FDA Approves First New Drug for Schizophrenia in Decades

Credit – Steve Belkowitz (Bristol Myers Squibb)

No New treatments for schizophrenia have been approved for nearly three decades, but that changed on September 26 when the US Food and Drug Administration (FDA) approved Cobenfy for the psychiatric disorder.

Developed by Karuna Therapeutics, which was later acquired by Bristol Myers Squibb, the drug works in an entirely different way than existing drugs for schizophrenia, which is creating enthusiasm and enthusiasm among doctors and patients.

How scientists developed the new drug

While treatments for schizophrenia primarily target the dopamine neurotransmitter system in the brain, Cobenfy targets a different one, the cholinergic system, through muscarinic receptors. Decades ago, scientists at Eli Lilly studied the muscarinic system as a possible treatment for Alzheimer’s disease, as manipulating it appeared to reduce some of the symptoms of Alzheimer’s-related psychosis that some patients develop. The company’s researchers also serendipitously discovered that a compound they developed to activate the system also improved symptoms of schizophrenia. But cells in many parts of the body – the brain, but also the bladder, intestine, salivary glands, eyes and heart – contain receptors for the muscarinic system, which meant it was challenging to selectively target just those in the brain and not elsewhere. . Because the compound, called xanomeline, caused widespread side effects, Lilly researchers shelved more studies on it.

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Andrew Miller, co-founder of Karuna, was intrigued by this research and tried to figure out how to activate the muscarinic system in the brain while suppressing it in other parts of the body. He and his team tested 7,000 compounds and ended up combining xanomeline with a drug that had been approved by the FDA in the 1970s for the treatment of overactive bladder, to suppress muscarinic activity in other parts of the body. “It’s a pretty innovative approach,” says Miller. Overactive bladder medication “has nothing to do with psychiatry,” he said. Combining it with the serendipitous discovery of xanomeline “didn’t fit the traditional model of innovative drug discovery.” But it worked.

What the studies found

In a study that the company published last December in the magazine Lancetresearchers reported that the combination – now called Cobenfy but later called KarXT – helped significantly reduce symptoms of schizophrenia, such as hallucinations, delusions, paranoia, social withdrawal and loss of motivation, compared to a placebo. This data was part of the application the company submitted to the FDA for approval.

Bristol Myers Squibb acquired Karuna in 2023, largely based on these encouraging results. “When we looked at the neuroscience and neuropsychiatric assets available, we didn’t want the next dopamine agonist or antagonist on the market that every doctor has (already) seen,” says Adam Lenkowsky, director of commercialization at Bristol Myers Squibb. “We wanted a truly revolutionary asset, with a different engine: a best-in-class, best-in-class asset that we believe could transform the space.”

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Samit Hirawat, chief medical officer at Bristol Myers Squibb, says Cobenfy not only addresses schizophrenia in a whole new way, but its approach could also be used for other neurological conditions. “The breadth of applicability of this medicine is what attracted us.”

Rishi Kakar, chief scientific officer at Segal Trials who has led several studies on Cobenfy, says “the uniqueness of the mechanism of action set this drug apart from everything else we had so far and really caught my attention right away.” Kakar — a psychiatrist who treats patients and also conducts research — says that, historically, only about 40% of people with schizophrenia respond to dopamine-based treatments, and the other 60% who can respond often stop taking their medications because cause intolerable side effects. , which can include uncontrolled muscle movements, dizziness, fainting, and weight gain.

The trials included patients who were hospitalized for acute schizophrenia and randomly assigned to receive Cobenfy – one pill taken twice a day – or a placebo for five weeks. In order to reflect the real-world patient population, some were taking existing medications but stopped due to side effects or were non-adherent. All patients underwent a withdrawal period of up to two weeks to ensure that any measurements of their results during the study were due solely to Cobenfy or placebo. Patients received increasing doses of the medication, and prescribing doctors were able to adjust dosages for their patients depending on symptoms.

Studies have documented a significant reduction in overall symptoms of schizophrenia in patients receiving Cobenfy compared to placebo. “My point of view is that (this difference) could mean that someone can potentially lead a better life by controlling symptoms,” says Kakar.

What else do you need to know about Cobenfy

The FDA has approved Cobenfy as a monotherapy – meaning it should be taken alone, without other medications – but more studies will be needed to see how the drug works in combination with existing treatments and what the benefits and risks of combining them are. “I think many doctors will try this as a first pharmacological option because they will find that the symptom reduction is quite robust,” says Kakar. “From what I’ve seen, it has true value for the unmet needs we have.” Lenkowsky says Bristol Myers Squibb is conducting a study studying Cobenfy in combination with dopamine medications that will produce results in about a year.

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In contrast to existing dopamine-based treatments, Cobenfy’s side effects reported by study volunteers were mostly mild to moderate, involving nausea and gastrointestinal discomfort, and tended to lessen over time. The label also warns patients that the medication is associated with urinary retention, increased heart rate, and swelling of the face in rare cases; The medicine is not recommended for people with a history of liver or kidney disease.

Bristol Myers Squibb continues to study the drug for its long-term effects, as well as to understand and potentially guide doctors on how to adjust patients’ doses as their symptoms change over time. Success in patients with schizophrenia could also lead to further uses of the drug in other conditions. “Neuropsychiatry is about to bring an explosion of new medicines and Cobenfy is the beginning of a series of potential products,” says Hirawat. The company is currently studying the drug in psychosis related to Alzheimer’s disease, and next year plans to begin late-stage trials investigating whether it can improve bipolar mania, the agitation associated with Alzheimer’s disease, and the cognitive impairment associated with Alzheimer’s disease. Alzheimer’s disease. In 2027, the company hopes to begin testing on people with autism.

How much will Cobenfy cost?

According to a Bristol Myers Squibb spokesperson, the wholesale cost of a month’s supply will be $1,850. Depending on people’s insurance coverage, this cost may be lower for individual patients. Bristol Myers Squibb estimates that 80% of people with schizophrenia in the U.S. have insurance coverage through Medicare or Medicaid.

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