Australian scientists pivotal in new drug class from BMS

Pharma News: The first new class of drug for schizophrenia in decades has been approved, offering a fresh approach by targeting cholinergic receptors instead of the traditionally focused dopamine receptors. This new treatment could reshape the standard of care for a poorly understood and devastating mental health condition.

Australian scientists from Monash University and the Florey Institute played a key role in paving the way for the U.S. Food and Drug Administration (FDA) approval of Bristol-Myers Squibb’s Cobenfy (formerly known as KarXT). Locally, the Therapeutic Goods Administration (TGA) has not received an application to register the drug on the Australian Register of Therapeutic Goods (ARTG) yet.

Cobenfy is a combination of two drugs: xanomeline, a dual M1- and M4-preferring muscarinic receptor agonist, and trospium chloride, a muscarinic receptor antagonist. Together, these medicines work to improve both the negative and cognitive symptoms of schizophrenia while minimising common side effects.

Schizophrenia, which affects approximately 1% of the population, carries an enormous societal and economic burden. Those living with the condition often face a significantly shortened life expectancy – by 15 to 20 years – due to associated comorbidities, with the annual economic impact of mental and physical health complications estimated at around A$15 billion.

Professor Arthur Christopoulos, Dean of the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University, hailed the approval as a milestone.

“This is a game changer as it is the first new drug with a truly different mechanism of action to treat schizophrenia in at least 30 years,” he said.

Professor Christopoulos and his colleagues at the Monash Institute of Pharmaceutical Sciences, along with the Florey Institute of Neuroscience and Mental Health, have long contributed to the foundational science behind this breakthrough. Their research on the muscarinic system, which is central to Cobenfy’s mechanism, has helped illuminate the role this system plays in schizophrenia. Interestingly, neither drug in the combination is entirely new; both have been repurposed from other uses.

Professor Brian Dean, Professorial Research Fellow at The Florey and the University of Melbourne, explained “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 activating the muscarinic M1 and M4 receptors would alleviate the symptoms of schizophrenia.

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

Professor Murray Cairns, from the University of Newcastle and Hunter Medical Research Institute, acknowledged the challenges of past treatments.

“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, where the majority of affected individuals continue with symptoms despite receiving standard-of-care antipsychotic treatment,” he explained.

Dr Paul Joyce, Head of the Translational Nanomedicine & Biotherapeutics Group at the University of South Australia, highlighted the critical need for improved treatment options.

“More than 30% of schizophrenia patients abandon their treatment due to poor 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 antipsychotics, 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,” he said.

Associate Professor Jess Nithianantharajah, who leads the Synapse Biology and Cognition Laboratory at the Florey Institute of Neuroscience and Mental Health, celebrated the breakthrough, stating, “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 will be beneficial to the many people for whom current medications don’t work.”

She added, “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.”

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