FDA approves the first new schizophrenia drug in decades

The Food and Drug Administration on Thursday approved the first novel antipsychotic treatment in decades, a drug developed to treat schizophrenia without disabling side effects like weight gain.

Until now, all available antipsychotics have worked by blocking a dopamine receptor. In most patients with schizophrenia, they can reduce symptoms like hallucinations and paranoia to a manageable level.

But they have serious flaws. Weight gain, a common side effect, contributes to a high rate of cardiac disease and early death among people with schizophrenia. And many patients stop taking the medications, complaining that they leave them sluggish and unmotivated.

The new drug, Cobenfy, also influences dopamine levels, but it does so indirectly, by changing levels of another neurotransmitter, acetylcholine. The new approach, researchers hope, will address some of the most intractable aspects of the disease, like lack of motivation and inability to feel pleasure.

"This is the first time, really since the advent of these medicines, that a new mechanism has come out, so there is really a lot of excitement that maybe we have something new to treat patients with," said Dr. Frederick C. Nucifora, director of the Adult Schizophrenia Clinic at the Johns Hopkins School of Medicine.

Still, there are unanswered questions about the new drug.

Only three controlled studies of the drug's efficacy have been published, and all three lasted for only five weeks. So it is not clear how effective Cobenfy will be over longer periods or whether it has long-term neurological side effects, like movement disorders, said Dr. David Rind, the chief medical officer of the Institute for Clinical and Economic Review, which reviews new drugs arriving on the market.

"We don't know how it works in any substantial way past five weeks," Rind said. Patients and doctors, he added, "are a little wary of claims before they actually see what happens with the drugs."

Bristol Myers Squibb, which is marketing Cobenfy, has released summaries of the drug's effects in patients who took it for a year and said they did not experience metabolic changes or develop a movement disorder. Full results would be published later this year, the company said.

Excitement about the drug is high on Wall Street and among drug companies already formulating other products they view as part of a promising new class of medications, with possible indications for bipolar mania, Alzheimer's disease and autism-related irritability, among other conditions.

Matt Phipps, head of biotechnology equity research at William Blair, said he expected the drug to generate $3 billion to $5 billion in revenue per year if studies of its use in psychosis for patients with dementia show positive results.

"It's a field that's been plagued by a lack of innovation for quite a while, so it definitely generated enthusiasm," Phipps said.

BMS has set its wholesale cost at $1,850 a month, or around $22,500 a year, in line with other branded antipsychotics, said Adam Lenkowsky, chief commercialization officer for BMS.

He said the drug should be seen as a "switch opportunity" for patients who have cycled through several antipsychotics and discontinued them because of unwanted side effects. Some 80% of patients with schizophrenia have already met those criteria, he said.

"We've been speaking with dozens of thought leaders in this space who are eagerly awaiting this approval, for patients they've already earmarked, for patients who are not responding to their current treatments," Lenkowsky said.

That pricing likely means that payers will require patients to try generic antipsychotic drugs first, and cover Cobenfy only for those who do not respond well, Rind said.

"A lower list price might make the therapy much more widely available while bringing in similar revenues based on much higher sales," he said.

In contrast to all the antipsychotics in use, Cobenfy will not carry an FDA boxed warning, the agency's strongest warning, which alerts patients and providers to serious adverse reactions, according to BMS.

Patients in clinical trials on the drug, which was long referred to as KarXT, reported gastrointestinal problems, including nausea, constipation and stomach pain.

The FDA said in its approval statement Thursday that the drug should not be given to patients with liver impairment and can cause liver damage.

Patty Mulcahy, a filmmaker who was diagnosed with schizophrenia in 2019, said her current medication controlled her paranoia and hallucinations, but at a heavy cost: repetitive body movements, like shaking and blinking, that made people stare at her in public.

Even after transitioning to a much lower dose, the treatment has sapped her sharpness and enjoyment of life, she said. "These are very crude tools the doctors are using," she added. "The psychiatrists are doing the best they can, but they are very crude tools."

She said she was so eager to try the new medication that she was already planning to take time off work early next year, in case she experiences gastrointestinal side effects.

