M4 PAM for Schizophrenia & Other Psychosis

We are developing muscarinic acetylcholine receptor subtype 4 positive allosteric modulator, or M4 PAM, as a novel orally available treatment for schizophrenia & other psychosis.  Schizophrenia affects approximately 24 million people worldwide, requiring lifelong treatment to reduce severe impact on their everyday life. The market for antipsychotics represents over $7B annual sales in the main markets, growing approximately 3.5% per year. There is a significant need for new treatment options, as currently available antipsychotics, that largely act via direct blockade of dopaminergic neurotransmission, fail to reduce negative symptoms and alleviate cognitive abnormalities, while also being linked to poor tolerability which leads to discontinuation of treatment. 

M4 PAM represents a novel therapeutic approach for the treatment of schizophrenia based on indirect modulation of the dopaminergic neurotransmission.  Therapeutic utility of targeting muscarinic acetylcholine receptors in schizophrenia has been demonstrated in the clinic with the non-selective M1/M4 agonist, xanomeline, which reduced positive and negative symptoms and alleviated cognitive abnormalities in patients with schizophrenia.  Genetic deletion studies in mice demonstrates that the antipsychotic effect of xanomeline is driven exclusively by the M4 receptor subtype. Patients treated with xanomeline experienced gastro-intestinal and cardiovascular side effects, driven largely by its activity on M1 receptors, limiting further development of the drug. 

The allosteric modulation approach allows identification of highly subtype-selective small molecule compounds. Addex used its proprietary allosteric modulation discovery platform to identify highly selective M4 PAMs.  Several structurally differentiated chemical series are currently being optimized to deliver lead compounds demonstrating robust antipsychotic-like effects in multiple rodent models of schizophrenia. 

Subject to regulatory approval, we believe our M4 PAM may offer an advantageous antipsychotic treatment option for schizophrenia with a novel mechanism of action. The program is in lead optimization stage and we expect to initiate clinical candidate selection phase in 2023.