EXPERT REACTION: New schizophrenia drug Cobenfy approved by FDA 

The release of xanomeline and trospium combination is a major breakthrough especially in the management of negative symptoms of schizophrenia, such as lack of motivation and initiative. This has long been a major unmet need.

The story has an Australian twist, in that Australian scientists like Brian Dean did early pivotal work on the role of the muscarinic system, on which this combination of medication works, in the symptoms of schizophrenia.

The other interesting aspect of this work is that neither of these medications are new, and are repurposed from other indications. Drug repurposing is a major focus of interest in Australia, with much development in this area happening at the moment.

I am delighted to hear this confirmation that the FDA has approved this new drug for schizophrenia.  

Schizophrenia has one of the highest burdens of disease of any human illness. Its onset is young (often in the teens or early twenties) and it severely impacts sufferers and their families.

This drug differs from existing drugs for schizophrenia and related psychosis (antipsychotic drugs) in that it targets different molecules in the brain. It is therefore the first new ‘drug in its class’ for the past few decades. 

This new drug is based on decades of fundamental discoveries in neuroscience, including some made at the Florey Institute, where a key role for specific muscarinic receptors in schizophrenia was identified.

The approval of the new drug demonstrates how important it is to understand the fundamental mechanisms involved in such brain disorders. These scientific discoveries can identify molecules that become targets for new therapies, as was the case for this new drug.

However, it should be noted that this new drug is not a cure, it does have side effects (as noted in the press release) and a lot more research is still required in order to better treat schizophrenia and related psychiatric disorders.

The FDA approval of Cobenfy to treat schizophrenia means, for the first time, that there is a drug with a mechanism of action that does not target the dopamine system in the brain to treat the disorder. 

The hope is this drug, which targets the brain's muscarinic M1 and M4 receptors, will be effective in people resistant to treatment with existing drugs and it will alleviate negative and cognitive symptoms of the disorder that do not respond to current drug treatments. 

What sets Cobenfy apart from other drugs used to treat schizophrenia is that its mechanism of action was suggested by multiple lines of research prior to the drug being tested in people with the disorder.

For example, ground-breaking research at the Mental Health Research Institute of Victoria and the Florey showed that muscarinic receptors in the brain were involved in the pathology of schizophrenia. This led to the proposal, in 2000, that a drug that activated the muscarinic M1 and M4 receptors would alleviate the symptoms of schizophrenia which is the mechanism of action of Cobenfy. 

Hence, the approval of Cobenfy emphasises the need for ongoing discovery research as a component of discovering new ways to treat brain disorders.

This is an important new therapy for schizophrenia which works by stimulating cholinergic signalling in the central nervous system without impacting the rest of the body.

It works by combining a dual selective agonist of the muscarinic acetylcholine receptors (M1 and M2), known as xanomeline, that crosses the blood brain barrier, with a muscarinic receptor antagonist, known as trospium chloride, that blocks the unpleasant side effects in the rest of the body.

Previously when xanomeline was used alone it did show benefit in reducing symptoms of schizophrenia but the side effects made it unacceptable. The combination is a great step forward in a field that has been difficult to progress despite a very significant unmet need and where the majority of affected individuals continue with symptoms despite receiving standard-of-care antipsychotic treatment.

The recent approval of a new anti-psychotic medication, Cobenfy, is a significant moment for patients suffering from schizophrenia – a highly debilitating mental illness that affects approximately 1% of the global population. Despite the debilitating nature of the disease and the suboptimal nature of existing anti-psychotics, very few new medications have been developed to treat this disease within the last few decades. 

By targeting cholinergic receptors in the brain, rather than dopamine receptors, as is the case for existing anti-psychotics, this medication offers promise to schizophrenia patients who have exhausted the current standard of care or have suffered from poor treatment outcomes. More than 30% of schizophrenia patients abandon their treatment due to poor treatment outcomes or negative side effects, so this medical advancement presents hope to this patient population.

Clinical studies have shown that Cobenfy is effective in treating schizophrenia in human patients, but as with all anti-psychotics, there are a range of side effects that should be taken into account. It is therefore essential that patients discuss their options with their practitioners.

Schizophrenia remains a poorly understood and often devastating disease associated with a number of challenging symptoms and even premature death. Yet, until now, all available medicines for the treatment of schizophrenia have predominantly been based on science that essentially dates back to the 1950s. The FDA approval of Bristol Myers Squibb’s and Karuna Therapeutics’ Cobenfy is incredibly exciting for people around the world living with schizophrenia, along with their loved ones.

The development of Cobenfy represents approximately a 30-year journey involving many dedicated scientists in the pharmaceutical industry and in academia. An early discovery of a drug called ‘xanomeline’ for the treatment of Alzheimer’s disease eventually evolved into a combination therapy of two drugs (‘xanomeline’ plus ‘trospium’ i.e., KarXT, now called Cobenfy) which work to simultaneously improve symptoms of schizophrenia while also mitigating specific debilitating side effects. I am humbled to have been part of the journey of research into these specific types of drugs over many years.

Cobenfy represents a whole new class of more targeted medicines; a major advancement for the treatment of schizophrenia and other difficult-to-treat neuropsychiatric and neurological diseases. The ultimate goal is to continue to refine and improve this class of medicines and, ultimately, transform the future of individuals, families and communities impacted by challenging mental ill-health conditions.

My research in the 1980s and 1990s - with colleagues including Elizabeth Scarr - showed that muscarinic receptors in the brain were involved in the pathology of schizophrenia.

In 2000 we proposed that a drug that activated the muscarinic M1 and M4 receptors would alleviate the symptoms of schizophrenia.

The licencing of the drug Cobenfy, a drug with that exact mechanism of action, has now validated our proposal.

The licensing of Cobenfy heralds a new era in treating the symptoms of schizophrenia as it is the first drug that does not act on dopamine neurotransmission in the brain. 

The licencing of the drug also emphasises the need for basic discovery research, the type of research carried out at The Florey, as a vital component of discovering new ways to treat disorders of the brain.

The approval of Cobenfy as a new treatment for those living with schizophrenia is a game-changer.

This landmark event underscores the incredible neuroscientific advancements that have been made in recent years to transform therapeutic discovery.

This is a completely new class of drug, so targets a different brain pathway to all the other existing medications for schizophrenia.

This will be beneficial to the many people for whom the current medications don’t work.

This progress highlights that we are just at the start of an exciting new era in the development of new and better medicines for complex mental health conditions.

I am very excited that at long last psychiatry has a new class of drug for the treatment of schizophrenia. Cobenfy promises to add a new approach in our pharmaceutical armaments to help this common, often chronic and potentially disabling disorder. I look forward to Cobenfy being available in Australia as soon as possible. 

Schizophrenia is a common, lifelong, serious and often debilitating mental health disorder, which causes enormous burdens on patients, families and healthcare resources. 

Cobenfy approaches the treatment of schizophrenia by a completely new mechanism of action, with demonstrated benefits for both the psychotic and the cognitive problems in the disorder. 

This is the biggest step forward in the treatment of schizophrenia in decades, because all drugs developed for schizophrenia in the last 70 years have targeted the same limited set of signalling pathways in the brain. 

The effectiveness of Cobenfy opens new horizons on understanding the disrupted brain systems in schizophrenia. The drug will be used, I expect, alongside existing medications, hopefully creating synergies that will bring even better improvements in outcomes in treating schizophrenia. 

We will now be entering a very promising new era of studying how Cobenfy is best used, and whether it may be useful for other disorders.