Maplight Therapeutics (NASDAQ:MPLT) reported that its Phase II ZEPHYR trial of ML-007C-MA met its primary endpoint in schizophrenia, with the twice-daily regimen producing a statistically significant improvement in Positive and Negative Syndrome Scale, or PANSS, total scores versus placebo at five weeks.
Chris Kroeger, the company’s co-founder and chief executive officer, said ZEPHYR was designed as a pivotal, registration-intended study. The company said the results support advancing ML-007C-MA into an additional confirmatory pivotal trial, with planning and site identification already underway ahead of end-of-Phase II discussions with the Food and Drug Administration.
Primary Endpoint and Secondary Measures
According to Chief Medical Officer Erin Foff, the twice-daily arm recorded a least-squares mean PANSS improvement of 11.7 points, compared with a 7.2-point improvement for placebo. The 4.5-point difference represented an effect size of 0.37 and was statistically significant after multiplicity adjustment.
The once-daily arm separated numerically from placebo on PANSS total score but did not achieve statistical significance on the primary endpoint. Foff said the once-daily regimen had lower total daily exposure than the twice-daily dose, although it showed separation on several secondary measures, including the Clinical Global Impression-Severity scale and positive-symptom measures.
In a pre-specified completer analysis using observed data from participants who completed the assessment period, the twice-daily regimen showed a 6-point difference from placebo and an effect size of 0.5. The company also reported statistically significant improvement on the Clinical Global Impression-Severity measure, with an effect size of 0.48.
On positive symptoms, the twice-daily regimen showed statistically significant results on both the PANSS positive Marder factor and PANSS positive subscale. The positive subscale result had an effect size of 0.56, according to the company.
- Participants receiving twice-daily ML-007C-MA were 2.4 times more likely to achieve a 30% improvement in PANSS total score by week five, Maplight said.
- They were also 2.8 times more likely to be considered ready for discharge from the inpatient setting.
- The PANSS negative factor showed numerical separation but did not reach statistical significance.
Cognitive Finding and Safety Profile
Maplight also highlighted a pre-specified cognitive endpoint. Among participants with cognitive impairment at baseline, the twice-daily arm showed an improvement versus placebo on a Cogstate cognitive composite score, with an effect size of 0.51 and a reported p-value of 0.041.
Foff said the company found no significant correlation between changes in cognition and PANSS scores in that population, which Maplight said suggests the cognitive finding was not simply a result of reduced psychotic symptoms. The company said no therapy has been approved specifically for cognitive impairment associated with schizophrenia.
ML-007C-MA was generally well tolerated, according to Maplight. The company reported no serious treatment-emergent adverse events and no drug-related severe adverse events in the active-treatment arms. A severe pneumonia event was deemed unrelated to study drug, while the single serious adverse event of worsened schizophrenia occurred in the placebo group.
All-cause discontinuation among actively treated participants was 19.9%. In the twice-daily arm, 7.1% of participants discontinued due to treatment-emergent adverse events, while two participants discontinued because of gastrointestinal adverse events. Four participants in the twice-daily group reduced their dose due to adverse events.
Foff said gastrointestinal events were primarily mild to moderate, and Maplight reported no hepatic, metabolic, weight-related or movement-disorder safety signal, as well as no urinary-retention signal. The company also said ML-007C-MA has no fasting requirement and uses a one-dose titration approach.
Next Steps in Schizophrenia and Alzheimer’s Disease Psychosis
Kroeger said Maplight plans two additional confirmatory pivotal schizophrenia studies following its FDA meeting. ZEPHYR-2 is expected to replicate the twice-daily arm of ZEPHYR in a similarly sized, two-arm U.S. study. ZEPHYR-3 is also expected to evaluate the twice-daily regimen and could assess alternative dosing regimens, including a potential once-daily option.
The company said an exposure-response analysis remains ongoing after it observed lower exposures in ZEPHYR than in its Phase I studies. Kroeger said the company is examining factors that could affect gastric retention, including timing relative to meals and time of day.
Separately, Maplight’s VISTA study of ML-007C-MA in Alzheimer’s disease psychosis is ongoing and remains on track for top-line results in the second half of 2027. VISTA uses the same twice-daily dose that met the primary endpoint in ZEPHYR.
Kroeger said Maplight believes the combination of psychosis efficacy, the cognitive result and tolerability could differentiate ML-007C-MA in schizophrenia and support its broader development in Alzheimer’s disease-related conditions.
About Maplight Therapeutics (NASDAQ:MPLT)
We are a clinical-stage biopharmaceutical company focused on improving the lives of patients suffering from debilitating central nervous system, or CNS, disorders. We were founded by globally recognized leaders in psychiatry and neuroscience research to address the lack of circuit-specific pharmacotherapies available for patients. Our discovery platform holds the potential to fill this void by identifying neural circuits causally linked to disease and targeting those circuits for therapeutic modulation.
