ML-007C-MA · program
ML-007C-MA for Alzheimer's disease psychosis
- FDA Fast Track (Hallucinations And Delusions Associated With Alzheimer'S Disease Psychosis; Granted December 2025, Announced 2026-01-05)
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 hallucinations and delusions associated with Alzheimer's disease psychosis (ADP). VISTA (NCT06887192, ML-007C-MA-221) is a randomised, double-blind, placebo-controlled Phase 2 trial enrolling approximately 300 participants aged 55-90 globally, randomised 1:1 to placebo or ML-007C-MA: one week of 105/1.5 mg BID titration then 210/3 mg BID maintenance, with a permitted one-time dose reduction. Primary endpoint: change from baseline to Week 7 in the NPI-C Hallucinations and Delusions (H+D) score. Secondaries: CGI-S for hallucinations and delusions, and NPI-C Agitation and Aggression in a qualifying subgroup. The trial started 2025-08-15, was announced 2025-09-17, and is recruiting (registry last updated 2026-05-15); topline is guided to the second half of 2027. FDA granted Fast Track designation for hallucinations and delusions associated with ADP in December 2025, announced 2026-01-05 — the only regulatory designation on this compound. A 210-participant open-label long-term safety extension (NCT07459660, ML-007C-MA-222) opened 2026-03-25 and runs to March 2029. The strategic case for ADP is that roughly 40% of Alzheimer's patients develop psychotic symptoms, which are associated with faster cognitive decline, higher institutionalisation and increased mortality, and there is no FDA-approved treatment for them; the mechanism avoids dopamine D2 blockade, which matters in a population where antipsychotics carry a boxed warning for increased mortality. This is the sponsor's second indication for the compound — schizophrenia is the lead and reads out roughly a year earlier.
Development timeline
- UpcomingTopline results from the Phase 2 VISTA trial of ML-007C-MA 210/3 mg BID versus placebo in hallucinations and delusions associated with Alzheimer's disease psychosis — primary endpoint change from baseline in NPI-C H+D score at Week 7 — expected in the second half of 2027.↗
- Actual start date of VISTA (NCT06887192, ML-007C-MA-221) per ClinicalTrials.gov, marking the program's entry into Phase 2 in Alzheimer's disease psychosis — about seven weeks after the schizophrenia trial started, and roughly six months later than the 'first half of 2025' guidance given in December 2024. MapLight announced the initiation on 2025-09-17. Still recruiting as of the registry's 2026-05-15 update.
- 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. Completing a Phase 1 package of four trials, 270 healthy participants and more than 1,500 doses of ML-007. Directly relevant to ADP: the elderly cohort is what established the 210/3 mg BID ceiling used in VISTA, since 330/6 mg QD was not tolerated in healthy elderly participants. 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
- 2H 2027AnticipatedTopline dataNCT06887192
Topline results from the Phase 2 VISTA trial of ML-007C-MA 210/3 mg BID versus placebo in hallucinations and delusions associated with Alzheimer's disease psychosis — primary endpoint change from baseline in NPI-C H+D score at Week 7 — expected in the second half of 2027. ↗
Clinical trials in Alzheimer's disease psychosis
NCT07459660ML-007C-MA-222Phase 2Recruitingn=210
An Open-Label Study to Assess the Long-Term Safety and Tolerability of ML-007C-MA in Adult Participants With Hallucinations and Delusions Associated With Alzheimer's Disease Psychosis
NCT06887192ML-007C-MA-221Phase 2Recruitingn=300
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ML-007C-MA for the Treatment of Hallucinations and Delusions Associated With Alzheimer's Disease Psychosis (VISTA)
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 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 Reports First Quarter 2026 Financial Results and Provides Business Update (2026-05-14) — MapLight Therapeutics, Inc. (via GlobeNewswire)
- 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)
- NCT06887192 (ML-007C-MA-221, VISTA) — A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ML-007C-MA for the Treatment of Hallucinations and Delusions Associated With Alzheimer's Disease Psychosis — ClinicalTrials.gov (U.S. National Library of Medicine)
- NCT07459660 (ML-007C-MA-222) — An Open-Label Study to Assess the Long-Term Safety and Tolerability of ML-007C-MA in Adult Participants With Hallucinations and Delusions Associated With Alzheimer's Disease Psychosis — ClinicalTrials.gov (U.S. National Library of Medicine)