ML-007C-MA

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.

Formulations

ML-007C-MA for Schizophrenia

Phase 2ActiveSchizophrenia indication →

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.

ML-007C-MA for Alzheimer's disease psychosis

Phase 2RecruitingAlzheimer's disease psychosis indication →

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.

Clinical trials