Treatment of schizophrenia, which affects over 20 million individuals across the globe, has historically relied on blockade of dopamine D2 receptors. This dopamine-based treatment strategy has many shortcomings, including lack of efficacy for positive (psychotic) symptoms in a significant portion of patients, lack of efficacy for non-positive symptoms (including cognitive impairment and negative symptoms such as asociality and anhedonia) in nearly all patients, and risk of severe, long-term side effects (including movement disorders such as tardive dyskinesia and cardiometabolic issues).

A new era of treatment strategies seems to be dawning with an increasing focus of research and development on novel, non-D2 receptor-targeting agents. Of these novel strategies, modulation of cholinergic, muscarinic receptors is one of the leading mechanisms showing positive clinical trial results in terms of efficacy for schizophrenia symptoms, safety, and tolerability. In particular, muscarinic M1 and M4 receptor agonism show great promise. Given that these two muscarinic receptors differ in terms of their locations and functions (Figure), numerous trials are underway investigating modulation of both M1 and M4 receptors, either alone or in combination.

Recent positive results for Neurocrine Biosciences’ selective M4 orthosteric agonist, NBI-1117568 (which acts the same site on the M4 receptor as the natural ligand, acetylcholine), join the growing evidence base for a muscarinic approach to schizophrenia treatment. In a Phase II trial of once-daily NBI-1117568 (20 mg) in 210 adults with schizophrenia, patients taking the M4 agonist demonstrated significant improvement on the PANSS Total Score (-18.2 change from baseline) at 6 weeks as well separation from placebo (-7.5 mean difference; p=0.011). Furthermore, 20 mg/day NBI-1117568 showed significant improvements on the Clinical Global Impression Severity Scale and the Marder Factor Score for both positive and negative symptoms of schizophrenia.

In addition to demonstrating efficacy in the treatment of schizophrenia, this dose-finding Phase II trial also showed that 20 mg/day NBI-1117568 is safe and tolerable for patients with schizophrenia. The most commonly reported side effects were somnolence, dizziness, and headache while gastrointestinal side effects (which are often a concern when cholinergic modulation is involved) occurred infrequently and were similar to placebo. Perhaps most notably, cardiovascular, metabolic, and movement-related side effects were not an issue (as they so commonly are with our current dopamine D2 receptor targeting antipsychotics).

These results, in addition to the growing evidence from clinical trials of other muscarinic M4 and/or M1 receptor modulators, offer great hope for emerging therapeutics that address the unmet needs of the many patients with schizophrenia who do not respond well to or tolerate dopamine D2 receptor blockade.

Reference:

Neurocrine Biosciences, Inc. Press Release