FDA approves new type of antipsychotic drug, a potential ‘game changer’

The drug was not without its own side effects. Participants in clinical trials reported higher levels of nausea, vomiting and constipation than in a placebo group. Even so, the arrival of Cobenfy offers a new tool for treating schizophrenia — a disease with profound societal consequences, including homelessness and encounters with police — beyond a class of drugs that has been prescribed for decades.

Based largely on Cobenfy’s promise, Bristol Myers Squibb paid $14 billion to acquire the company that developed the drug, Karuna Therapeutics, completing the acquisition March 18. Wall Street analysts say clinical trials suggest that Cobenfy is at least as effective as other blockbuster antipsychotics, like Risperdal and Zyprexa, and project that it could eventually generate billions of dollars a year in sales.

“This drug takes the first new approach to schizophrenia treatment in decades,” Tiffany Farchione, director of FDA’s division of psychiatry, said in a statement. “This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed.”

Bristol Myers Squibb is exploring Cobenfy for Alzheimer’s-related psychosis, which has no approved treatment, among other conditions.

“Cobenfy, we believe, will usher in a new class of medicine and will be truly transformational in a space that hasn't seen innovation for decades,” Adam Lenkowsky, chief commercialization officer for Bristol Myers Squibb, said in an interview. He was responsible for launching the company’s last major drug to treat schizophrenia, the antipsychotic Abilify, in 2002.

Cobenfy, set to launch in October, will have a list price that would cost about $22,500 a year. The influential Institute for Clinical and Economic Review this year estimated that a price in line with expected clinical benefits to patients should be in the range of $16,000 to $20,000 a year. Bristol Myers Squibb executives say most eligible patients are covered by Medicare or Medicaid and wouldn’t pay the list price.

The approval of Cobenfy could provide a rare innovation for people affected by schizophrenia, a disease that afflicts about 24 million people globally — including 2.8 million in the United States — and can have drastic effects on their loved ones and communities.

“How often do people walk by people on the street, and despair and keep walking?” said Gordon Lavigne, CEO of the Schizophrenia & Psychosis Action Alliance. “There haven’t been breakthroughs, new innovations in the treatment of schizophrenia in a really, really, long time,” he said, calling Cobenfy “game-changing, potentially.”

The story behind Cobenfy follows a familiar arc in the development of treatments for mental disorders: It was discovered by accident.

In the 1990s, Eli Lilly researched a molecule called xanomeline for Alzheimer’s disease and found that it had potent antipsychotic properties. Despite xanomeline’s promise, the company didn’t move forward with developing it due to gastrointestinal side effects that led many participants in a clinical trial to drop out.

Then two decades later, Eli Lilly’s 1997 paper on xanomeline caught the attention of Andrew Miller, a young entrepreneur who had recently earned his PhD in chemical engineering at MIT.

Miller, who was in his late 20s, knew nothing about schizophrenia but was intrigued by a disease that, though it affected millions, seemed hidden by stigma. Xanomeline’s side effects were believed to come from stimulating the surrounding tissue of the brain receptors that it activated. Miller thought up a new approach: combining xanomeline with another molecule that would counteract this effect in the peripheral tissue.

“That idea, that concept, that is the genesis of everything that we find ourselves with today,” he said in an interview.

Miller founded Karuna Therapeutics, and a team sorted through more than 7,000 combinations before hitting on trospium chloride — a generic drug approved by the FDA to treat overactive bladder — as a complement to xanomeline. They called their experimental drug KarXT, and shepherded it through clinical trials to prove its safety and effectiveness.

In November, the FDA agreed to review Karuna’s application. The next month, Bristol Myers Squibb announced that it was buying the company.

There have been innovations in antipsychotic drugs over the decades, with a second generation of FDA-approved medicines shown to have fewer side effects like involuntary muscle contractions. But they all involve blocking dopamine transmission, and even the more recent drugs can cause significant weight gain.

Patients with schizophrenia are “all treated with pretty much the same medicines that work the same way,” Samit Hirawat, Bristol Myers Squibb’s chief medical officer, said in an interview. While they’ve helped many patients, he said, “they do come with a side-effect profile that least about 60 to 70 percent of these patients to go off treatment within a year and a half or so.”

The evidence so far suggests that Cobenfy could be the “first viable antipsychotic alternative” to blocking dopamine transmission that has been the standard for 70 years, said Andrea Cipriani, a psychiatry professor at the University of Oxford. Still, she said, the evidence is based on clinical rating tools, and it can be hard to know how a score on such a test “translates into real world effects.”

What sets Cobenfy apart is that it is both highly effective at treating symptoms like delusions without the more serious side effects of existing treatments like gaining weight, said Joshua Kantrowitz, director of the Columbia Schizophrenia Research Center at the New York State Psychiatric Institute. There are also some hints that it could improve cognition, he said.

If further studies conclusively show such a benefit, he said, “then it’s getting to the point where it could be a true game changer.”