Breakthrough Schizophrenia Drug Gets U.S. Approval

Brain activity is represented in gold (artist's illustration). A recently approved antipsychotic medication achieves its effects by activating brain proteins called muscarinic receptors. Credit: Sebastian Kaulitzki/Science Photo Library

The first schizophrenia drug with a new mechanism of action in decades won U.S. regulatory approval today. This approval gives hope for an antipsychotic that is more effective and better tolerated than current therapies.

The drug, known as KarXT, targets proteins in the brain called muscarinic receptors, which relay neurotransmitter signals between neurons and other cells. Activation of these receptors dampens the release of the chemical dopamine, a nervous system messenger that is central to the hallmark symptoms of schizophrenia, such as hallucinations and delusions.

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But muscarinic signaling also modulates other brain circuits involved in cognition and emotional processing. This mode of action gives KarXT a more comprehensive therapeutic effect than other schizophrenia treatments, which primarily attenuate dopamine activity alone.

In clinical trials, KarXT not only alleviated core symptoms of schizophrenia, but also showed signs of improved cognitive function, while avoiding many of the burdensome side effects typically associated with older antipsychotics.

This will be a revolution in the treatment of psychosis, and I don't say that lightly, says Christoph Correll, a psychiatrist at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, who helped analyze the data from the tests. We will now be able to treat people who have not been helped by traditional antipsychotics. It's very exciting.

Hope for a tailor-made treatment

KarXT is just the first in a long line of next-generation drug candidates designed to interact with muscarinic receptors in the brain. Several follow-up therapies for schizophrenia are already in or near clinical trials, showing promise in terms of improved tolerability and more practical dosing regimens.

These advances lead clinicians and drug developers to imagine a future in which schizophrenia treatment is better tailored to individual needs, providing an alternative to the many people who do not benefit from current therapies or abandon them due to side effects. intolerable.

This offers an option that is completely outside of the toolbox we currently have, says Ann Shinn, a psychiatrist at McLean Hospital in Belmont, Mass., who has no commercial ties to KarXT.

From rejection to rebirth

KarXT dates back to the early 1990s, when researchers at Eli Lilly in Indianapolis, Indiana, began developing xanomeline, a muscarinic enhancing agent designed primarily to boost memory in people with Alzheimer's disease, but it has been explored as a potential treatment for schizophrenia. Also.

Trials showed that the drug provided both antipsychotic and cognitive benefits1,2. But xanomeline also caused nausea, vomiting, and stomach pain because muscarinic receptors are active in the gut as well as the brain, leading Lilly to ultimately put the drug aside.

Flashes of activity (red and yellow; artificially colored) light up the brain of a person suffering from hallucinations caused by schizophrenia. Credit: Wellcome Center Human Neuroimaging/Science Photo Library

Years later, biotechnology executive Andrew Miller developed a strategy to revive the therapy. He recognized that administering the muscarinic activating agent with another compound blocking the effects of xanomelines outside the brain could maintain the cognitive and antipsychotic benefits without causing serious gastrointestinal distress.

In 2009, Miller started a company called Karuna Therapeutics, based in Boston, Massachusetts. Karuna combined xanomeline with a drug called trospium. This well-known molecule blocks muscarinic receptors and does not cross the blood-brain barrier, meaning it selectively prevents side effects in the gut without interfering with the action of xanomelines in the brain.

Thus KarXT was born.

In clinical trials, the two-in-one pill outperformed a placebo in relieving the characteristic symptoms of schizophrenia,3,4 without the weight gain, sedation, or movement problems that are typically associated with existing antipsychotics. KarXT's side effects were largely limited to intestinal upset, which tended to go away after a week or two of daily use.

There were also clear signs of cognitive benefits, with preliminary indications5 that KarXT may also help alleviate symptoms such as weakened emotions and lack of motivation. That's encouraging, says Stephen Marder, a psychiatrist at the University of California, Los Angeles, of these side effects. (Marder participated in some analyses). But these effects need to be verified in a targeted study, he says.

High price

The drug has some drawbacks. On the one hand, it requires twice-daily dosing, and studies indicate that more frequent dosing regimens are linked to higher rates of noncompliance and treatment discontinuation in people with schizophrenia6. That's a big limitation, says Nate Sutera, a psychiatric pharmacist at the University of Nebraska Medical Center in Omaha, especially because many antipsychotics are now available in long-acting injectable form, requiring only a few doses per year.

KarXT is also priced at an estimated US$20,000 per year7, raising concerns among health economists about its cost-effectiveness compared to alternatives. Despite this, most industry analysts predict strong demand, with peak annual sales estimated in the billions. That potential prompted Bristol Myers Squibb (BMS) of Princeton, New Jersey, to acquire Karuna for about $14 billion this year.

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Other drugmakers also see value in targeting muscarinic receptors, pursuing various strategies to improve KarXT's profile. Some are developing formulations with more convenient dosing regimens. Others focus on greater target selectivity, aiming to design molecules that activate only specific muscarinic receptors, either the M1 receptor, linked to cognitive benefits, or the M4 receptor, which underlies antipsychotic effects, but not both, like KarXT does.

One of these drug candidates, an M4-selective agent called emraclidine, appears to offer antipsychotic effects similar to those of KarXT, with improved tolerability, although it potentially offers less cognitive benefit, according to early clinical testing8.

Former Karuna CEO Steven Paul, a psychiatrist now at Washington University School of Medicine in St. Louis, Missouri, welcomes the wave of innovation in targeting muscarinic signaling that KarXT has helped liberate and he's eager to discover the best ways to harness that. therapeutic strategy.

We now have new biology and new pharmacology to explore, he says. It will be fun and scientifically relevant and hopefully clinically beneficial for patients to find out.

Sources 1/ https://Google.com/ 2/ https://www.nature.com/articles/d41586-024-03123-9 The mention sources can contact us to remove/changing this article

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