"I just want to go back to waking up full of energy and excited for the day, looking at the blue sky and feeling pleasure," said Mulcahy, 58, who works as a peer specialist in the psychiatry department at Brigham and Women's Faulkner Hospital.

Psychotic disorders like schizophrenia are not common, affecting 1% to 3% of the adult population. But they are a crushing burden, in part because the United States lacks a robust system of community care. Although many people manage psychotic illnesses with the help of their families, others end up living on the street, cycling through incarcerations, homelessness and brief hospitalizations.

One frustration for psychiatrists is that existing treatments address only one cluster of symptoms. Patients "can be tormented by voices," Nucifora said. "I've had people jump off bridges because the voices were bothering them, just tormenting them."

The FDA said people with schizophrenia are at a greater risk of dying prematurely, with nearly 5% dying of suicide.

"Schizophrenia is a leading cause of disability worldwide," Dr. Tiffany Farchione, the agency's director of the psychiatry division of its drug center, said in a statement Thursday evening. "It is a severe, chronic mental illness that is often damaging to a person's quality of life."

The antipsychotics on the market effectively control these symptoms, which are known as "positive." But they have troubling side effects, Nucifora said, and have little effect on "negative" symptoms, like social withdrawal, cognitive impairment and lack of motivation.

"It can be very frustrating to try to treat patients and hope they improve in positive symptoms," he said. "I mean, how do you move them forward and improve the quality of their life?"

The new drug arose, as so many do, out of a disappointment. Eli Lilly developed one of its ingredients, xanomeline, in the early 1990s as a treatment for dementia but ultimately shelved it because it caused gastrointestinal side effects, like nausea and vomiting, that caused patients to drop out of clinical trials.

In 2012, Karuna Therapeutics acquired the license for xanomeline from Lilly and began looking for ways to block those side effects. Researchers used an algorithm to predict which of 7,410 possible compounds would work best and landed on trospium chloride, which counters some effects of xanomeline in the gastrointestinal tract but does not enter the brain, said Andrew Miller, Karuna's founder and former president of research and development.

"This was the invention of KarXT," Miller said.

In its submission of the drug for FDA approval, Karuna cited a five-week study of 252 people with schizophrenia, half of whom were given Cobenfy and the other half, a placebo. The results were measured by comparing patient scores on a long list of symptoms, including hallucinations, hostility, tension and disorientation.

By the end of the five weeks, the patients who took Cobenfy saw their symptom scores fall by about 20 points, compared with a 10-point drop in the placebo group, an improvement considered significant enough to merit approval by the FDA.

Roughly 20% of the patients experienced nausea, constipation or stomach pain, and about 14% dealt with vomiting.

Seven of the nine authors of the study held equity in Karuna Therapeutics, according to the report published in The Lancet medical journal.

BMS, which acquired Karuna Therapeutics, released study summaries and a brief review of data on 134 patients who had taken Cobenfy for a year, though the full results will not be made public until later this year.

The summary said that the patients lost weight and did not experience metabolic changes, side effects of the current standard drugs, or develop movement disorders. But 62% of participants experienced unwanted side effects like nausea, vomiting and constipation. Additional abstracts of yearlong studies of KarXT, now called Cobenfy, were presented at a conference in Italy in the spring.

The first antipsychotic medication, chlorpromazine, was introduced around 70 years ago, and though waves of new treatments emerged in the decades that followed, they use the same basic mechanism, altering dopamine pathways in the brain.

In the meantime, vast sums in research funding went toward investigating the biology of the disease, which identified hundreds of genetic variants that confer some small degree of risk but did not lead to any breakthrough treatments.

"As a schizophrenia researcher, I'm embarrassed to say we've spent literally billions of American taxpayer dollars on genetics, looking to understand what causes schizophrenia to help us develop new drugs for schizophrenia, and we have not been successful," said Mark Weiser, the chief of the division of psychiatry at the Sheba Medical Center in Tel Aviv, Israel.

"That's what's so exciting about this," he said. "There's been a real dearth of stuff that's new."