ML-007C-MA · program
ML-007C-MA for Schizophrenia
Indications for ML-007C-MA: Schizophrenia · Phase 2 Alzheimer's disease psychosis · Phase 2
ML-007C-MA (M1/M4 muscarinic agonist ML-007 co-formulated with the peripherally acting anticholinergic fesoterodine) for schizophrenia. This is MapLight's lead indication and its first efficacy readout. ZEPHYR (NCT07038876, ML-007C-MA-211) is a randomised, double-blind, placebo-controlled Phase 2 trial in inpatient adults aged 18-64 with DSM-5 schizophrenia experiencing an acute exacerbation of psychosis within two months of screening; 307 participants were randomised 1:1:1 to placebo, ML-007C-MA 210/3 mg BID, or ML-007C-MA 330/6 mg QD for 5 weeks. Primary endpoint: change from baseline in PANSS total score at Week 5. Key secondaries: PANSS-Marder positive and negative factor scores and CGI-S; cognition across multiple domains is exploratory. Enrollment completed 2026-05-01 (the sponsor had guided to reaching 300 in April 2026) and the registry now records ACTUAL primary completion 2026-06-04 and study completion 2026-06-11, with overall status Completed as of the 2026-07-07 update — the trial is done and the topline is pending, guided 'by mid-August of 2026'. Completers may roll into NCT07459647 (ML-007C-MA-212), a 500-participant open-label long-term safety extension at 210/3 mg BID that began 2026-03-31 and runs to February 2030. No dose arm has been dropped, no clinical hold or safety signal has been disclosed, and the schizophrenia indication carries no regulatory designation (the FDA Fast Track designation belongs to the Alzheimer's disease psychosis program). Program status is recorded 'active' rather than 'recruiting' because the pivotal Phase 2 trial has finished enrolling and finished dosing; only the open-label extension is still recruiting.
Development timeline
- UpcomingTopline results from the Phase 2 ZEPHYR trial of ML-007C-MA (210/3 mg BID and 330/6 mg QD) versus placebo in acute exacerbation of schizophrenia — primary endpoint change from baseline in PANSS total score at Week 5 — expected by mid-August 2026.↗
- Enrollment completed in ZEPHYR with 307 participants randomised 1:1:1 (placebo / 210/3 mg BID / 330/6 mg QD), and topline guidance set to 'by mid-August of 2026'. The trial stopped recruiting at this point; ClinicalTrials.gov subsequently moved it to Completed with actual primary completion 2026-06-04 and actual study completion 2026-06-11. The program remains active pending topline and through the open-label extension NCT07459647.↗
- Actual start date of ZEPHYR (NCT07038876, ML-007C-MA-211) per ClinicalTrials.gov, marking the program's entry into Phase 2 in schizophrenia. The registry record was first posted 2025-06-26 and MapLight announced the initiation publicly on 2025-07-07, roughly six months later than the 'first half of 2025' guidance given in December 2024.
- MapLight reported results from the fourth and final Phase 1 trial (Study ML-007-013), the first to use the bi-layer co-formulated ML-007C-MA tablet — then still called ML-007/PAC: 82 healthy adult and elderly volunteers across four cohorts dosed up to 14 days, favourable safety and tolerability, mild and transient TEAEs with no severe or serious events, plasma and CSF exposures above clinically relevant levels on both once- and twice-daily dosing, similar PK in adults and elderly, and no fasted-state requirement. This completed a Phase 1 package of four trials, 270 healthy participants and more than 1,500 doses of ML-007. The release guided to initiating Phase 2 in schizophrenia and ADP in the first half of 2025. NOTE: none of the four Phase 1 trials is registered on ClinicalTrials.gov, so this milestone is documented from the sponsor only.↗
Readouts
- by mid-August 2026AnticipatedTopline dataNCT07038876
Topline results from the Phase 2 ZEPHYR trial of ML-007C-MA (210/3 mg BID and 330/6 mg QD) versus placebo in acute exacerbation of schizophrenia — primary endpoint change from baseline in PANSS total score at Week 5 — expected by mid-August 2026. ↗
Clinical trials in Schizophrenia
NCT07459647ML-007C-MA-212Phase 2Recruitingn=500
An Open-Label Study to Assess the Long-Term Safety, Tolerability, and Effectiveness of ML-007C-MA in Adult Participants With Schizophrenia
NCT07038876ML-007C-MA-211Phase 2Completedn=307
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, and Tolerability of Orally Administered ML-007C-MA in Inpatient Adult Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis (ZEPHYR)
