On 26 September 2024, Cobenfy (KarXT) gained US Food and Drug Administration (FDA) approval as the first novel class of antipsychotics in decades. Developed by Karuna Therapeutics, recently acquired by Bristol Myers Squibb, Cobenfy diverges from the industry’s dopamine-dominated approach, targeting muscarinic acetylcholine receptors instead. This landmark approval positions Cobenfy as a unique alternative to the industry-standard dopamine-receptor-based therapies, and highlights the ongoing evolution within the antipsychotic space.

Cobenfy is an innovative small molecule that combines xanomeline and trospium. It is administered as a twice-daily oral medication that works by interacting with muscarinic acetylcholine receptors (mAChR) (M1, M2, M3, and M4) in the brain. Xanomeline acts as a mAChR agonist at the M1 and M4 receptors, increasing striatal acetylcholine levels. Trospium chloride acts as a mAChR antagonist binding to the M2 and M3 receptors, which can lead to reduced psychosis and improved cognition.  

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According to GlobalData’s drugs database, the schizophrenia market is currently dominated by dopamine-targeted mechanisms of action (MoAs), led by D2 receptor antagonism, as seen in Figure 1. Other key MoAs include serotonin-based pathways, such as 5-HT2A receptor antagonists, which rank second overall. In contrast, muscarinic pathways are a new addition to the treatment arsenal, with Cobenfy’s MOA involving the activation of M1 and M4 muscarinic acetylcholine receptors. This pathway may reduce psychosis and improve cognitive function, without the severe side effects often associated with dopamine-modulating drugs. Furthermore, Cobenfy’s mechanism circumvents the FDA’s boxed warning for D2 antagonists, which is associated with motor side effects and increased mortality in elderly dementia patients. This could improve its uptake among certain patient populations and make it highly competitive.

The top 10 MoAs do not include mAChR agonists, which rank 42nd on the list, and Cobenfy is the first marketed product in this space to use this non-dopaminergic approach. Cobenfy’s entry into the market highlights the established market’s reliance on dopamine and serotonin pathways, and its novel mode of action (MoA) could spark further interest in the development of non-dopaminergic therapies.

Cobenfy is not alone, as AbbVie’s emraclidine – a small molecule muscarinic-targeting candidate acquired from Cerevel Therapeutics for schizophrenia – is advancing in development. Emraclidine was anticipated to be a promising candidate for modulating schizophrenia symptoms due to its once-daily dosing. However, on 11 November 2024, AbbVie announced that emraclidine failed to meet its primary endpoint in two Phase II trials, leaving its future in the schizophrenia market uncertain. This emphasises that while muscarinic modulation represents a new frontier, it is still largely untested and may not be a perfect solution. While dopamine-based MoAs will remain dominant in the near term, the entrance of muscarinic drugs such as Cobenfy could reshape the antipsychotic market, providing a more nuanced range of options tailored to efficacy, safety and patient adherence needs. Emraclidine’s recent failure in Phase II trials may hinder AbbVie’s efforts to secure market share in the muscarinic receptor space, potentially reinforcing Cobenfy’s position as the preferred option. As the market matures, close monitoring of drugs such as Cobenfy, and potentially emraclidine, could ultimately provide insights into the potential role of muscarinic modulation as a meaningful complement to established dopamine and serotonin therapies.

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