A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders

Abstract

Background: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders.

Methods: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented.

Results: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05-0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A's inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life.

Conclusions: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.

Keywords: PDE10; PET; pharmacology; phase 1; proof of mechanism; toxicology.

Figure 1

EM-221’s plasma concentration time course after its oral administration at 0.3 mg/kg in rats.

Figure 2

In vivo PDE10A occupancy in the rat striatum after oral administration. Left panel—PDE10A enzyme occupancy at 2 h after different doses of EM-221 p.o. Right panel—PDE10A occupancy as a function of time after an oral dose of 0.1 mg/kg EM-221. Each point is the mean of data collected from 3 rats.

Figure 3

Levels of cAMP and cGMP in striatum (pmol/mg tissue) at 2 h after different oral doses of EM-221. Asterisks represent statistical differences from the vehicle group: * p < 0.05, ** p < 0.01.

Figure 4

Single-dose plasma concentration time profiles (linear scale) by treatment dose in humans.

Figure 5

Multiple-dose plasma concentration time profiles (linear scale) by treatment dose in humans, day 1 (dosed with food).

Figure 6

Global ΔBPND data plotted against measured plasma concentrations in humans.