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| ML-007C-MA extended-release bi-layer fixed-dose combination tabletBi-layer co-formulated extended-release tablet (ML-007 ER layer + peripherally acting anticholinergic ER layer, release profiles matched to hold the plasma ratio in range) Doses are written as ML-007 mg / PAC (fesoterodine) mg. Phase 2 VISTA (Alzheimer's disease psychosis): 105/1.5 mg BID titration for one week then 210/3 mg BID maintenance, randomised 1:1 against placebo over 7 weeks, with one permitted one-time dose reduction for tolerability (participants requiring it stay on the reduced dose for the remainder of the study). Phase 2 ZEPHYR (schizophrenia): 210/3 mg BID or 330/6 mg QD versus placebo, randomised 1:1:1, 5 weeks. Both open-label extensions dose 210/3 mg BID (the ADP extension also allows 105/1.5 mg BID). Phase 1 Study 013 evaluated single and multiple doses up to 210/3 mg BID and 330/6 mg QD for up to 14 days in healthy adult and elderly participants; in healthy ELDERLY participants 165/3 and 210/3 mg BID were well tolerated but 330/6 mg QD was NOT, which is precisely why the elderly ADP program caps at 210/3 mg BID. Earlier Phase 1 work used non-combination presentations: immediate-release ML-007 oral solution (single doses 0.8-49 mg, MTD 32 mg) with or without oral-solution PAC in Studies 001 and 011, and extended-release 'ML-007 ER' co-administered with PAC ER as separate units in Study 012. | Oral | Twice daily | — |
Mechanism of action
Dual-component muscarinic strategy. The active central moiety is ML-007, an orthosteric agonist at the M1 and M4 muscarinic acetylcholine receptors (CHRM1, CHRM4), both class-A GPCRs concentrated in the cortical and striatal circuits implicated in psychosis and cognition; post-mortem work in Alzheimer's disease and schizophrenia brain shows altered muscarinic receptor binding, which is the sponsor's rationale for the shared mechanism across both indications. In aequorin-based calcium assays ML-007 is a full agonist at human M1 (EC50 120 nM, pEC50 6.93, Emax 100% of acetylcholine) and a near-full agonist at human M4 (EC50 830 nM, pEC50 6.08, Emax 81%), i.e. ~7-fold M1-biased; rat orthologs are ~3-fold weaker (rM1 340 nM, rM4 1600 nM). ML-007 is 30- to 100-fold LESS potent in vitro than xanomeline (hM1 2.3 nM, hM4 5.5 nM) yet ~10-fold MORE potent in three standard mouse psychosis models — the disconnect is pharmacokinetic: intraperitoneal bioavailability 94.6% vs 8.6% for xanomeline, and a CSF Cmax of 115 ng/mL (698 nM) at 0.3 mg/kg IP where xanomeline is below the limit of quantification (CSF-Kp-Cmax 0.54, CSF-Kp-AUClast 0.67). Efficacy in those models required both receptors. Because muscarinic agonism in the periphery produces salivation, nausea, vomiting, diarrhoea, sweating and GI effects — a particular liability in the elderly, frail ADP population — ML-007 is co-formulated with fesoterodine, an FDA-approved peripherally acting anticholinergic whose muscarinic antagonism is confined largely to the periphery by low brain penetration; the two components' extended-release profiles were matched so that the ML-007:PAC plasma ratio stays inside the empirically derived 100:1 to 600:1 tolerability window across the dosing interval. Below ~100:1 the antagonist over-blocks (anticholinergic events, an added concern in a dementia population); above ~600:1 procholinergic events dominate. No dopamine D2 blockade is involved — relevant in ADP, where antipsychotics carry a boxed warning for increased mortality in elderly patients with dementia-related psychosis.
| Target | Action | Affinity |
|---|---|---|
| M1primaryCHRM1 | Agonist | EC50 120 nMⓘ |
| M4CHRM4 | Agonist | EC50 830 nMⓘ |
← Full ML-007C-MA compound page (identity, identifiers, all indications)
Sources
- Chatterjee S, Soria M, Norville ZC, Thompson KR, Lillie J, Kreitzer AC, Wood MW. Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors. Neuropsychopharmacology. 2025 (PMID 41046244; doi:10.1038/s41386-025-02256-3) — Neuropsychopharmacology (Springer Nature) via PubMed Central
- MapLight Therapeutics Announces Completion of Enrollment in ZEPHYR Phase 2 Trial and Updates Expected Timing of Topline Results (2026-05-01) — MapLight Therapeutics, Inc. (via GlobeNewswire)
- MapLight Therapeutics Announces Results From Phase 1 Trial of Novel M1/M4 Muscarinic Agonist in Development for Treatment of Schizophrenia and Alzheimer's Disease Psychosis (2024-12-02; Study 013, 82 participants) — MapLight Therapeutics, Inc. (via PR Newswire)
- MapLight Therapeutics, Inc. Annual Report on Form 10-K for the fiscal year ended December 31, 2025 (filed 2026-03-26; Commission File 001-42914) — U.S. Securities and Exchange Commission (EDGAR)
- NCT07038876 (ML-007C-MA-211, ZEPHYR) — A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety, and Tolerability of Orally Administered ML-007C-MA in Inpatient Adult Participants With Schizophrenia Experiencing an Acute Exacerbation of Psychosis — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT07459647 (ML-007C-MA-212) — An Open-Label Study to Assess the Long-Term Safety, Tolerability, and Effectiveness of ML-007C-MA in Adult Participants With Schizophrenia — ClinicalTrials.gov (U.S. National Library of Medicine)