Karuna Pharmaceutical’s lead program, KarXT, is a clinical stage program targeting the muscarinic acetylcholine receptors composed of xanomeline, a novel muscarinic acetylcholine receptor agonist (activator) and trospium chloride, an FDA-approved and well-established muscarinic receptor antagonist (blocker) that has been shown not to enter the central nervous system. 

The muscarinic receptors in the nervous system bind to acetylcholine (a neurotransmitter). There are five types of muscarinic receptors (M1-M5), all of which are expressed in the brain, with the M2 and M3 receptors also significantly expressed in the periphery outside the brain (e.g., in sweat glands, salivary glands and the GI tract). Activation of muscarinic receptors outside of the brain is associated with side effects (e.g. GI adverse events).  The muscarinic system has long been of interested for drug development, however, side effects associated with activation of peripheral muscarinic receptors has not allowed any medicine to reach the market.  KarXT is a novel approach designed specifically to overcome this fundamental roadblock and unlock the potential of muscarinic agonists that has yet to be realized.  Karuna's first clinical trial demonstrated the proof-of-concept for the KarXT approach by showing that trospium could significantly improve the tolerability profile of xanomeline in healthy volunteers, enabling further development.  

Xanomeline has demonstrated efficacy in reducing psychosis and improving cognition in placebo-controlled human trials in both Alzheimer’s disease and schizophrenia. Xanomeline has been dosed to date in over 800 subjects and with 150 patients have been dosed for up to six months and a subset of these patients having been dosed for up to three years. In a double-blind, placebo-controlled monotherapy trial in schizophrenia patients, a significant 24-point reduction over placebo was observed in the Positive and Negative Symptom Scale (prespecified primary endpoint), a gold standard instrument used for FDA approval.   Current antipsychotic medicines typically show a 5-10 pt change over placebo in trial of this type.  In a Phase II study in Alzheimer's, xanomeline demonstrated a robust, dose-dependent reduction in behavioral symptoms (e.g., hallucinations, delusions) and provided evidence of cognitive benefit. 

The clinical data with xanomeline significantly de-risks KarXT development moving forward by providing a clear efficacy signal in humans and long term safety data devoid of the safety issues that are associated with current antipsychotic medicines - tardive dyskinesia, metabolic dysfunction, weight gain, glucose intolerance, sedation and others. This data provides KarXT with significant data not typically available to a development program entering Phase II and provides a level of validation well beyond the animal model data that often is the key support for novel MOA CNS programs prior to Phase II readout.

Karuna has a worldwide exclusive license for xanomeline and has a patent portfolio more broadly covering selective muscarinic targeting enabled by the KarXT approach.