Programs Pipeline KarXT Novel MOA Supporting Research Pipeline Our pipeline is built on the broad therapeutic potential of our lead product candidate, KarXT, an oral modulator of muscarinic receptors that are located both in the central nervous system (CNS) and various peripheral tissues. KarXT is our proprietary product candidate that combines xanomeline, a novel muscarinic agonist, with trospium, an approved muscarinic antagonist, to preferentially stimulate muscarinic receptors in the CNS. PRODUCT CANDIDATE INDICATION PRECLINICAL PHASE 1 PHASE 2 PHASE 3 KarXT M1-M4 muscarinic agonist Product Candidate: KarXT M1-M4 muscarinic agonist Indication: Schizophrenia Psychosis Schizophrenia Psychosis This item is in Phase 3 Product Candidate: KarXT M1-M4 muscarinic agonist Indication: Schizophrenia Psychosis in adults with inadequate response to standard of care Schizophrenia Psychosis in adults with inadequate response to standard of care This item is in Phase 2 Product Candidate: KarXT M1-M4 muscarinic agonist Indication: Schizophrenia Negative and cognitive symptoms* Schizophrenia Negative and cognitive symptoms* This item is in Phase 1 Product Candidate: KarXT M1-M4 muscarinic agonist Indication: Dementia-related Psychosis Dementia-related Psychosis This item is in Phase 1 KAR-201 Muscarinic-targeted drug candidate Product Candidate: KAR-201 Muscarinic-targeted drug candidate Indication: Undisclosed Undisclosed This item is in the Preclinical phase KAR-301 Muscarinic-targeted drug candidate Product Candidate: KAR-301 Muscarinic-targeted drug candidate Indication: Undisclosed Undisclosed This item is in the Preclinical phase KAR-401 Muscarinic-targeted drug candidate Product Candidate: KAR-401 Muscarinic-targeted drug candidate Indication: Undisclosed Undisclosed This item is in the Preclinical phase KAR-501 Target-agnostic drug candidate^ Product Candidate: KAR-501 Target-agnostic drug candidate^ Indication: Undisclosed Undisclosed This item is in the Preclinical phase ^In collaboration with PsychoGenics; *Planning stage, ongoing collection of data in EMERGENT program & inadequate response trial KarXT Our lead product candidate, KarXT, selectively activates muscarinic acetylcholine receptors in the brain to unlock the therapeutic potential of xanomeline, which previously demonstrated significant benefits in Phase 2 studies in schizophrenia and Alzheimer’s. Xanomeline MUSCARINIC AGONIST Human PoC in double-blind, placebo-controlled trials in schizophrenia and Alzheimer’s Trials enrolled over 800 patients including 68 patients for ≥ 1 year Exclusively licensed from Eli Lilly KarXT XANOMELINE + TROSPIUM CHLORIDE KarXT is designed to ameliorate cholinergic AEs of xanomeline while maintaining it’s efficacy Trospium Chloride MUSCARINIC ANTAGONIST Does not meaningfully cross the blood brain barrier, limiting effects to the peripheral tissues. No known metabolic overlap with xanomeline Generic drug for overactive bladder used since the 1960’s M1 and M4 muscarinic receptors are the receptor subtypes believed to mediate the antipsychotic, procognitive and analgesic effects of xanomeline and other muscarinic agonists. Results from preclinical studies and clinical trials conducted by third parties support the hypothesis that xanomeline can reduce psychosis and improve cognition. Like all muscarinic receptor agonists studied to date, however, xanomeline’s tolerability has been limited by side effects arising from muscarinic receptor stimulation in peripheral tissues, leading to nausea, vomiting, diarrhea and increased salivation and sweating, collectively referred to as cholinergic adverse events. Trospium is a muscarinic receptor antagonist approved in the United States and Europe for the treatment of overactive bladder that inhibits all five muscarinic receptor subtypes in peripheral tissues. We believe that the combination of xanomeline, a centrally- acting muscarinic agonist, and trospium, a peripherally-acting muscarinic antagonist, will have the therapeutic benefits of xanomeline but with markedly reduced side effects. We assessed the potential of over 7,000 possible combinations of muscarinic receptor agonists and antagonists to find an optimized combination that could preferentially stimulate muscarinic receptors in the CNS to improve the symptoms of psychosis, while avoiding stimulation of muscarinic receptors in the peripheral tissues and the associated side effects. As a result of our research, we identified xanomeline and trospium as the most promising pairing for development in the form of KarXT (Karuna-xanomeline-trospium). Trospium is a potent and effective muscarinic receptor antagonist that does not measurably cross the blood-brain barrier, confining its effects to peripheral tissues, and it currently marketed for the treatment of overactive bladder in the U.S. and other territories worldwide. Karuna co-founder and chief operating officer, Andrew Miller, Ph.D., was responsible for identifying the initial hypothesis and driving the execution of the completed Phase I studies supporting the combination of xanomeline and trospium. Despite xanomeline’s promising therapeutic benefit in treating psychosis and related behavioral symptoms in patients with schizophrenia and AD, its potential has been