Quantifying VMAT2 target occupancy at effective valbenazine doses and comparing to a novel VMAT2 inhibitor: a translational PET study

Positron emission tomography (PET) is frequently used to obtain target occupancy (%TO) of central nervous system (CNS) drug candidates during clinical development. Obtaining %TO with PET can be particularly powerful when the %TO associated with efficacy is known for a protein target. Using the radiotracer [¹⁸F]AV-133, the relationship between plasma concentration (PK) and %TO of NBI-750142, an experimental inhibitor of the vesicular monoamine transporter type 2 (VMAT2) was obtained in both nonhuman primate (NHP) and human. This work established [¹⁸F]AV-133 PET as capable of providing a VMAT2 inhibitor PK-%TO relationship that translated from NHP to human. To establish the VMAT2%TO benchmark, PET was performed in NHP with NBI-98782, the main active metabolite of valbenazine, and this PK-%TO relationship was used to estimate VMAT2%TO at NBI-98782 exposures associated with valbenazine therapeutic effects in the treatment of tardive dyskinesia (TD). This work defined 85-90% as the VMAT2%TO achieved by exposures associated with daily dosing with 80 mg valbenazine, a dosing regimen known to exhibit a large effect size in the treatment of TD and in the treatment of chorea associated with Huntington's Disease. NBI-750142 was estimated to achieve 36-78% VMAT2 target occupancy at acceptable doses, indicating potential inferiority in conferring clinical benefit compared to valbenazine. It is recommended that the %TO benchmark of valbenazine derived from [¹⁸F]AV-133 PET serve as a gold standard biomarker to evaluate novel VMAT2 inhibitors undergoing clinical development.