PSYCHOPHARMACOLOGY OF ENX-104: A POTENT DOPAMINE (DA) D2/D3 RECEPTOR ANTAGONIST FOR THE TREATMENT OF NEUROPSYCHIATRIC DISORDERS ASSOCIATED WITH ANHEDONIA

Background

ENX-104 is a potent dopamine (DA) D2/D3 receptor antagonist that enhances dopaminergic neurotransmission at low doses, representing a potential new therapeutic modality for the treatment of neuropsychiatric disorders associated with anhedonia. Preclinically, ENX-104 has demonstrated a favorable pharmacokinetic (PK) and safety profile, increased DA levels in the reward circuitry, and enhanced reward responsiveness at low doses preferentially blocking presynaptic D2/D3 autoreceptors. Additionally, its high selectivity and potent D2/D3 activity suggests relatively lower risk of off-target effects compared with (a)typical antipsychotics. The objective of this First-in-Human study was to evaluate the safety, tolerability, PK and pharmacodynamic (PD) profiles of single ascending oral doses of ENX-104 in healthy participants.

Methods

This was a randomized, double-blind, placebo-controlled, single ascending dose study. Of a total of 46 healthy male and female participants, 11 received placebo and 35 received ENX-104 across 5 dose levels orally while in-clinic for a period of 3 days. Safety measures included adverse events (AE), labs, vital signs, physical exams, electrocardiograms (ECGs), and extrapyramidal symptoms scales. Blood samples for plasma PK analysis were collected pre-dose through 48h. PK parameters for ENX-104 and its primary metabolites were determined by noncompartmental analysis. Central nervous system target engagement was measured using the NeuroCart test battery analyzed by mixed model analyses of covariance. This battery assessed saccadic peak velocity, subjective alertness as measured by the Bond and Lader visual analogue scale, visuomotor coordination and attention as measured by adaptive tracking, psychomotor function as measured by body sway, and fine motor skills as measured by alternate side tapping. Peripheral target engagement was measured by analyzing serum prolactin levels.

Results

ENX-104 was safe and well tolerated at all doses tested with no serious or severe AEs reported. 62.9% of participants on ENX-104 experienced at least one AE vs 81.8% on placebo; > 97% of AEs were mild in intensity. No clinically meaningful trends in labs, vital signs, physical exams, ECGs or extrapyramidal symptoms scales were observed. Plasma exposure increased dose-proportionally, with low to moderate variability. ENX-104 demonstrated doserelated decreases in adaptive tracking that were sustained > =48h. No systematic dose-related changes in saccadic peak velocity, body sway, or finger tapping were noted, indicating little to no impairment in arousal or psychomotor function. Consistent with peripheral postsynaptic D2/D3 receptor antagonism and short plasma half-life, transient, dose-related increases in serum prolactin were observed.

Conclusion

Single oral doses of ENX-104 were safe and well tolerated and demonstrated a favorable PK profile with a short plasma half-life. Consistent with preclinical findings, evidence for sustained central target engagement was demonstrated by decreases in adaptive tracking and peripheral target engagement was evidenced by increases in prolactin.