Note: This blog is for informational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of a qualified healthcare provider.

On September 26, 2024, the U.S. Food and Drug Administration (FDA) approved Cobenfy, a new prescription treatment for adults with schizophrenia. Cobenfy’s approval is widely regarded as a breakthrough, as it is the first drug in decades approved for schizophrenia that targets a novel mechanism. This innovation represents a promising shift in how we understand and treat schizophrenia.

This blog will briefly introduce this novel medication: its components, development story, safety profile, and more.

What is Schizophrenia?

Schizophrenia is a chronic mental illness featuring “positive” symptoms (such as delusions, hallucinations, disorganized speech, or catatonic behaviour) and/or “negative” symptoms (such as diminished emotional expression or avolition). Patients generally must present with at least two of these symptoms for a formal diagnosis. Around 24 million people worldwide – about 1 in 300 (0.32%) – are affected by schizophrenia, which is less common than many other mental disorders (see WHO).

While the exact cause of schizophrenia remains under investigation, the mainstream hypothesis has long been that the disease is driven by abnormal dopamine activity (an essential chemical messenger in our brain). Therefore, most existing antipsychotic medications other than Cobenfy are developed based on this hypothesis and act directly on dopamine receptors (proteins that interact with dopamine) in the brain. However, clinical practices show that 20-50% of patients with schizophrenia do not respond to these treatments (a condition called treatment-resistant schizophrenia).

Cobenfy: A Novel Mechanism

Unlike other existing antipsychotic medications, Cobenfy targets a different type of protein that helps regulate functions like memory, learning and muscle movement. These proteins are called muscarinic acetylcholine receptors, and they are also believed to be associated with schizophrenia symptoms.

Cobenfy contains two active ingredients, xanomeline and trospium chloride, that work together to balance efficacy and safety. Xanomeline enhances the activity of M1 and M4 receptors (subtypes of muscarinic acetylcholine receptors), which may help alleviate both positive and negative symptoms of schizophrenia. Trospium chloride helps prevent xanomeline from acting on muscarinic receptors in the rest of the body, as it is a muscarinic receptor blocker that largely remains outside the brain after administration. It may reduce the likelihood of severe side effects due to general muscarinic receptor overactivation.

The exact mechanism by which M1 and M4 receptor activation leads to Cobenfy’s therapeutical action is not fully understood. Nonetheless, this new pathway of action marks an exciting innovation in antipsychotic treatment.

From Alzheimer’s Research to Schizophrenia Breakthrough

Xanomeline was initially developed by Novo Nordisk and Eli Lilly in the mid-1980s to treat Alzheimer’s disease. In earlier studies, xanomeline worked in improving patients’ condition, however, it also came with unbearable side effect – especially gastrointestinal symptoms. In these studies, xanomeline also unexpectedly improved the psychotic symptoms of Alzheimer’s.

Around the same time, preclinical studies and research on other drugs targeting the muscarinic system suggested that muscarinic receptors might also be a novel target for schizophrenia treatment. In 2009, Karuna Therapeutics (originally a small company, now fully owned by Bristol Myers Squibb) combined xamoneline and trospium chloride into a single treatment referred to as KarXT. Recently, in two 5-week studies and one 52-week study, patients with schizophrenia showed improvements in both positive and negative symptoms after KarXT treatment, compared with patients receiving placebo.

In September 2024, under a new brand name Cobenfy, this combination drug with a novel mechanism of action was approved by the FDA for schizophrenia treatment.

In October 2024, the results from another 53-week study with Cobenfy were published, further confirming its long-term efficacy and tolerance.

How Safe is Cobenfy?

A good thing about Cobenfy is that it does not have an FDA-mandated boxed warning like some other antipsychotic drugs. Unlike classic antipsychotics, xanomeline/trospium chloride has not been associated with weight gain or extrapyramidal symptoms (movement disorders).

However, Cobenfy is not a drug without side effects.The most common side effects of Cobenfy include nausea and vomiting, indigestion, constipation, hypertension, abdominal pain, diarrhea, tachycardia (increased heartbeat), dizzines, and gastroesophageal reflux disease (in which stomach acid repeatedly flows back up into the tube connecting the mouth and stomach).

Given its side effects, Cobenfy should not be used by patients with:

• Urinary retention
• Moderate or severe kidney or liver disease
• Gastric retention
• Untreated narrow-angle glaucoma
• A history of hypersensitivity to either Cobenfy or its components.

What’s Next?

Cobenfy’s approval marks a new chapter in schizophrenia treatment, offering hope for patients who haven’t benefited from traditional therapies. However, as mentioned, we do not yet know how exactly the drug’s activation of its target receptors leads to its therapeutic effects. Ongoing research may help further explain the pathophysiology of schizophrenia and Cobenfy’s therapeutic action.

Other drugs with similar mechanisms are also being developed. For example, AbbVie is developing emraclidine, a selective M4 enhancer, for treating schizophrenia. However, on November 11, 2024, AbbVie announced that its phase-2 trials with emraclidine did not meet their primary endpoints at week 6 in patients. This result underscores that more studies are needed to further understand the exact role of the muscarinic system in schizophrenia.

In addition to schizophrenia, Cobenfy is also being reconsidered as a treatment for psychosis associated with Alzheimer’s disease. Researchers hope the trospium chloride component may also mitigate the severe side effects historically associated with xanomeline in older adults.

Conclusion

While success in Cobenfy’s development is not the end of the schizophrenia story, it sheds light on understanding more about the condition and inspires further investigation into novel therapies. Standing together with the patients and their loved ones, we look forward to more promising innovations in mental health treatment.

Disclaimer: This information is educational in nature and does not constitute medical advice. If you or someone you know has schizophrenia or any other mental health condition, please consult a qualified healthcare professional.