Higher VMAT2 Target Occupancy Observed in Valbenazine Over Deutetrabenazine Extended-Release Capsules

Neurocrine Biosciences recently announced that data from a first-of-its-kind head-to-head study showing that valbenazine (Ingrezza) had significantly higher vesicular monoamine transporter 2 (VMAT2) target occupancy (TO) compared with deutetrabenzaine extended release (Auestedo XR; Teva Pharmaceuticals), a comparator drug for dyskinesia.

The study, presented at the 64^th Annual Meeting of the American College of Neuropsychopharmacology, held January 12-15, 2025, in the Bahamas, utilized positron emission tomography (PET) imaging in patients to evaluate VMAT2 TO following single doses of either valbenazine (40 mg or 80 mg) or austedo XR (24 mg or 48 mg) over 4 PET visits. The trial, testing the two FDA-approved VMAT2 inhibitors, consisted of three cohorts, cohort 1 (n = 6) cohort 2 (n = 8) and cohort 3 (n = 4).

The primary outcome analysis, conducted in cohort 2 (mean age, 36 years [SD, 7]), showed a least square (LS) mean VMAT2 occupancy of approximately 76.5% with valbenazine compared with approximate percentages of 38.3% for deutetrabenazine XR. Overall, results indicated a between-group LS mean difference of 38.2% (P = 0.0002). In addition, pharmacokinetic exposure modeling incorperating data from cohorts 2 and 3 further estimated steady-state VMAT2 TO, demonstrating higher engagement with valbenazine across doses.

In the study, estimated steady-state TO was 83% and 92% for valbenazine 40 mg and 80 mg, respectively, compared with 54% and 70% for AUSTEDO XR 24 mg and 48 mg. In terms of safety of the study, all doses of valbenazine and deutetrabenazine XR were generally well tolerated and consistent with the known safety profile of each compound.

"In this head-to-head assessment, Ingrezza demonstrated approximately two-fold higher target occupancy compared with Austedo XR at therapeutic doses," said Sanjay Keswani, MD, Chief Medical Officer, Neurocrine Biosciences, in a statement.¹ "The significantly higher VMAT2 occupancy observed with Ingrezza adds to the already established differences between VMAT2 inhibitors in pharmacologic and clinical profiles. The high occupancy of Ingrezza may contribute to the robust early and sustained clinical efficacy consistently demonstrated in multiple tardive dyskinesia and Huntington's disease chorea clinical trials."

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A previous study involving valbenazine linked the treatment to positive, real-world changes in physical, social, and emotional outcomes in patients with tardive dyskinesia (TD). Titled KINECT-PRO, the open-label, phase 4 post-marketing study, comprised a 4-week screening period, followed by a 4-week initial loading phase, and a 12-week treatment period in patients with TD. Participants began treatment with 40 mg of valbenazine during the loading phase, with the option to either remain on that dose or increase to 60 mg or 80 mg. Coming into the study, patients had at least mild TD severity, per Abnormal Involuntary Movement Scale (AIMS) item 8, and mild or worse associated distress from their dyskinetic movements (AIMS item 10).²

Led by Joseph McEvoy, MD, Case Distinguished Chair in Psychotic Disorders, at the Medical College of Georgia, 52 of the originally enrolled 59 participants (mild TD: n = 24; mod/severe TD: n = 35) completed week 24 visit, with 45 included in the efficacy analyses. After 24 weeks of treatment, those on valbenazine saw several positive impacts on a number of patient-reported outcome (PRO) measures, with these changes observed as early as week 4.

The study results, presented at the 2025 International Parkinson and Movement Disorders Society Congress (MDS), held September 5-10 in Hawaii, displayed mean changes of –6.8, –8.9, and –8.0 in Tardive Dyskinesia Impact Scale (TDIS) for the mild, moderate/severe, and overall cohorts, respectively. On Sheehan Disability Scale (SDS), these groups reported mean changes of –1.8, –2.8, and –2.3 for social life, and –1.3, –1.8, and –1.6 for family life. In addition, positive impacts were seen on EQ-5D-5L visual analog scale (+12.8, +13.3, and +13.1).²

REFERENCE
1. Neurocrine Biosciences Presents Head-to-Head INGREZZA® (valbenazine) Capsules Data Demonstrating Higher VMAT2 Target Occupancy Compared to AUSTEDO XR. Neurocrine Biosciences, Inc. News Release. January 15, 2026. Accessed January 16, 2026. https://www.prnewswire.com/news-releases/neurocrine-biosciences-presents-head-to-head-ingrezza-valbenazine-capsules-data-demonstrating-higher-vmat2-target-occupancy-compared-to-austedo-xr-302661800.html
2. Dunayevich E, Parameswaran A, Bron M, et al. Valbenazine Improves the Burden and Symptoms of Tardive Dyskinesia: Topline Results from the Phase 4 KINECT-PRO Study. Presented at: 2025 MDS Congress; October 5-10; Hawaii.