MapLight Therapeutics (Nasdaq: MPLT) reported positive topline results from its Phase II ZEPHYR trial of ML-007C-MA in adults with acute exacerbation of schizophrenia, with the 210/3 mg twice-daily dose meeting the primary endpoint and demonstrating a statistically significant reduction in PANSS total score versus placebo at Week 5 — results the company says were designed and sized to support registration.
The trial enrolled 307 inpatient adults randomized 1:1:1 to placebo, ML-007C-MA 210/3 mg BID, or 330/6 mg once daily across 25 US sites. In the modified intent-to-treat population, the BID arm produced a least-squares mean difference of −4.5 points on the PANSS total score versus placebo (effect size 0.37, p=0.015). Among completers, the effect size reached 0.50 (LS mean difference −6.0, p=0.002). The BID dose also achieved separation on CGI-S (effect size 0.48, p=0.002) and PANSS positive Marder factor (effect size 0.39, p=0.012). The once-daily 330/6 mg dose showed numerical improvement but did not reach statistical significance on the primary endpoint, though it separated on CGI-S (p=0.036) and PANSS positive Marder factor (p=0.045).
A prespecified secondary endpoint assessed cognitive performance via the Cogstate battery in participants with baseline cognitive impairment. The BID arm produced an effect size of 0.51 (0.44 points versus placebo, p=0.041), and MapLight reported that this cognitive benefit did not correlate with PANSS score change — indicating an effect independent of antipsychotic symptom improvement. No approved therapy currently carries an indication for cognitive impairment associated with schizophrenia.
ML-007C-MA is an oral, extended-release fixed-dose combination of betovumeline, an investigational M1/M4 muscarinic agonist, co-formulated with fesoterodine, a peripherally acting anticholinergic. The design activates M1 and M4 muscarinic receptors in the central nervous system to drive antipsychotic and cognitive effects, while the co-formulated anticholinergic mitigates peripheral cholinergic side effects by synchronizing the pharmacokinetics of both components. The mechanism is non-dopaminergic, placing ML-007C-MA in the same mechanistic class as Bristol Myers Squibb's Cobenfy (xanomeline-trospium chloride), which received FDA approval in September 2024 as the first non-D2 antipsychotic. Every other approved agent in schizophrenia — including cariprazine, lumateperone, and paliperidone — works primarily through dopamine D2 receptor blockade.
Tolerability in the ZEPHYR trial was generally favorable. Treatment-emergent adverse events in the BID arm were reported in 74.7% of participants versus 48.1% on placebo, mostly mild and cholinergic in nature. There were no serious adverse events or drug-related severe TEAEs in either active arm. GI-related discontinuations occurred in only two participants (2.0%) in the BID arm, and no participant failed to reach target dose due to tolerability. All-cause discontinuation across both active arms was 19.9%. Small increases in heart rate were observed, consistent with the known fesoterodine profile.