KarXT is an investigational oral dual-drug fixed-dose combination of

xanomeline Xanomeline (LY-246,708; Lumeron, Memcor) is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatme ...

and trospium. It is undergoing a phase 3 clinical trial for the treatment of patients suffering from the symptoms of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

. Xanomeline is a functionally preferring muscarinic M4 and M1 receptor agonist that readily passes into the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

(CNS) to stimulate these receptors in key areas of the brain. Trospium is a non-selective muscarinic antagonist that does not cross into the CNS and reduces peripheral

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...

side effects associated with xanomeline.

Mechanism of action

Preclinical data supports the hypothesis that xanomeline’s central mechanism of action is mediated primarily through stimulation of brain muscarinic M4 and M1 receptors. M4 muscarinic receptors are most highly expressed in the midbrain, which controls motor and action planning, decision-making, motivation, reinforcement, and reward perception. M1 muscarinic receptors are most highly expressed in the cerebral cortical regions, which regulate higher-level processes including language, memory, reasoning, thought, learning, decision-making, emotion, intelligence, and personality. Unlike direct dopamine D2 and

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

5HT2A The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor, but has several intracellular locations. 5-HT is sh ...

blocking antipsychotic medications, M4 and M1 receptor stimulation indirectly rebalances

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...

and

glutamatergic Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/ aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonist ...

circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such as schizophrenia and

Alzheimer’s disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate both

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...

and cognitive symptom domains and M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.

History

Xanomeline was first synthesized in a collaboration between pharmaceutical firms

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and r ...

and Novo-Nordisk with the goal of delaying the cognitive decline in patients suffering from Alzheimer’s disease. In a phase 2 study, significant improvements in cognition were observed in Alzheimer’s patients along with surprising improvements in psychotic symptoms. In a follow-up placebo-controlled study in patients with treatment resistant schizophrenia, similar antipsychotic activity was observed with xanomeline. However, cholinergic-mediated side effects prevented advancement of xanomeline into phase 3 trials. Xanomeline was licensed to Karuna Therapeutics in 2012 and KarXT was subsequently created as a dual drug formulation by adding trospium. Trospium is a non-brain-penetrant and non-selective muscarinic receptor blocker that may ameliorate the peripheral side effects of xanomeline. In a 2021 placebo controlled phase 2 clinical trial, KarXT met the primary endpoint.

References

{{reflist Muscarinic agonists Combination drugs