Karuna Pharmaceutical’s lead program, KarXT, targets the muscarinic system and is composed of xanomeline, a novel clinical-stage 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).
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 including a PET study establishing receptor occupancy. Over 150 patients have been dosed for up to six months, with a subset of these patients having been dosed for up to two 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 Alzhiemer’s, xanomeline demonstrate a robust, dose-dependent reduction in behavioral symptoms (e.g., hallucinations, delusions).
While xanomeline alone has displayed strong efficacy, it has side effects associated with binding to muscarinic receptors outside the central nervous system. Karuna believes that combining trospium chloride with xanomeline has the potential to reduce side effects typically seen with xanomeline alone. As a muscarinic antagonist (blocker), trospium chloride could potentially inhibit xanomeline’s binding to the peripheral muscarinic receptors, and therefore improve xanomeline’s safety profile. At the same time, since it has been shown that trospium chloride does not enter the central nervous system, it would not inhibit xanomeline’s binding to muscarinic receptors in the brain, leaving xanomeline’s efficacy profile unchanged. Trospium chloride is approved by the FDA and is now a generic.
Karuna has a worldwide exclusive license for xanomeline and has a patent portfolio more broadly covering selective muscarinic targeting enabled by the KarXT approach.