¹Oban BioPharma, R&D, Stamford, CT 06901, United States, ²Oban BioPharma, Chemistry, Stamford, CT 06901, United States, ³Oban BioPharma, CSO, Stamford, CT 06901, United States, ⁴Oban BioPharma, CEO, Stamford, CT 06901, United States

Background: The FDA approval of Cobenfy™ (xanomeline/trospium) established muscarinic receptor modulation as a validated approach for schizophrenia treatment. While Cobenfy™ avoids extrapyramidal side effects and weight gain associated with dopamine antagonists, anticholinergic side effects from trospium remain a limitation. Xanomeline’s antipsychotic efficacy derives primarily from M4 muscarinic receptor agonism, while peripheral side effects involve M2/M3 receptors.

Aims & Objectives: To discover and develop a highly selective M4 ago-PAM (combined agonist and positive allosteric modulator) with improved efficacy and reduced off-target effects compared to existing muscarinic therapies.

Method: Virtual libraries (>14 billion compounds) were screened using OpenEye software and cryo-EM structures of human muscarinic receptors. Compounds with high M4-selective docking scores were assessed for drug-like properties using AI/machine learning. High-scoring compounds were synthesized and tested for M4 agonist and PAM activity in cells expressing human M4 receptors using G protein readouts. Lead compound OBN-06 was evaluated for pharmacokinetics and efficacy in rodent models of amphetamine- and PCP-induced hyperactivity and amphetamine-induced PPI impairment.

Results: OBN-06 exhibited M4 PAM activity (EC50=54 nM, Emax=85%) and agonist activity (EC50=115 nM, Emax=51%), with negligible M2 ago-PAM activity. Pharmacokinetic properties included favorable metabolic stability (T½ >145 min; CYP IC50 >50 μM), high free fraction (19.9%), oral bioavailability (>90%), and favorable CNS penetration (primate CSF:plasma=1), with predicted human T½ >12 hours suitable for once-daily dosing. In amphetamine-evoked hyperlocomotion in wild-type mice, dose-related inhibition occurred at 10 mg/kg p.o. (p<0.01) and 30 mg/kg p.o. (p<0.0001). The 30 mg/kg dose also reversed PCP-induced hyperlocomotion (p<0.0001) and amphetamine-induced PPI impairment (p<0.01). In human M4 receptor knock-in mice, 0.3 mg/kg p.o. provided robust inhibition of amphetamine-evoked hyperlocomotion (p<0.0001), comparable to maximum effects at 30 mg/kg in wild-type animals, while emraclidine at the same dose showed no effect. OBN-06 was well-tolerated in rats and monkeys without the tachycardia observed with xanomeline.

Discussion & Conclusions: OBN-06 represents a novel M4 ago-PAM with robust activity in rodent antipsychotic models and favorable ADME/safety profiles. The ~100-fold potency shift observed in humanized M4 knock-in mice compared to wild-type animals supports strong translational potential. These findings support further development for schizophrenia treatment, with Phase 1a/1b studies planned for Q3 2026. Studies supported by Oban BioPharma, Inc.