A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders

Area of Science:

• Neuroscience
• Pharmacology
• Movement Disorders

Background:

• Tourette syndrome is a neurodevelopmental disorder linked to basal ganglia dysfunction.
• Phosphodiesterase 10A (PDE10A) inhibitors are being investigated for movement disorder therapeutics.
• Modulating striatal basal ganglia signaling is a key therapeutic strategy.

Purpose of the Study:

• To present preclinical and clinical data for the PDE10A inhibitor EM-221.
• To evaluate the safety, tolerability, and target engagement of EM-221.
• To assess the potential of EM-221 for treating Tourette syndrome and related movement disorders.

Main Methods:

• In vitro enzyme inhibition assays to determine IC50 and selectivity.
• Animal studies (rats) to assess behavioral effects and PDE10A inhibition.
• Preclinical toxicology studies in rats and dogs.
• Human safety, tolerability, and PET imaging for striatal enzyme occupancy in healthy volunteers.

Main Results:

• EM-221 demonstrated potent and selective inhibition of PDE10A (IC50 = 9 pM).
• In vivo, EM-221 showed effects consistent with PDE10A inhibition in rats.
• EM-221 was well-tolerated in preclinical toxicology and human safety studies.
• PET imaging confirmed significant PDE10A striatal enzyme occupancy (up to 92.8%) in humans.

Conclusions:

• EM-221 exhibits favorable preclinical and clinical safety and tolerability profiles.
• The drug effectively engages its target, PDE10A, in the human brain.
• These findings support the progression of EM-221 into Phase 2 trials for Tourette syndrome and other movement disorders.