Revolutionary drug for schizophrenia receives US approval

The first schizophrenia drug in decades with a new mechanism of action received regulatory approval in the US today. The 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 known as 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 typical symptoms of schizophrenia such as hallucinations and delusions.

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But muscarinic signals also modulate other brain circuits involved in perception 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 the core symptoms of schizophrenia but also showed signs of improving cognitive function while avoiding many of the distressing side effects commonly 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 the exams. “Now we can treat people who have not been helped by conventional antipsychotics. This is very exciting.”

I hope for a tailor-made treatment

KarXT is just the first of many next-generation drug candidates aimed at targeting muscarinic receptors in the brain. Several follow-on therapies for schizophrenia are already in clinical trials or are about to begin and promise improved tolerability and more convenient dosing schedules.

This advance is leading clinicians and drug developers to imagine a future in which schizophrenia treatment is more tailored to individual needs – providing an alternative for the many people who do not benefit from current therapies or discontinue them due to intolerable side effects.

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

From rejection to revival

KarXT’s roots date back to the early 1990s, when researchers at Eli Lilly in Indianapolis, Indiana, began developing xanomeline – a muscarinic inactivating agent designed primarily to improve memory in people with Alzheimer’s disease, but has also been researched as a potential treatment for schizophrenia.

Studies showed the drug provided both antipsychotic and cognitive benefits^1,2. But xanomeline also caused nausea, vomiting and stomach pain — because muscarinic receptors are active in both the gut and the brain — which led Lilly to eventually stop the drug.

Years later, biotech executive Andrew Miller developed a strategy to revive the therapy. He realized that administering the muscarinic inactivating agent along with another compound that blocks xanomeline’s effects outside the brain could maintain the cognitive and antipsychotic benefits without causing severe gastrointestinal distress.

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

This is how KarXT was born.

In clinical trials, the two-in-one pill outperformed a placebo in relieving characteristic symptoms of schizophrenia^3,4without weight gain, sedation, or movement problems commonly associated with existing antipsychotics. The side effects of KarXT were largely limited to intestinal discomfort, which subsided after one to two weeks with daily use.

There was also strong evidence of cognitive benefit, although there was preliminary evidence⁵ that KarXT could also help relieve symptoms such as loss of feeling and lack of motivation. “It’s encouraging,” says Stephen Marder, a psychiatrist at the University of California, Los Angeles, about these side effects. (Marder assisted with some analysis). However, these effects need to be checked in a “focused study,” he says.

High price

The drug has some shortcomings. For one thing, twice-daily dosing is required, and studies suggest that more frequent dosing schedules are associated with higher rates of noncompliance and treatment discontinuations 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 as long-acting injectables that require only a few doses per year.

KarXT is also expected to cost around $20,000 per year⁷which raises concerns among health economists about its cost-effectiveness compared to alternatives. Still, most industry analysts predict strong demand, with peak annual sales predicted to be in the billions. That potential led Princeton, New Jersey-based Bristol Myers Squibb (BMS) to acquire Karuna for about $14 billion this year.

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Other drugmakers are also recognizing the value of targeting muscarinic receptors and are pursuing various strategies to improve KarXT’s profile. Some are developing formulations with more convenient dosing schedules. Others focus on greater target selectivity and aim to develop molecules that activate only specific muscarinic receptors – either the M1 receptor, which is linked to cognitive benefits, or the M4 receptor, which underpins antipsychotic effects, but not both, like KarXT does.

One such drug candidate, an M4-selective agent called emraclidine, appears to have an antipsychotic effect similar to that of KarXT with improved tolerability, although it may provide fewer cognitive benefits, according to initial clinical testing⁸.

Former Karuna CEO Steven Paul, now a psychiatrist at Washington University School of Medicine in St. Louis, Missouri, welcomes the wave of innovation in combating muscarinic signaling sparked by KarXT – and he looks forward to exploring the best opportunities find these to use this therapy strategy.

“Now we have to explore new biology and new pharmacology,” he says. “It will be fun and scientifically relevant – and hopefully clinically useful for patients – to find out.”