessica Maynard-Scott1, Ryan Terry-Lorenzo1, Ava Nguyen1, Zeynep Demir1, Christine Sandiego2, Cristian Constantinescu2, Eugenii A. Rabiner2, David S. Russell2, Dietrich Haubenberger1 1Neurocrine Biosciences, Inc., 2Perceptive, Inc.

2026 ASCP Annual Meeting

Background

Vesicular monoamine transporter 2 (VMAT2) inhibition is a known therapeutic mechanism for the treatment of tardive dyskinesia (TD) and chorea associated with Huntington’s disease (HD). A relationship between VMAT2 target occupancy (TO) levels and clinical efficacy was predicted in previous analyses of positron emission tomography (PET) data in non-human primates after administration of [+]-αdihydrotetrabenazine ([+]-α-HTBZ), which is the primary active metabolite of valbenazine (VBZ). However, VMAT2 TO levels associated with administration of FDA-approved VMAT2 inhibitors were yet to be assessed in humans. Therefore, we conducted the first study in healthy male volunteers to measure VMAT2 TO levels after single doses of oncedaily VBZ and deutetrabenazine extended release (DTBZ XR, an XR formulation of a previously developed VMAT2 inhibitor without published clinical safety and efficacy data).

Methods

The study included a cohort of 8 participants who had arterial input function for absolute quantification of PET data with analyzable pharmacokinetic (PK) data and who underwent a two-period crossover treatment design: VBZ (40 or 80 mg), followed by ≥7-day washout and then DTBZ XR (24 or 48 mg), or vice-versa (i.e., DTBZ XR, followed by washout and VBZ). [18F]AV-133 PET scans were conducted at the reported time of maximum plasma concentration (Tmax) for the active HTBZ metabolites for each compound: 4-8 hours post-dose for VBZ metabolite ([+]-α-HTBZ); 3-5 hours post-dose for DTBZ XR total metabolites (total of [+/-]-α-deuHTBZ and [+/-]-β-deuHTBZ). Outcomes included the following: VMAT2 TO, derived from volume of distribution (VT) in predefined brain regions of interest and modified Lassen plot analysis; relationship between plasma concentration of VBZ / DTBZ XR metabolites and VMAT2 TO (i.e., exposure-occupancy); predicted VMAT2 TO at steady-state; and plasma concentrations of VBZ / DTBZ XR metabolites for 24 hours after VBZ and DTBZ XR dose.

Results

VMAT2 TO levels were higher after single doses of VBZ (40 and 80 mg) than single doses of DTBZ XR (24 and 48 mg). The least-squares (LS) mean VMAT2 TO was 76.5% for VBZ and 38.3% for DTBZ XR, with a LS mean difference of 38.2% (P=0.0002). Population PK modeling was used to predict maximal steady-state HTBZ metabolite concentrations (Cmax) following daily VMAT2 inhibitor dosing. Estimated VMAT2 TO based on steady-state Cmax was higher with VBZ (82% for 40 mg, 92% for 80 mg) than with DTBZ XR (52% for 24 mg, 68% for 48 mg). 24-hour plasma concentrations of HTBZ metabolites showed less variability with VBZ than with DTBZ XR.

Conclusions

Substantially greater VMAT2 occupancy was found after single doses of VBZ than after single doses of DTBZ XR, as indicated by PET scans and higher predicted steadystate TO. In addition, less variability in plasma metabolite concentrations indicated a more predictable exposure with a once-daily drug (VBZ) than with a once-daily formulation (DTBZ XR).