KarXT

Current antipsychotic medicines rely on the same primary pathway and approach of inhibiting D2 dopamine receptors, and frequently 5HT-52A serotonin receptors, and are often used by physicians to address a wide range of psychiatric conditions, including schizophrenia and bipolar disorder, among others.

While these medicines have been the standard of care for many years, people living with psychiatric conditions, such as schizophrenia, their doctors, and researchers have been looking for alternatives to improve treatment outcomes.

This has led to interest in investigating treatments that work through different neurotransmitters such as acetylcholine, located in the cholinergic pathway. Within the cholinergic pathway, acetylcholine interacts with a type of receptor called the muscarinic receptor. There are five distinct muscarinic receptors, M1-M5, found in the brain as well as various peripheral tissues.

Muscarinic receptor agonists emerged in the 1990s as a promising new approach for treating psychosis and cognitive impairment. The link between muscarinic receptor stimulation in the central nervous system (CNS), particularly the stimulation of M1 and M4 receptors, and the reduction of symptoms of psychosis and improvement in cognition, has been well studied and is supported by research from preclinical studies and clinical trials. However, the successful development of a therapy targeting muscarinic receptors has been limited by undesirable side effects that are believed to arise primarily as a result of stimulation of muscarinic receptors in peripheral tissues.

KarXT is an oral, investigational M1/M4-preferring muscarinic agonist in development for the treatment of psychiatric and neurological conditions, including schizophrenia and psychosis in Alzheimer’s disease.

KarXT, comprised of muscarinic agonist xanomeline and muscarinic antagonist trospium, is designed to preferentially stimulate muscarinic receptors in the CNS, and unlock the therapeutic potential of xanomeline while ameliorating side effects seen in earlier studies.

Research indicates that activity at M1 and M4 receptors indirectly affects dopamine neurotransmission in brain regions involved in mediating symptoms of serious mental illness, such as psychosis in Alzheimer’s disease, as well as the positive, negative, and cognitive symptoms of schizophrenia.^1-6

KarXT is the first potential medicine of its kind with a truly new and unique dual mechanism that doesn’t rely on the dopaminergic or serotonergic pathway to treat symptoms of serious mental illness. This approach has the potential to provide a differentiated therapy, and, if approved, to beneficially impact the lives of millions of people with serious mental illness.

1. Woolley ML, Carter HJ, Gartlon JE, Watson JM, Dawson LA. Attenuation of amphetamine-induced activity by the non-selective muscarinic receptor agonist, xanomeline, is absent in muscarinic M4 receptor knockout mice and attenuated in muscarinic M1 receptor knockout mice. Eur J Pharmacol. 2009;603(1-3):147-149.
2. Shannon HE, Rasmussen K, Bymaster FP, et al. Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res. 2000;42(3):249-259.
3. Wess, J., Eglen, R. M. & Gautam, D. Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development. Nature Rev. Drug Discov. 6, 721–733 (2007).
4. Gomeza J, Zhang L, Kostenis E, et al. Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockout mice. Proc Natl Acad Sci U S A. 1999;96(18):10483-10488.
5. Thomsen M, Wess J, Fulton BS, Fink-Jensen A, Caine SB. Modulation of prepulse inhibition through both M(1) and M (4) muscarinic receptors in mice. Psychopharmacology (Berl). 2010;208(3):401-416.
6. Gerber DJ, Sotnikova TD, Gainetdinov RR, Huang SY, Caron MG, Tonegawa S. Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice. Proc Natl Acad Sci U S A. 2001;98(26):15312-15317.