MapLight Therapeutics announced this week that its candidate drug for treatment of schizophrenia had achieved its primary endpoint in a Phase II trial, but only at the twice daily dose tested in the trial.
As reported by the California-based company, while participants of the trial who were given the candidate drug, ML-007C-MA, once a day did show some signs of improvement it was not statistically significant.
ML-007C-MA is a combined muscarinic agonist (betovumeline) and peripherally acting anticholinergic (fesoterodine). It acts by turning on two receptors in the brain, M1 and M4.
M1 is the main receptor the drug is trying to stimulate in the brain cortex and hippocampus, where it is linked to cognition, attention, and possibly some aspects of psychosis. Turning on M4 also helps by acting like a brake on the overactive signaling that contributes to hallucinations and delusions. Betovumeline activates both M1 and M4 centrally, while fesoterodine is there mainly to block unwanted side effects outside the brain, like gastrointestinal issues.
In this study, MapLight randomized 307 adults with an acute exacerbation of schizophrenia to treatment with either a twice daily or once daily treatment with ML-007C-MA or placebo for five weeks.
At five weeks, patients given the twice daily dose had a statistically significant and clinically meaningful reduction in Positive and Negative Syndrome Scale (PANSS) total score of 4.5 points compared to placebo. Cognitive scores were also better in the twice daily group versus placebo.
While this result is positive overall, the non-statistically significant result for the once daily dose proved unpopular with investors and company shares on the Nasdaq fell 40% after the announcement.
In September 2024, Cobenfy, the first muscarinic M1/M4 agonist drug for treatment of schizophrenia was approved by the FDA. Now owned by BMS, Cobenfy will be the main competitor for ML-007C-MA if approved.
Cobenfy was groundbreaking because it was the first new mechanism of action for schizophrenia in decades, moving beyond dopamine blockade to a muscarinic approach and targeting both hallucinations and delusions as well as the more cognitive aspects of the disease, which are not well treated with other drugs.
Despite the approval of Cobenfy, a number of other competitors developing treatments for schizophrenia have failed in recent years. Whether MapLight can succeed at Phase III with ML-007C-MA—which is also being tested as a treatment for psychosis linked to Alzheimer’s disease—and compete with Cobenfy, remains to be seen.
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