MapLight Therapeutics (NASDAQ: MPLT) reported positive topline results from the Phase 2 ZEPHYR trial of ML-007C-MA in patients experiencing acute schizophrenia exacerbations. The twice-daily dose produced a statistically significant improvement in overall symptoms and showed evidence of cognitive benefit in impaired patients. The findings strengthen the clinical rationale for regulatory discussions, although the unsuccessful once-daily arm highlights the importance of dose frequency.

Key Highlights

  • The twice-daily 210/3 mg dose met the primary endpoint at week five.
  • PANSS total score improved by an LS mean of 4.5 points versus placebo.
  • Cognitively impaired patients recorded a 0.51 effect size in cognitive measures.
  • No serious drug-related adverse events were reported during the trial.
  • The once-daily treatment arm did not achieve statistical significance.

ZEPHYR Trial Meets Primary Schizophrenia Endpoint

MapLight Therapeutics (NASDAQ: MPLT) said its Phase 2 ZEPHYR trial met the primary efficacy endpoint for the twice-daily 210/3 mg dose of ML-007C-MA. The study evaluated the therapy in patients with schizophrenia experiencing acute exacerbations, a population requiring rapid and sustained symptom control.

At week five, the twice-daily regimen produced a least-squares mean reduction of 4.5 points in Positive and Negative Syndrome Scale total score relative to placebo. The result was statistically significant, with a p-value of 0.015. PANSS measures a broad range of positive, negative and general psychiatric symptoms and remains a standard efficacy measure in schizophrenia trials.

ML-007C-MA combines an M1/M4 muscarinic receptor agonist with a peripherally acting anticholinergic. The formulation is designed to preserve the central therapeutic activity of muscarinic receptor stimulation while limiting peripheral side effects commonly associated with this drug class.

Cognitive Data Broaden the Clinical Profile

The trial also generated evidence of cognitive improvement among participants who had impairment at baseline. In this subgroup, ML-007C-MA delivered an effect size of 0.51 compared with placebo, reaching statistical significance with a p-value of 0.041.

Cognitive dysfunction can materially affect daily functioning and long-term outcomes in schizophrenia but is not adequately addressed by many established antipsychotic treatments. The subgroup result therefore provides an additional clinical signal, although further testing in a larger and appropriately designed registrational programme will be necessary to establish its consistency and relevance.

Safety Results and Phase 3 Considerations

ML-007C-MA was generally well tolerated, with no serious adverse events judged to be related to treatment. Gastrointestinal side effects resulted in a discontinuation rate of 2%, indicating relatively limited treatment interruption during the study.

However, the once-daily arm failed to achieve statistical significance on the primary endpoint. The difference between the dosing schedules suggests that maintaining sufficient therapeutic exposure may be important and will influence Phase 3 dose selection and trial design.

The company plans to hold an End-of-Phase 2 meeting with the US Food and Drug Administration to align on a registrational programme. It also intends to continue evaluating ML-007C-MA for Alzheimer’s disease psychosis, extending the candidate’s potential application across disorders involving neuropsychiatric symptoms.