Karuna Pharmaceuticals are a clinical-stage biopharmaceutical company driven to create and deliver transformative medicines for people living with psychiatric and neurological conditions.
KarXT is Karuna's lead product candidate that 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. Karuna 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. Karuna believes 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.
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.
Karuna's 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.
Organisation
Address: 33 Arch Street Suite 3110 Boston, MA 02110
Country: United States of America
Email: info@karunatx.com
