KarXT is a co-formulation of Xanomeline, a dual M1 and M4 receptor agonist, and trospium chloride, a pan-mAChR antagonist approved for an overactive bladder.

M4 and M1 agonists may reduce psychotic symptoms by reducing presynaptic dopamine release via bottom-up and top-down dopamine modulation.

In the initial trials, whilst Xanomeline showed antipsychotic efficacy, its tolerability was limited due to dose-dependent cholinergic adverse events such as nausea, vomiting, diarrhoea, sweating, and hypersalivation mediated by stimulation of peripheral muscarinic cholinergic receptors.

Trospium, a peripherally restricted muscarinic receptor antagonist, can reduce the peripheral cholinergic effects of Xanomeline. In addition, Trospium has a strong positive charge on the ammonium group, which makes trospium too hydrophilic to cross the blood-brain barrier and, therefore, has limited central anticholinergic effects.

The synergy thus provides an agent with improved efficacy and tolerability.

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As KarXT does not act on D2 or histamine receptors, it does not pose a risk of D2-related movement disorders and adverse metabolic effects.

Trial results:

On March 20th, Karuna Therapeutics announced positive results from a Phase 3 clinical trial evaluating the effectiveness, safety, and tolerability of KarXT (xanomeline-trospium) in patients with schizophrenia. The trial showed KarXT was associated with a significant and clinically relevant reduction of 8.4 points in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at week 5, with a Cohen’s d effect size of 0.60.

This result adds to the previous positive results.

In a randomised, placebo-controlled phase 2 clinical trial (EMERGENT-1), KarXT significantly improved least square mean PANSS scores in patients with schizophrenia compared with placebo. In addition, cholinergic or anticholinergic adverse events were reported more frequently in the KarXT group, but this did not increase trial discontinuations. 182 patients were enrolled and randomly assigned 1:1 to receive KarXT or placebo twice daily for 5 weeks. The primary endpoint was the change from baseline to week 5 in PANSS total score. Secondary endpoints included changes in PANSS positive and negative symptom subscores and the change from baseline in the CGI-S scale.

More recently, initial results from a multicentre phase 3 clinical trial (EMERGENT-2; NCT04659161) were presented on a poster at Psych Congress in September 2022, which showed that KarXT significantly reduced PANSS total scores after 5 weeks compared with placebo. Complete results of EMERGENT-2 are expected to be published in mid-late 2023.

The recent Phase 3 trial builds on the promising results from the previous trials and confirms the potential of KarXT as a treatment for patients with schizophrenia.

The drug’s ability to reduce psychotic symptoms without causing D2-related movement disorders and adverse metabolic effects makes it a promising candidate for further development. The complete results of the Phase 3 trial are eagerly awaited and will provide more information on the efficacy and safety of KarXT in patients with schizophrenia.