A new medicine for treating schizophrenia—one that appears to help reduce both positive and negative symptoms of the illness—has passed a first hurdle in phase 3 clinical testing. Phase 3 is often pivotal in deciding whether a medicine is effective and safe enough to obtain FDA approval.  

The medicine, xanomeline-trospium, is called KarXT by Karuna Therapeutics, the company that is developing it and which paid for the initial phase 3 trial. The drug has a novel mechanism of action that distinguishes it from all previously approved antipsychotic medicines.  

In December 2023, the pharmaceutical giant Bristol-Myers Squibb Co. entered into a deal valued at over $14 billion to purchase Boston-based Karuna. The announcement came just weeks after positive results of the first of two positive KarXT phase 3 trials were published in the journal Lancet. Senior author of the paper reporting the results was Steven M. Paul, M.D., a BBRF Scientific Council emeritus member who is currently Chief Scientific Officer and President of R&D at Karuna. One of the paper’s co-authors was 2007 BBRF Young Investigator Christoph U. Correll of Northwell/Zucker Hillside Hospital.

252 patients with acute psychosis requiring hospitalization were enrolled in the randomized, double-blinded, placebo-controlled trial. Half received KarXT for 5 weeks and half received placebo. KarXT was observed to significantly reduce both “positive” and “negative” symptoms of schizophrenia compared with placebo. In addition to reductions in both kinds of symptoms, patients receiving the new medicine in most cases were able to tolerate it well, reporting only moderate side effects. Larger and longer phase 3 clinical trials are now underway.

KarXT is the culmination of research begun decades ago to find a new way of treating symptoms of schizophrenia. Since the first antipsychotic medicine approved in the 1950s, every antipsychotic approved to date targets a cellular receptor for the neurotransmitter dopamine called the D2 receptor. Some “atypical” or second-generation antipsychotic medicines, including clozapine, also have important therapeutic effects related to their impact on receptors for serotonin. Both first- and second-generation antipsychotics are often very effective in reducing delusions and hallucinations that are the chief positive symptoms of the illness. But they have essentially no impact on negative symptoms such as blunted affect, anhedonia, lack of motivation and asociality, and no appreciable impact on cognitive symptoms that are also among the core symptoms of schizophrenia (reduced executive function, difficulty in sustaining attention, impaired long-term memory, among others).      

An estimated 30%-40% of schizophrenia patients are resistant to the therapeutic benefits of current antipsychotic medicines; others derive only partial positive-symptom benefits. Short- and long-term side effects associated with approved antipsychotics are also an issue for many patients, and range from motor impacts, such as akathisia, Parkinsonism and tardive dyskinesia, to cardiometabolic effects including weight gain, lipid and glucose abnormalities, hyperprolactinemia and sexual dysfunction, as well as somnolence and sedation.  

The idea that led to KarXT began with the aim of developing a drug with a novel mechanism of action—one that would not block D2 dopamine receptors but rather would stimulate cellular receptors called the M₁ and M₄ muscarinic receptors. These receptors are part of the cholinergic (acetylcholine) neurotransmitter system. The theory was that agents targeting the muscarinic acetylcholine receptors might indirectly impact the balance in the brain between the dopamine and acetylcholine systems, including in the brain’s striatum, which in turn might help therapeutically address pathology that gives rise to psychosis.

For many years, preliminary tests of medicines targeting the muscarinic M₁ and M₄ receptors suggested that they had excellent potential for reducing schizophrenia’s positive, psychosis-related symptoms. The problem has always been side effects: the early candidate drugs had significant side effects in the body’s gastrointestinal system, including nausea and vomiting. To potentially overcome this obstacle, developers of KarXT have tested the idea of combining a compound (xanomeline) that stimulates the M₁ and M₄ muscarinic receptors in the brain with a compound (trospium chloride) that blocks the M₁ and M₄ receptors in bodily tissue outside the brain, including the gastrointestinal tract. In phase 1 and 2 trials, KarXT appeared to demonstrate antipsychotic efficacy while reducing the frequency and severity of gastrointestinal side effects.

The 252 individuals recruited for the phase 3 trial just reported were drawn from 22 inpatient sites in the U.S.; all had experienced a recent worsening of psychosis warranting hospital admission. The average participant was about 46 years old; about three-fourths were Black. On a scale of symptom severity (called PANSS, the Positive and Negative Symptom Scale), the average participant scored close to 100 (the scale ranges from 30 to 210). Participants went through a “wash-out” period from prior antipsychotic medications that lasted in most cases for one week. Then, participants were randomly assigned to receive KarXT or placebo twice a day for 5 weeks. Those receiving KarXT were started on a dose of 50mg of xanomeline and 20mg of trospium twice daily for 2 days, then 100mg and 20mg of the two drugs, respectively, from days 3-7. Beginning on the 8th day, dosing was flexible, and increased to 125mg/30mg twice daily if tolerated by the patient, otherwise the dose was reduced to the 100mg/20mg level. Nearly all participants were able to tolerate the maximum dose after day 8 for the duration of the trial.

After 5 weeks, those in the KarXT group had significant reductions in both positive and negative schizophrenia symptoms, as measured by the PANSS assessment tool. From an average total symptom score of about 98, the typical participant had a 21-point reduction after 5 weeks on KarXT, compared with an 11.6-point reduction in the placebo group.  On separate “subscales” measuring positive or negative symptoms, KarXT was also superior to placebo. KarXT-treated patients had a reduction of nearly 7 points compared with about 4 points in the placebo group. Negative symptoms declined 3.4 points in the KarXT group vs. 1.6 points in the placebo group. In the KarXT group, 55% had an overall symptom reduction of 30% or greater, compared with 28% in the placebo group.  

Side effects were present, as they are with virtually all medications, but were considered comparatively mild to moderate by the researchers. The most common were constipation, dyspepsia, headache, and nausea. Importantly, KarXT “was not associated with many of the adverse events typically associated with current antipsychotic treatments including extrapyramidal motor symptoms, weight gain, changes in lipid and glucose parameters, prolactin elevation/sexual dysfunction and somnolence.”

Noting KarXT’s apparent ability to significantly reduce both positive and negative schizophrenia symptoms as well as the reports on side effects, the researchers concluded that KarXT “has the potential to be the first of a new class of effective and well-tolerated antipsychotic medicines.”

The team looked forward to results from additional clinical trials now in progress. Among other things, these may help assess whether the observed decline in negative symptoms in the KarXT patients was a direct result of the medicine’s mechanism of action or might be related in part to its ability to reduce positive symptoms. Also, trials in progress will explore over the longer-term the drug’s impact as adjunctive treatment on patients with ongoing positive symptoms due to only a partial response to currently available antipsychotics. Future trials may explore the new drug’s impact in patients whose predominant symptoms are negative symptoms or cognitive dysfunction. Still other trials might pit KarXT against an active control group, to enable direct comparison with other antipsychotic medicines in patients with schizophrenia. Finally, trials are also ongoing to examine the efficacy and safety of KarXT for psychosis in patients with Alzheimer’s dementia.