FDA approves schizophrenia drug with new mechanism of action

In a milestone for schizophrenia treatment, the US Food and Drug Administration (FDA) has approved the drug Cobenfy (xanomeline and trospium chloride) for oral use in adults.

The antipsychotic drug targets cholinergic receptors as opposed to dopamine receptors, which has long been the standard of care. This makes it the first in an entirely new class of drug for patients with schizophrenia in more than 70 years, with researchers hoping it will benefit those who don’t respond to — or who suffer side effects from — existing drugs.

Schizophrenia is a lifelong, serious and often debilitating mental health disorder that can cause psychotic symptoms including hallucinations (such as hearing voices), difficulty controlling one’s thoughts and being suspicious of others, as well as cognitive problems and difficulty with social interactions and motivation. It is a leading cause of disability, with individuals with schizophrenia at greater risk of dying at a younger age; nearly 5% die by suicide. And while the current standard of care can be effective in managing the disorder, up to 60% of people experience inadequate improvement in symptoms or intolerable side effects during therapy.

Cobenfy’s development was based on a discovery by Australian researchers at The Florey about differences in the brains of people with schizophrenia. Key to this was Professor Brian Dean, whose research in the 1980s and 1990s showed that muscarinic receptors in the brain were involved in the pathology of schizophrenia.

In 1993, Dean discovered that M1 and M4 muscarinic receptors, which are integral to the brain’s cholinergic system, were lower in some people with schizophrenia; such changes would affect their ability to interact with others and their cognition. A drug that activated the muscarinic M1 and M4 receptors could therefore potentially alleviate these symptoms of schizophrenia.

“At that time, no drug treatment was effective in reversing these two symptoms of the disorder,” Dean said. He added that “many people with the disorder are non-responsive and many experience unpleasant side effects such as weight gain, dizziness and sleepiness. I really hoped my discovery could lead to a drug that was effective without side effects to put people off taking it.”

Pharmaceutical company Eli Lilly developed the drug xanomeline that, as suggested by Dean’s research, activated muscarinic M1 and M4 receptors. But while the treatment lessened the positive, negative and cognitive symptoms of schizophrenia in a group of treatment-resistant people, it caused unacceptable side effects. Trials were stopped and Eli Lilly ceased work on xanomeline.

Karuna Therapeutics eventually pursued a treatment combining xanomeline with trospium, a drug to counter xanomeline’s side effects, which they originally dubbed KarXT (this was later changed to Cobenfy). Cobenfy’s effectiveness for the treatment of schizophrenia in adults was evaluated in two five-week, randomised, double-blind, placebo-controlled, multi-centre studies in adults with a diagnosis of schizophrenia according to DSM-5 criteria.

The primary efficacy measure was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score, the PANSS being a 30-item scale that measures symptoms of schizophrenia. In both studies, the participants who received Cobenfy experienced a meaningful reduction in symptoms from baseline to week five as measured by the PANSS Total Score compared to the placebo group. Patients in a one-year extension trial meanwhile experienced a significant and consistent improvement in symptoms, with the drug favourably impacting their weight and long-term metabolic profiles.

“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,” said Professor Ashley Bush, Clinical Lead of Mental Health at The Florey.

“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.”

The FDA’s approval of Cobenfy was granted to Bristol Myers Squibb — which acquired Karuna Therapeutics back in March — over 30 years since Dean’s initial discovery. Other countries are expected to follow suit.

Image credit: iStock.com/KatarzynaBialasiewicz