limited by cholinergic side effects, which are believed to result from the stimulation of muscarinic receptors in peripheral tissues. We believe that the above data, as well as our Phase 1 and 2 clinical trials with KarXT demonstrating robust efficacy and significant reductions in the adverse events associated with xanomeline, support the further development of KarXT in multiple neuropsychiatric disorders, including schizophrenia and dementia-related psychosis. Novel MOA Current antipsychotic treatments rely on the same primary mechanism of action (MOA) as they did when the first antipsychotic was discovered in the 1950s: inhibiting D2 dopamine receptors. Current antipsychotics are often used by physicians to address a wide range of neuropsychiatric disorders in addition to schizophrenia, including bipolar disorder and psychotic depression, as well as psychosis and agitation in elderly patients with dementia, but are associated with modest efficacy and significant side effects. Muscarinic receptor agonists emerged in the 1990s as a promising innovative approach for treating psychosis and cognitive impairment. Muscarinic receptors are g-protein linked receptors (GPCRs) that bind the neurotransmitter acetylcholine. There are five distinct muscarinic receptors, M1-M5, found in the brain as well as various peripheral tissues. The link between muscarinic receptor stimulation in the CNS, particularly stimulation of M1 and M4 receptors, and the reduction of psychotic symptoms and cognitive impairment, has been well studied and is supported by data from preclinical studies and randomized, double-blind, placebo-controlled clinical trials with xanomeline published in peer reviewed journals. However, the successful development of a therapeutic agent 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. We believe a therapeutic agent that can preferentially target and stimulate muscarinic receptors in the CNS, but not in peripheral tissues, has the potential to treat psychosis in schizophrenia and AD, including the associated agitation in patients with AD. We also believe the preferential stimulation of M1 and M4 muscarinic receptors in the CNS may address the negative symptoms of schizophrenia, such as apathy, reduced social drive and loss of motivation, as well as cognitive deficits in working memory and attention, all of which currently lack any approved treatments. This approach has the potential to produce a differentiated therapy relative to current D2 dopamine receptor-based antipsychotic drugs and to beneficially impact the lives of millions of patients with schizophrenia and other psychotic and cognitive disorders. Selected Conference Presentations and Manuscripts Choose a Research Area: Clinical Preclinical SAUDER, C., BRANNAN, S.K., ET AL. Characterizing the Antipsychotic Activity and Safety Profile of the Novel Muscarinic Agonist KarXT (Xanomeline + Trospium ): Primary and Secondary Results from a Phase 2 Placebo Controlled Trial in Schizophrenia [Poster #W47]. 2021 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; 2021 June 1-4. BRANNAN, S.K., SAWCHAK, S., ET AL. Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia N Engl J Med 2021; 384:717-726 BRANNAN, S.K., SAWCHAK, S., ET AL. The M1/M4 agonist xanomeline, in combination with the peripheral anticholinergic trospium, is effective for acute treatment of schizophrenia: results of a Phase 2 RCT comparing KarXT vs placebo [Poster #M110]. 59th Annual Meeting of The American College of Neuropsychopharmacology (ACNP); 2020 Dec 6-9. BRANNAN, S.K. Phase 2 trial results of KarXT (xanomeline + trospium) in patients with schizophrenia: superior efficacy to placebo across positive and negative symptoms and a favorable safety/tolerability profile [Oral presentation]. 33rd European College of Neuropsychopharmacology (ECNP) Congress; 2020 Sep 12-15. BRANNAN, S.K. KarXT (a new mechanism antipsychotic based on xanomeline), is superior to placebo in patients with schizophrenia: Phase 2 clinical trial results [Oral presentation]. 2020 American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; 2020 May 29-30. BODICK, N.C., OFFEN W.W., ET AL. Effects of Xanomeline, a Selective Muscarinic Receptor Agonist, on Cognitive Function and Behavioral Symptoms in Alzheimer Disease Arch Neurol. 1997; 54(4): 465–473. FARDE, L., SUHARA, T. ET AL. PET Study of the M1-Agonists [11C]Xanomeline and [11C]Butylthio-TZTP in Monkey and Man. Dementia and Geriatric Cognitive Disorders, 1996; 7(4), 187-195. SHEKAR, A., POTTER, W.Z., ET AL. Selective Muscarinic Receptor Agonist Xanomeline as a Novel Treatment Approach for Schizophrenia American Journal of Psychiatry 2008; 165:1033–1039. © 2021 Karuna Therapeutics™. All Rights Reserved. Privacy Policy. Terms of Use. Our purpose is to create and deliver transformative medicines for people living with psychiatric and neurological conditions About The Unmet Need Programs Careers Investors & Media Contact Top We use cookies on our website to give you the most relevant experience by remembering your preferences and repeat visits. By clicking “Accept”, you consent to the use of ALL the cookies. If you require further information and/or do not wish to have cookies placed when using the site, visit:About Cookies Cookie Settings Accept