Current treatments for schizophrenia, although effective for some positive symptoms, have not proven as effective for negative symptoms and cognitive dysfunction. And combining antipsychotics, the main treatment options for the disease, with other agents have also yielded disappointing results. To add to that, available drugs have serious side effects, including movement disorders, weight gain, diabetes, risk of metabolic syndrome and sedation.
The Boston-based startup Karuna Pharmaceuticals aim to develop agents that dramatically improve the lives of people living with schizophrenia. Their lead program, KarXT, is composed of xanomeline, a novel clinical-stage muscarinic acetylcholine receptor agonist, and trospium chloride, a FDA-approved and well-established muscarinic receptor antagonist.
Xanomeline has demonstrated efficacy in reducing psychosis and improving cognition in placebo-controlled human trials. In a double-blind, placebo controlled trial, xenomeline showed a significant 24-point reduction over placebo in the Positive and Negative Syndrome Scale (PANSS), a medical scale used for measuring symptom severity of patients with schizophrenia, and gold standard used for FDA approval.
However, it has side effects associated with binding to muscarinic receptors outside the central nervous system, limiting its therapeutic utility. But, trospium chloride, which block xanomeline from binding to muscarinic receptors, is unable to enter the central nervous system. It is therefore believed that combining the two will reduce side effects, ultimately improving xanomeline’s safety profile without inhibiting its efficacy.
The novel drug candidate is based on a growing understanding of the underlying mechanisms of schizophrenia, as well as the muscarinic acetylcholine system. Data from clinical, postmortem, neuroimaging and preclinical and clinical pharmacology studies support the hypothesis of muscarinic acetylcholine system playing a crucial role in schizophrenia. And since acetylcholine also play a crucial role in a variety of the central and peripheral nervous system’s functions, KarXT also has potential in treating other diseases, including Alzheimer’s, Parkinson’s and Huntington’s. Karuna has worldwide exclusive license for xanomeline and a patent portfolio covering selective muscarinic targeting enabled by KarXT. If studies show that KarXT reduce the side effects associated with xanomeline, the drug could significantly improve the lives of millions of people.