ML-007C-MA, A NOVEL INVESTIGATIONAL M1/M4 MUSCARINIC AGONIST IN PHASE 2 DEVELOPMENT FOR THE TREATMENT OF SCHIZOPHRENIA AND ALZHEIMER’S DISEASE PSYCHOSIS

Muscarinic agonists have emerged as a new class of therapeutic agents for the treatment of psychosis with a mechanism distinct from typical and atypical antipsychotics. M1 and M4 receptor subtypes show the highest expression in brain regions implicated in psychosis, negative symptoms, and cognition, and thus have therapeutic potential across several neuropsychiatric disorders including schizophrenia and Alzheimer’s disease psychosis. ML-007C-MA is an investigational fixed-dose combination of a novel M1/M4 muscarinic agonist, ML-007 and fesoterodine fumarate, a peripherally-acting muscarinic antagonist. Fesoterodine is ideally suited for the combination due to its low brain penetration, predictable pharmacokinetics, and favorable physicochemical properties that enabled precision matching of the exposure profiles. By synchronizing the pharmacokinetic exposures of agonist and antagonist components in the periphery, ML-007C-MA was designed to mitigate cholinergic side effects while maintaining strong activation of M1 and M4 receptors in the brain to drive efficacy. In preclinical evaluations, ML-007 was determined to be a potent brain-penetrant agonist at both M1 and M4 receptors with high oral bioavailability, low protein binding, and low peripheral tissue accumulation. ML-007 also showed robust activity across mouse models of psychosis and cognitive impairment. Four Phase 1 clinical trials were then conducted, with a total of 270 healthy participants and more than 1,500 doses of ML-007 administered alone, co-administered, or co-formulated with fesoterodine. These trials evaluated a broad range of doses and dose ratios to identify an optimal range of agonistto-antagonist ratios to minimize peripheral cholinergic side effects. This ratio was then coformulated into a fixed dose product, ML-007C-MA that was found to be generally well tolerated with minimal titration at doses selected for Phase 2 studies. Most treatmentemergent adverse events were mild and transient in nature, with no severe or serious adverse events observed. Pharmacokinetic parameters were similar between adult and elderly study participants and confirmed that dosing in the Phase 2 trials did not require administration in a fasted state. ML-007C-MA has the potential to be a well-tolerated treatment option that is currently being evaluated in two Phase 2 clinical trials: the ZEPHYR trial for schizophrenia and the VISTA trial for Alzheimer’s disease psychosis.