MapLight reports positive Phase 2 ZEPHYR results for ML-007C-MA in schizophrenia, showing significant PANSS improvement, cognitive benefits, and favorable safety.
Written By: Chikkula Pavan Kumar, PharmD
Reviewed By: Pharmacally Editorial Team
MapLight Therapeutics has reported positive topline results from the Phase 2 ZEPHYR trial evaluating ML-007C-MA (NCT07038876), an investigational oral fixed-dose combination of the M1/M4 muscarinic agonist betovumeline (ML-007) and the peripherally acting anticholinergic fesoterodine, in adults experiencing an acute exacerbation of schizophrenia.
The registrationally intended study met its primary endpoint, with the 210/3 mg twice-daily (BID) regimen producing a statistically significant and clinically meaningful improvement in Positive and Negative Syndrome Scale (PANSS) total score versus placebo at Week 5. The results support advancement into a registrational development program, with the company planning an End-of-Phase 2 (EOP2) meeting with the US Food and Drug Administration (FDA).
Muscarinic Agonist Strategy Targets Psychosis While Preserving Tolerability
ML-007C-MA combines the investigational M1/M4 muscarinic receptor agonist betovumeline with fesoterodine to activate central muscarinic receptors while limiting peripheral cholinergic adverse effects. The therapy is formulated to synchronize the pharmacokinetics of both components, aiming to maintain antipsychotic efficacy with improved gastrointestinal and peripheral tolerability.
Schizophrenia affects millions of people worldwide, and cognitive impairment remains one of the disease’s most disabling features. Although newer therapies have expanded treatment options, no approved antipsychotic specifically addresses cognitive deficits associated with schizophrenia.
Phase 2 ZEPHYR Trial Met Primary Endpoint
The randomized, double-blind, placebo-controlled ZEPHYR trial enrolled 307 adults across 25 US sites, randomizing participants in a 1:1:1 ratio to receive placebo, ML-007C-MA 210/3 mg BID, or 330/6 mg once daily (QD) for five weeks. The primary endpoint assessed change in PANSS total score from baseline to Week 5, while key secondary endpoints included Clinical Global Impression-Severity (CGI-S), PANSS Positive Marder Factor, and cognitive performance measured using the Cogstate battery in participants with baseline cognitive impairment.
In the modified intent-to-treat population, the BID regimen achieved a 4.5-point greater reduction in PANSS total score than placebo (LS mean difference −4.5; p=0.015) with an effect size of 0.37. Among participants completing five weeks of treatment, the effect size increased to 0.50, corresponding to a 6.0-point improvement over placebo (p=0.002). The BID regimen also significantly improved CGI-S (effect size 0.48; p=0.002) and the PANSS Positive Marder Factor (effect size 0.39; p=0.012), while showing favorable trends across multiple exploratory endpoints.
Participants with baseline cognitive impairment experienced a significant improvement in cognitive performance (effect size 0.51; p=0.041). The company reported that this benefit appeared independent of improvements in psychotic symptoms, suggesting a potential direct effect on cognitive function.
The 330/6 mg QD regimen, which provided lower overall daily drug exposure than the BID regimen, showed numerical improvement but did not reach statistical significance for the primary endpoint. However, it achieved significant improvements in CGI-S (p=0.036), PANSS Positive Marder Factor (p=0.045), and the Readiness for Discharge Questionnaire (p=0.027). Additional analyses are underway to assess the future role of a once-daily regimen.
Safety Profile Supports Continued Development
ML-007C-MA was generally well tolerated across both dose groups. Most treatment-emergent adverse events were mild and predominantly cholinergic in nature, with no serious adverse events or drug-related severe adverse events reported in either active treatment arm. The only severe adverse event in the treatment group was pneumonia, which investigators considered unrelated to study treatment, while one serious event of worsening schizophrenia occurred in the placebo group.
In the BID arm, treatment-emergent adverse events occurred in 74.7% of participants compared with 48.1% receiving placebo. Gastrointestinal events were mostly mild, and only 2.0% of participants discontinued treatment because of gastrointestinal adverse events. No participant failed to reach the target dose because of tolerability, dose reductions were uncommon, and rates of anticholinergic adverse events remained low. Investigators also reported no clinically meaningful safety signals involving urinary retention, extrapyramidal symptoms, metabolic or hepatic parameters, or blood pressure. Small increases in heart rate were consistent with the known profile of fesoterodine. The absence of a fasting requirement and the simple one-step titration schedule may support treatment adherence in routine clinical practice.
Clinical Implication
Chris Kroeger, MD, Co-Founder and Chief Executive Officer of MapLight Therapeutics, said the results demonstrated clinically meaningful antipsychotic efficacy alongside a tolerability profile that could support real-world use. He also highlighted the significant improvement in cognition, noting that cognitive impairment remains an area where no approved therapy currently exists for people living with schizophrenia.
John M. Kane, MD, Professor of Psychiatry and Molecular Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and a member of MapLight’s Clinical Advisory Board, said the combination of significant symptom improvement, cognitive benefit, and favorable tolerability could provide physicians with an important additional treatment option if confirmed in future studies.
Regulatory Path Forward
MapLight plans to meet with the FDA during an End-of-Phase 2 meeting to discuss a registrational Phase 3 program that, together with the ZEPHYR trial, could support an initial New Drug Application (NDA). Planning for the confirmatory study is already underway, and the company also intends to evaluate additional dosing regimens, including a potential once-daily option.
Beyond schizophrenia, ML-007C-MA is being evaluated in the ongoing Phase 2 VISTA trial for hallucinations and delusions associated with Alzheimer’s disease psychosis using the same 210/3 mg BID regimen. Topline results from VISTA are expected in the second half of 2027.
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About the Writer
Chikkula Pavan Kumar (LinkedIn), PharmD is a Doctor of Pharmacy with a keen interest in clinical pharmacy, pharmacovigilance, and evidence-based practice. In his words, he is passionate about patient safety and translating complex medical information into clear, research-driven communication.