KarXT

KarXT is an investigational oral dual-drug fixed-dose combination of xanomeline and trospium. It is undergoing a phase 3 clinical trial for the treatment of schizophrenia. Xanomeline is a functionally preferring muscarinic M4 and M1 receptor agonist that readily passes into the central nervous system (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 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.[1] 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.[2] Unlike direct dopamine D2 and serotonin 5HT2A blocking antipsychotic medications, M4 and M1 receptor stimulation indirectly rebalances dopaminergic and glutamatergic circuits involved in the symptoms associated with neurological and neuropsychiatric diseases such as schizophrenia and Alzheimer’s disease. Based on preclinical pharmacological and genetic studies, M4 receptors appear to modulate both psychosis and cognitive symptom domains and M1 predominantly modulates cognitive symptom domains and modestly regulates psychosis symptom domains.[3][4]

## History

Xanomeline was first synthesized in a collaboration between pharmaceutical firms Eli Lilly and Novo-Nordisk with the goal of delaying cognitive decline in patients with 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.[5] In a follow-up placebo-controlled study in patients with treatment resistant schizophrenia, similar antipsychotic activity was observed with xanomeline.[6] 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.[7] In March 2023, Karuna Therapeutics announced that KarXT had met its primary endpoint in a phase III trial, EMERGENT-3, and that it was submitting the drug for approval by the Food and Drug Administration.[8]

On November 29, 2023, Karuna Therapeutic announced that the FDA has officially begun its review and the PDUFA date has been set for September 26, 2024.[9]

## References

1. ↑ Shannon, Harlan E.; Rasmussen, Kurt; Bymaster, Frank P.; Hart, John C.; Peters, Steven C.; Swedberg, Michael D.B.; Jeppesen, Lone; Sheardown, Malcolm J. et al. (May 2000). "Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice". Schizophrenia Research 42 (3): 249–259. doi:10.1016/s0920-9964(99)00138-3. ISSN 0920-9964. PMID 10785583. http://dx.doi.org/10.1016/s0920-9964(99)00138-3.
2. ↑ Volpicelli, Laura A.; Levey, Allan I. (2004), Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus, Progress in Brain Research, 145, Elsevier, pp. 59–66, doi:10.1016/s0079-6123(03)45003-6, ISBN 9780444511256, PMID 14650906, http://dx.doi.org/10.1016/s0079-6123(03)45003-6, retrieved 2022-08-05
3. ↑ Woolley, Marie L.; Carter, Helen J.; Gartlon, Jane E.; Watson, Jeanette M.; Dawson, Lee A. (January 2009). "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". European Journal of Pharmacology 603 (1–3): 147–149. doi:10.1016/j.ejphar.2008.12.020. ISSN 0014-2999. PMID 19111716. http://dx.doi.org/10.1016/j.ejphar.2008.12.020.
4. ↑ Paul, Steven M.; Yohn, Samantha E.; Popiolek, Michael; Miller, Andrew C.; Felder, Christian C. (2022-06-27). "Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia". American Journal of Psychiatry 179 (9): 611–627. doi:10.1176/appi.ajp.21101083. ISSN 0002-953X. PMID 35758639. http://dx.doi.org/10.1176/appi.ajp.21101083.
5. ↑ Bodick, N. C.; Offen, W. W.; Levey, A. I.; Cutler, N. R.; Gauthier, S. G.; Satlin, A.; Shannon, H. E.; Tollefson, G. D. et al. (1997-04-01). "Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease". Archives of Neurology 54 (4): 465–473. doi:10.1001/archneur.1997.00550160091022. ISSN 0003-9942. PMID 9109749. http://dx.doi.org/10.1001/archneur.1997.00550160091022.
6. ↑ Shekhar, Anantha; Potter, William Z.; Lightfoot, Jeffrey; Lienemann, John; Dubé, Sanjay; Mallinckrodt, Craig; Bymaster, Frank P.; McKinzie, David L. et al. (August 2008). "Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia". American Journal of Psychiatry 165 (8): 1033–1039. doi:10.1176/appi.ajp.2008.06091591. ISSN 0002-953X. PMID 18593778. http://dx.doi.org/10.1176/appi.ajp.2008.06091591.
7. ↑ Brannan, Stephen K.; Sawchak, Sharon; Miller, Andrew C.; Lieberman, Jeffrey A.; Paul, Steven M.; Breier, Alan (2021-02-25). "Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia". The New England Journal of Medicine 384 (8): 717–726. doi:10.1056/NEJMoa2017015. ISSN 1533-4406. PMID 33626254.
8. ↑ "Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia". March 20, 2023. https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-positive-results-phase-3-0.
9. ↑ "FDA kicks off review of Karuna’s schizophrenia drug KarXT". pharmaphorum. 2023-11-29. https://pharmaphorum.com/news/fda-kicks-review-karunas-schizophrenia-drug-karxt.

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