ENX-104 · program
ENX-104 for Major depressive disorder
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.
Development timeline
- metFirst-in-human single-ascending-dose results for ENX-104 presented at ASCP 2026: safe and well tolerated at all 5 dose levels with no serious or severe adverse events, dose-proportional plasma exposure, sustained central target engagement (dose-related decreases in adaptive tracking lasting >=48 h) and prolactin-confirmed peripheral D2/D3 antagonism.↗
- Actual primary completion and study completion of the multiple-ascending-dose study in anhedonic MDD (NCT07253324, 48 participants enrolled, actual), following completion of the PET occupancy study on 2025-09-02. The Phase 1 patient work is therefore finished, with no topline disclosed. Phase remains phase_1 and status remains active: no Phase 2 study is registered or announced, and the subsequent tablet-versus-solution bridging study (NCT07472361, Feb-Mar 2026) is itself Phase 1.
- First dosing in the target patient population: the multiple-ascending-dose study in participants with major depressive disorder with anhedonia (NCT07253324, ENX-104-003) started 2025-02-17 at four MAC Clinical Research sites in England, and the D2/D3 PET receptor-occupancy study in healthy volunteers (NCT07253272, ENX-104-002) started a week later on 2025-02-24 at Parexel London. Both dates are ACTUAL start dates on ClinicalTrials.gov — but note that neither study was registered until November 2025, so no contemporaneous public disclosure of this transition existed.
- Engrail announced initiation of the ENX-104 clinical program — a randomized, double-blind, placebo-controlled single ascending dose study in up to 48 healthy adult volunteers (cohorts of 8: 6 active, 2 placebo), with safety and tolerability as the primary objective plus PK and dopamine-related pharmacodynamic biomarkers. This is the compound's first-in-human entry and the only dated public marker of the preclinical-to-Phase 1 transition; the actual first-dose date was not disclosed, so this announcement date is an upper bound. The study is not registered on ClinicalTrials.gov.↗
Readouts
- 2026-05-01ReportedFull resultsmet
First-in-human single-ascending-dose results for ENX-104 presented at ASCP 2026: safe and well tolerated at all 5 dose levels with no serious or severe adverse events, dose-proportional plasma exposure, sustained central target engagement (dose-related decreases in adaptive tracking lasting >=48 h) and prolactin-confirmed peripheral D2/D3 antagonism. ↗
- No guidance — study completed 26 Nov 2025, topline undisclosedAnticipatedTopline dataNCT07253324
Topline from the Phase 1 multiple-ascending-dose study of ENX-104 in 48 patients with major depressive disorder with anhedonia (NCT07253324) — safety, tolerability, PK and pharmacodynamics, the first data in the target population. Completed 26 November 2025; nothing disclosed.
- No guidance — study completed 2 Sep 2025, results undisclosedAnticipatedFull resultsNCT07253272
D2/D3 receptor occupancy results from the Phase 1 PET study of single-dose ENX-104 in 10 healthy volunteers (NCT07253272) — the dose-to-occupancy relationship that would anchor Phase 2 dose selection against the intended 10-50% occupancy window. Completed 2 September 2025; nothing disclosed.
Clinical trials in Major depressive disorder
NCT07472361ENX-104-004Phase 1Completedn=12
A Randomized, Open-Label, Three-Way Crossover Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of a Single Dose of ENX-104 Administered Orally as a Solution Fasted, a Tablet Fasted, or a Tablet With a High Fat Meal in Healthy Participants
NCT07253272ENX-104-002Phase 1Completedn=10
An Open-label Positron Emission Tomography (PET) Study to Demonstrate Safety, Tolerability, Receptor Occupancy, and Pharmacokinetics After a Single Oral Dose Administration of ENX-104 in Healthy Volunteers
NCT07253324ENX-104-003Phase 1Completedn=48
A Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ENX-104 in Participants With Major Depressive Disorder With Anhedonia
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| ENX-104 oral solution Oral solution used in the Phase 1 clinical package: single ascending oral doses across 5 dose levels in the first-in-human study (46 healthy participants, 35 active / 11 placebo, dosed in-clinic over 3 days), a single oral dose in the D2/D3 PET receptor-occupancy study (NCT07253272), and multiple ascending doses over a 21-day assessment window in patients with anhedonic MDD (NCT07253324). No milligram doses have been disclosed for any study. | Oral | — | — |
| ENX-104 oral tablet Tablet presentation evaluated against the oral solution in a randomized, open-label, three-way crossover relative-bioavailability and food-effect study in 12 healthy participants (NCT07472361, ENX-104-004, 2026-02-25 to 2026-03-19): solution fasted vs tablet fasted vs tablet with a high-fat meal. Strength not disclosed. | Oral | Once daily | — |
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.
| Target | Action | Affinity |
|---|---|---|
| D2primaryDRD2 | Antagonist | —ⓘ |
| D3DRD3 | Antagonist | —ⓘ |
| D4DRD4 | Antagonist | —ⓘ |
← Full ENX-104 compound page (identity, identifiers, all indications)
Sources
- Engrail Therapeutics Initiates ENX-104 Clinical Program for the Treatment of Major Depressive Disorder Characterized by Anhedonia (2024-09-18) — Engrail Therapeutics, Inc.
- Engrail Therapeutics Non-Confidential Corporate Summary, 1Q24 — pipeline table, ENX-104 structure (deuterated nemonapride enantiomer, 'D2/3/4 antagonist'), ENX-105 contrast slide, aMDD market sizing — Engrail Therapeutics, Inc.
- NCT07253272 (ENX-104-002) — An Open-label PET Study to Demonstrate Safety, Tolerability, Receptor Occupancy, and Pharmacokinetics After a Single Oral Dose of ENX-104 in Healthy Volunteers — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT07253324 (ENX-104-003) — A Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ENX-104 in Participants With Major Depressive Disorder With Anhedonia — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT07472361 (ENX-104-004) — A Randomized, Open-Label, Three-Way Crossover Study of a Single Dose of ENX-104 as Solution Fasted, Tablet Fasted, or Tablet With a High Fat Meal in Healthy Participants — ClinicalTrials.gov (U.S. National Library of Medicine)
- Psychopharmacology of ENX-104: A potent dopamine (DA) D2/D3 receptor antagonist for the treatment of neuropsychiatric disorders associated with anhedonia — poster W39, 2026 ASCP Annual Meeting (Geever R, Coppell A, Vadodaria K, Borghans L, Post T, Nezic K, Horrigan J, Kipperman S, Parks S, Serrano N, Sudarsan V, Taylor E, Vanover KE, Jacobs G, Arce E; Centre for Human Drug Research and Engrail Therapeutics) — CNS Pulse (American Society of Clinical Psychopharmacology 2026 Annual Meeting)
- Vadodaria K, Serrats J, Brubaker W, et al. ENX-104: a selective and potent D2/D3 receptor antagonist enhances dopamine neurotransmission and reward responsiveness in translational rodent models. Neuropsychopharmacology. 2026;51:1065-1073 — Neuropsychopharmacology (Springer Nature) / PubMed