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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.
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KarXT consists of xanomeline, a muscarinic acetylcholine
receptor agonist, and trospium chloride, a muscarinic receptor
antagonist that block xanomeline from binding to receptors
outside the central nervous system, improving safety profile
of the drug.
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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.
With the
backing of PureTech and Wellcome Trust, Karuna plans to conduct a safety proof of
concept study this year to demonstrate the improvements in xanomeline’s safety
profile, followed by a Phase II efficacy study.
