Muscarinic agonism with ML-007C-MA for the treatment of schizophrenia: results from the phase 2 randomized, double-blind, placebo-controlled ZEPHYR trial

ZEPHYR was a randomized, double-blind, placebo-controlled Phase 2 trial conducted at 25 sites across the United States. Participants (N=307) were randomized 1:1:1 to placebo, ML-007C-MA 210/3 mg twice daily (BID), or ML-007C-MA 330/6 mg once daily (QD). The primary endpoint was change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 5. Key secondary endpoints included the change in Clinical Global Impression–Severity (CGI-S) and PANSS-Marder positive and negative factor scores. Change in cognitive function was assessed as a prespecified secondary endpoint in participants with baseline cognitive impairment using the Cogstate battery.

The ZEPHYR Phase 2 trial met both its primary and multiple secondary endpoints for the BID arm, demonstrating consistent antipsychotic efficacy across numerous outcome measures, with a favorable side effect profile in participants with schizophrenia. Robust and clinically meaningful improvement in cognitive performance on the pre-specified Cogstate battery suggests the potential for improving cognitive dysfunction in schizophrenia. No fasting requirement and a one-dose titration support a tolerability profile that is expected to translate into real-world adherence. These positive results with ML-007C-MA further strengthen the clinical evidence for the emerging class of muscarinic agonists, and support plans for an additional pivotal trial to toward registration.