Valbenazine Effects on the Dopamine System in Humans, as Measured by [¹¹C]-PHNO Positron Emission Tomography (PET)

Ryan Terry-Lorenzo,¹ Daniel Albrecht, ¹ Satjit Brar, ¹ Brittany Harbert,¹ Graham Searle,² Frans Van Den Berg,² Ilan Rabiner,² and Dietrich Haubenberger¹

¹Neurocrine Biosciences, Inc., San Diego, CA, USA; ²Invicro, London, UK

Background: Valbenazine, a potent, selective, orally active vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved by the US Food and Drug Administration for the treatment of tardive dyskinesia (TD) at doses of 40 to 80 mg once daily. By inhibiting VMAT2, valbenazine disrupts the packaging of monoamines into synaptic vesicles, subsequently decreasing the release of monoamines including dopamine into the synaptic cleft. The reduction of dopamine is thought to be the foundational basis for the efficacy of valbenazine in treating TD and other hyperkinetic movement disorders. Reduction in synaptic dopamine is also a rationale for the potential utility of valbenazine in the treatment of psychosis. To our knowledge, however, there has not been a demonstration of dopamine reduction by valbenazine, or any other VMAT2 inhibitor, in humans. The aim of this study was to investigate the change in synaptic dopamine following valbenazine administration, using positron emission tomography (PET) imaging in healthy human volunteers.

Methods: Imaging and tolerability data in this adaptive study were collected and analyzed in cohorts of 2-4 healthy volunteers. For each scan, participants received an injection of the D2/D3 dopamine receptor agonist radioligand [¹¹C]-PHNO, followed by 90 min of data acquisition using Siemens Biograph PET/CT. For post-valbenazine scans, participants received an oral dose of valbenazine 6-8 hours before the administration of [¹¹C]-PHNO, with PET imaging occurring around the time of maximal valbenazine plasma concentration. The binding potential relative to the non-displaceable binding (BP_ND) in the putamen, caudate, and ventral striatum, was used as the primary endpoint. The cerebellum was used as the reference region to estimate the regional BP_ND. Decreases in synaptic dopamine following valbenazine administration corresponded to an increase in [¹¹C]-PHNO BP_ND relative to baseline (ΔBP_ND). Plasma concentrations of valbenazine and (+)-α-dTBZ (dihydrotetrabenazine), the active metabolite of valbenazine, were measured at the start and end of each post-valbenazine PET scan. The mean plasma (+)-α-dTBZ concentration (C_ave) was matched to the ΔBP_ND for each participant to provide an exposure- response curve.

Results: To date, 9 participants (5 male, 4 female) have completed the trial. These participants received between 40-160 mg valbenazine, which resulted in plasma (+)-α-dTBZ C_ave between approximately 10-60 ng/mL. Eight participants displayed valbenazine-induced, dose-dependent increases in [¹¹C]-PHNO ΔBP_ND (21-44%). Higher exposures to (+)-α-dTBZ from higher doses of valbenazine resulted in greater ΔBP_ND, revealing a monotonic exposure-response curve. Adverse events in this study were consistent with the known safety and tolerability profile of valbenazine, as reported in TD clinical trials.

Conclusions: Valbenazine appears to decrease synaptic dopamine in a dose- and concentration-dependent manner, as indicated by an increase in [¹¹C]-PHNO ΔBP_ND. The approximately 20-40% [¹¹C]‑PHNO ΔBP_ND increase observed in this study is similar to the [¹¹C]-PHNO ΔBP_ND seen previously following treatment with a tyrosine hydroxylase inhibitor to deplete dopamine (Caravaggio et al, Neuropsychopharmacology 2014;39:2769). Thus, at pharmacological and therapeutic valbenazine doses, biologically meaningful dopamine decreases were observed in humans. These data will enable future exploration of the relationship between VMAT2 inhibition and the potential treatment of other central nervous system disorders.