ENX-104

Mechanism of action

Potent, selective antagonist at the dopamine D2 and D3 receptors (DRD2/DRD3, Gi/o-coupled class-A GPCRs), with the therapeutic effect deliberately sited at LOW receptor occupancy. Because presynaptic D2/D3 autoreceptors on dopaminergic terminals and somatodendritic sites are engaged before postsynaptic receptors, low-dose antagonism removes dopamine's own negative feedback and increases dopamine release in the reward circuitry, instead of blocking downstream dopamine signalling. The published translational package reports high brain penetrance with rapid plasma clearance, sustained (8-hour) increases in nucleus accumbens dopamine in rats, and enhanced reward responsiveness in the rodent Probabilistic Reward Task at doses corresponding to approximately 10-50% D2/D3 receptor occupancy — below the ~65-80% occupancy at which antipsychotic-like activity appears and well below the >80% at which motor effects emerge. That occupancy window, not a potency number, is the differentiating claim, and the once-daily oral regimen is designed to hold exposure inside it. Engrail additionally labels ENX-104 a D2/D3/D4 antagonist and asserts that its high selectivity implies a lower risk of off-target effects than typical or atypical antipsychotics. In the first-in-human SAD study, central target engagement was evidenced by dose-related, >=48 h decreases in adaptive tracking without systematic changes in saccadic peak velocity, body sway or finger tapping (i.e. target engagement without arousal or psychomotor impairment), and peripheral postsynaptic D2/D3 antagonism by transient dose-related prolactin increases. No absolute binding affinity for ENX-104 is publicly citable at any target.

Formulations

ENX-104 for Major depressive disorder

Phase 1ActiveMajor depressive disorder indication →

ENX-104, a potent and selective dopamine D2/D3 receptor antagonist, for major depressive disorder characterized by anhedonia (aMDD) — Engrail Therapeutics' stated lead indication for the asset and its second clinical-stage program after ENX-102 in generalized anxiety disorder. The clinical rationale is that dysregulated dopaminergic neurotransmission in reward circuitry underlies anhedonia, that anhedonia affects 60-70% of MDD patients and predicts poor antidepressant response, and that no approved treatment specifically targets it; ENX-104 is dosed low enough to block presynaptic D2/D3 autoreceptors and raise dopamine release rather than blockading postsynaptic receptors. The Phase 1 package, run entirely in the UK/EU, comprises four studies: an unregistered first-in-human single-ascending-dose study in 46 healthy participants across 5 dose levels (run with the Centre for Human Drug Research and reported at ASCP 2026), an open-label single-dose D2/D3 PET receptor-occupancy study in 10 healthy volunteers at Parexel London (NCT07253272, ENX-104-002, Feb-Sep 2025), a randomized, triple-blind, placebo-controlled multiple-ascending-dose study in 48 patients with anhedonic MDD across four MAC Clinical Research sites in England (NCT07253324, ENX-104-003, Feb-Nov 2025), and a three-way crossover tablet-versus-solution relative-bioavailability and food-effect study in 12 healthy participants (NCT07472361, ENX-104-004, Feb-Mar 2026). All four are complete. The first-in-human study was positive on its own terms — well tolerated at all doses, no serious or severe adverse events, dose-proportional exposure, sustained central target engagement and prolactin-confirmed peripheral D2/D3 antagonism. Critically, however, NO results have been disclosed from either the D2/D3 PET occupancy study or the multiple-ascending-dose study in patients, and those two datasets — the occupancy-to-dose relationship and the first pharmacodynamic signal in the target population — are what a Phase 2 dose selection would rest on. Engrail has issued no press release on ENX-104 since announcing the Phase 1 program on 2024-09-18, has given no readout guidance, and files nothing with the SEC. No Phase 2 study is registered on ClinicalTrials.gov and none has been announced. No FDA designation (fast track, breakthrough or orphan) has been granted. The program is recorded as active rather than completed on the strength of the Feb-Mar 2026 tablet bridging study, which is the most recent evidence of investment and is consistent with Phase 2 preparation.

Clinical trials