The US Food and Drug Administration (FDA) recently approved the drug Cobenfy for the treatment of schizophrenia. Developed by Karuna Therapeutics (now part of Bristol Myers Squibb), Cobenfy is the first schizophrenia therapy to target muscarinic cholinergic receptors. This represents the first novel mechanism of action in schizophrenia treatment in over 70 years.
Schizophrenia affects nearly 25 million people worldwide. The psychiatric condition has a complex symptomatology, broadly split into three categories — positive, negative, and cognitive symptoms. Positive symptoms include delusions and hallucinations. Negative symptoms involve loss of pleasure and emotion, and cognitive symptoms reflect deficits in memory and attention.
Cobenfy is an atypical antipsychotic with an unusual development history. The drug is a combination of two previously approved compounds that target muscarinic receptors: xanomeline and trospium.
Xanomeline is an agonist of muscarinic M1 and M4 receptors in the central nervous system. Eli Lilly first tested the drug in 1997 as a cognitive treatment for Alzheimer’s disease (1). The trial team noted that patients with psychotic symptoms became calmer and less prone to delusions and hallucinations.
We wouldn’t expect someone to get a new job, move out on their own, get married during a 5-week trial — and there was clearly improvements in symptoms — but many of us who work in the field are eager to see if longer-term use can in fact move the needle on functional recovery.
- Margaret McNamara McClure, Fairfield University
Unfortunately, xanomeline’s voyage to approval was dragged along a jagged reef that damaged the chances of several acetylcholine receptor-targeting compounds. Xanomeline activates receptors throughout the body, causing symptoms like vomiting and diarrhea. Eli Lilly shelved the drug.
Ten years on, Cobenfy’s creator Andrew Miller, who now advises Bristol Myers Squibb, came back to xanomeline. He had realized that its unpleasant side effects might be counteracted by adding another drug, the pan-muscarinic antagonist trospium, which was approved to treat overactive bladder in 1974. “The cool thing about this is that [trospium] will block a lot of the muscarinic receptors in the periphery, but it won't get into the brain,” explained Ken Kramer, who is the Vice President and Head of Medical Affairs, Neuropsychiatry Therapeutic Area at Bristol Myers Squibb.
The drug combination has now paid off. The FDA approved Cobenfy after analyzing the results of two Phase 3 trials, EMERGENT-2 and EMERGENT-3 (2,3). Each trial recruited roughly 250 people with schizophrenia. The recruited cohort was diverse, with Black or African American volunteers the largest racial group in both trials; this is important as Black people are 2.5 times more likely to be diagnosed with the condition (4).
The placebo-controlled trials lasted five weeks and used a primary endpoint of the change from baseline on the positive and negative syndrome scale (PANSS). The test groups in both trials saw significantly larger improvements to their PANSS scores than placebo groups, and while some gastrointestinal side effects persisted, the dropout rate in the test group was not significantly higher than the placebo group.
This successful set of results is predicted to dramatically increase Bristol Myers Squibb’s annual sales by up to $10 billion. Cobenfy’s main draw is its novel mechanism, said Kramer. “When you look at the history of antipsychotic medications, you will see between 1957 and 2024 basically variations on a common theme — blocking dopamine D2 receptors, partial agonism of dopamine D2 or D3 receptors.”
The muscarinic acetylcholine receptors that Cobenfy targets are thought to presynaptically slow down dopamine release. In the EMERGENT-2 and -3 studies, the researchers broke down the overall PANSS scores to look at how the drug affected negative symptoms, which classical dopaminergic antipsychotics struggle to improve. Cobenfy’s performance against these metrics was a mixed bag of results. Participants in EMERGENT-2 showed a significant improvement in negative symptoms at the trial endpoint, but those in EMERGENT-3 did not.
Margaret McNamara McClure is a psychologist at Fairfield University who was not involved in Cobenfy’s development. While McClure welcomed a novel treatment mechanism for patients, she said longer-term data is needed to assess whether Cobenfy could be the solution to hard-to-treat schizophrenia symptoms clinicians have called for. “We wouldn’t expect someone to get a new job, move out on their own, get married during a 5-week trial — and there was clearly improvements in symptoms — but many of us who work in the field are eager to see if longer-term use can in fact move the needle on functional recovery,” McClure said.
The researchers at Bristol Myers Squibb will be producing that data as part of Cobenfy’s approval process. Kramer said that the company is also exploring data that suggest Cobenfy may offer improvement to cognitive symptoms through a mechanism of action unrelated to dopamine. “We produce evidence not for ourselves, but to ensure that healthcare providers and their patients have all the data they need to make informed treatment decisions. That's our goal,” Kramer said.
References
- Bodick, N.C. et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 54, 465-473 (1997).
- Kaul, I. et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet 403, 160-170 (2024).
- Kaul, I. et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry 81, 749-756 (2024).
- Faber, S.C. et al. The weaponization of medicine: Early psychosis in the Black community and the need for racially informed mental healthcare. Front Psychiatry 14 (2024).
