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Revolutionary drug for schizophrenia receives US approval
A novel schizophrenia drug, KarXT, received approval in the US today and promises improved efficacy and tolerability.
Revolutionary drug for schizophrenia receives US approval
The first schizophrenia - Medication for decades with a new mechanism of action received approval from US authorities today. This approval offers the hope of an antipsychotic that may be more effective and better tolerated than current therapies.
The drug, known as KarXT, targets proteins in the brain called muscarinic receptors are known and transmit neurotransmitter signals between neurons and other cells. Activation of these receptors dampens the release of the chemical Dopamine, a messenger substance in the nervous system that is central to... typical symptoms of schizophrenia, such as hallucinations and delusions, is.
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 that primarily suppress dopamine activity alone.
In clinical trials, KarXT was not only able to relieve the core symptoms of schizophrenia, but also showed signs of improving cognitive function while avoiding many of the distressing side effects often 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 data from the studies. "Now we will be able to treat people who could not be helped with traditional antipsychotics. This is extremely exciting."
Hope for tailor-made treatment
KarXT is just the first of many next-generation drug candidates designed to activate muscarinic receptors in the brain. Several subsequent schizophrenia treatments are already in clinical trials or are about to begin, and show promise for improved tolerability and more convenient dosing regimens.
This advance has clinicians and drug developers envisioning a future in which schizophrenia treatment is more personalized to patients' needs — providing an alternative for the many people who do not benefit from current therapies or who discontinue them due to intolerable side effects.
“This provides an option that is completely outside of our current toolbox,” says Ann Shinn, a psychiatrist at McLean Hospital in Belmont, Massachusetts, who has no business ties to KarXT.
From demolition to revival
KarXT has its roots in the early 1990s, when researchers at Eli Lilly in Indianapolis, Indiana began developing xanomeline - a muscarinic activating agent primarily used to improve the Memory in Alzheimer's patients was intended, but was also being studied as a potential treatment for schizophrenia.
Studies showed that the drug provides both antipsychotic and cognitive benefits 1, 2. However, xanomeline also caused nausea, vomiting and abdominal pain — because muscarinic receptors are active not only in the brain but also in the gut — which led Lilly to ultimately shelve the drug.
Years later, biotechnologist Andrew Miller developed a strategy to revive the therapy. He realized that administering the muscarinic activating 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. It therefore selectively prevents side effects in the intestines without affecting the effects of xanomeline in the brain.
This is how KarXT came into being.
In clinical trials, the combination tablet outperformed a placebo in relieving the characteristic symptoms of schizophrenia 3, 4, without the weight gain, sedation, or movement problems often associated with existing antipsychotics. KarXT's side effects were largely limited to gastrointestinal disorders, which usually improved after a week or two of daily use.
There was also strong evidence of cognitive benefits, with preliminary signs 5 that KarXT could also help Symptoms such as flattened feelings and lack of motivation to mitigate. “It's encouraging,” says Stephen Marder, a psychiatrist at the University of California, Los Angeles, about these additional effects. (Marder contributed to some of the analysis). But these effects need to be tested in a “focused study,” he says.
High price
The drug has some disadvantages. For one thing, it requires twice-daily administration, and studies show that more frequent dosing schedules are associated with higher rates of nonadherence and treatment discontinuation in people with schizophrenia 6. “That's a big limitation,” says Nate Sutera, a psychiatric pharmacologist at the University of Nebraska Medical Center in Omaha — especially because many antipsychotics are now available as long-acting injections that require only a few doses annually.
KarXT also comes with an expected price tag of around $20,000 per year 7 offered, raising concerns among health experts about its cost-benefit ratio compared to alternatives. Despite this fact, most industry analysts predict high demand, with annual peak sales that could run into the billions. This potential prompted Bristol Myers Squibb (BMS) in Princeton, New Jersey, to acquire Karuna for about $14 billion this year.
Other drug manufacturers are also recognizing the value of targeted activation of muscarinic receptors and are pursuing various strategies to improve the properties of KarXT. Some are developing formulations with more convenient dosing schedules. Others are focusing on greater target selectivity, with the goal of designing molecules that activate only specific muscarinic receptors — either the M1 receptor, which is linked to cognitive benefits, or the M4 receptor, which supports antipsychotic effects, but not both, as KarXT does.
One such drug candidate, an M4-selective agent called emraclidine, appears to provide similar antipsychotic effects to KarXT, with improved tolerability, although it potentially offers smaller cognitive benefits, based on early clinical testing 8.
Former Karuna CEO Steven Paul, a psychiatrist at Washington University School of Medicine in St. Louis, Missouri, welcomes the wave of innovation in targeted muscarinic signaling sparked by KarXT — and he looks forward to finding the best ways to exploit this therapeutic strategy.
“Now we have new biology and new pharmacology to explore,” he says. “It will be exciting and scientifically relevant — and hopefully clinically beneficial to patients — to find out.”
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