3 Things to Know About Cobenfy, the New Schizophrenia Drug

A new antipsychotic medication for schizophrenia—the first potential breakthrough for this condition in decades—may ease the debilitating symptoms associated with the disease, such as hearing voices, hallucinating, illogical or delusional thinking, and being suspicious of other people. And it doesn’t appear to cause side effects, such as weight gain, pacing, and drowsiness—issues that force some patients taking older schizophrenia drugs to abandon their medical regimen.

The drug, from Bristol Meyers Squibb, is called Cobenfy™ (previously known as KarXT), and it was approved by the Food and Drug Administration (FDA) in September.

Cobenfy uses a different mechanism of action than previous drugs for schizophrenia. Older medicines work by blocking dopamine, a neurotransmitter (a chemical messenger in the body that controls movement, among other functions)—too much dopamine activity is associated with schizophrenia symptoms. Instead, Cobenfy targets proteins in the brain called muscarinic receptors, which may indirectly impact dopamine.

Although many psychiatrists who care for patients with schizophrenia say Cobenfy is promising, others are cautious, noting that the FDA approval of the twice-a-day capsule was based on two small, short clinical trials, leaving questions about longer-term use. Many people take medication for schizophrenia all their lives.

“The new drug is promising,” says Vinod Srihari, MD, a Yale Medicine psychiatrist. “But we need to keep in mind that these were five-week studies of a drug to treat an illness that is lifelong, and further studies need to be done to evaluate longer-term impact and side effects.”

Cobenfy could also be considered a potential breakthrough in that it is the first drug for schizophrenia in decades that uses a novel mechanism, which could raise interest in developing even more options, says Dr. Srihari. “An approval like this will stimulate other pharmaceutical companies to develop other new drugs for the disease, which benefits patients. There may be a signal here that this is an area where progress is possible, in terms of developing new marketable medications.”

About 1% of Americans—roughly 3 million people—have schizophrenia, and the disease can have a profound impact on their lives. It’s a chronic brain disorder with no cure, although medications are helpful in managing many of the symptoms. In addition to those symptoms, people with schizophrenia—who are usually diagnosed in young adulthood—are at higher risk of disability and of dying at a younger age. Close to 5% of patients with schizophrenia die by suicide.

Below, Dr. Srihari answered three questions about Cobenfy.

Antipsychotic drugs that target dopamine directly have been given to patients with schizophrenia in the form of pills, liquids, and injections since the 1950s. Cobenfy is the first of what could potentially be several new medications that target receptors in the brain other than dopamine. Similar drugs are still in or may soon be in clinical testing phases.

Cobenfy, which comes in a single capsule, is a combination of two drugs: xanomeline and trospium chloride. Xanomeline was tested in the late 1990s to reduce cognitive decline in people with Alzheimer’s disease, but it showed unexpected benefits for psychotic symptoms. Further development of the drug for the treatment of Alzheimer's was stalled because the drug also caused nausea, vomiting, and other gastrointestinal symptoms that participants had trouble tolerating. The new addition of trospium chloride (to reduce these side effects) to xanomeline resulted in a more tolerable compound: Cobenfy.

Researchers have yet to understand Cobenfy’s exact mechanism; its efficacy is thought to be due to the agonist activity of xanomeline on muscarinic receptors in the central nervous system. These receptors have a variety of functions in the body, including the relaying of neurotransmitter signals among cells, and they have a connection with cognition. In people with schizophrenia, they may affect the release of dopamine.

Cobenfy’s efficacy is based on two studies that were identically designed and included 252 participants. Both were five-week, randomized, double-blind, placebo-controlled, multicenter studies in adults with a diagnosis of schizophrenia. Bristol Meyers Squibb published its findings in The Lancet earlier this year, saying that KarXT (as Cobenfy was then called) had a “significant” impact on some of the most difficult symptoms of schizophrenia.

“It’s important to note that to be marketed in the U.S., drugs like this only need to show that they are better than a placebo [no treatment], which then leaves the task of clarifying their comparative effectiveness with respect to existing medications and the measurement of rare or longer-term side effects to post-marketing studies,” says Dr. Srihari. “That is not a critique of these trials or the drug per se, but rather a limitation of the current FDA approval process.”

Both older schizophrenia drugs and Cobenfy primarily target psychosis—a sub-group of schizophrenia symptoms that includes abnormal subjective experiences, such as hearing voices, delusions, and disorganized speech or behavior, says Dr. Srihari. “That is what these drugs all target. It usually is the one syndrome within schizophrenia that responds to medication,” he adds.

Dr. Srihari says it remains to be seen whether the drug might have a sizeable impact on other types of symptoms, including acting withdrawn, having little social interest, and lacking energy or motivation. “There are also difficulties that people have with cognitive functioning, including executive functioning and working memory, for which none of the existing antipsychotics appear to have much of an effect,” he says. While Cobenfy also appeared to be promising in the clinical trials, more evidence is needed to know whether it will have a significant cognitive effect, he adds.

As far as side effects, the most common ones participants reported were nausea, indigestion, constipation, vomiting, hypertension, and gastrointestinal reflux disease (GERD), among others. The company also reports a risk of liver damage.

Unlike some other antipsychotic drugs, Cobenfy does not carry an FDA boxed warning (the highest warning intended to bring a consumer’s attention to major risks associated with a medication).

“The absence of a boxed warning is good, but not a real accomplishment for a medication that a relatively small number of human subjects have been exposed to for only five weeks,” Dr. Srihari says. “A need for such a warning can emerge over time—or become less of a concern as more patients are exposed to the drug and the data is more reassuring about the magnitude of risk,” he says. “The evaluation of actual risk will occur over time with post-marketing studies that follow patients systematically and with patients and clinicians reporting any unexpected side effects over long-term use.”

People with schizophrenia often find themselves in a cycle of discontinuing and switching therapies, so having another choice—and one that works differently—could be helpful, says Dr. Srihari.

“If I were advising a friend or family member, I would tell them to have a very open conversation with their prescriber and learn about the potential benefits and side effects,” Dr. Srihari says. “They should become informed about the potential advantages for their specific situation, compared to whatever medication they are currently taking. For example, if they are having persistent weight gain on their current antipsychotic and this has not responded to changes in diet and exercise, it may be worth switching to Cobenfy, but with careful follow-up for both weight and any worsening in psychosis symptom control.”

They also should talk to their insurance provider about whether they have coverage for the drug.

In addition, it’s important to remember that medication is one part of the treatment for schizophrenia. Others, including psychotherapy, family education and support, and support for work or educational goals, are also important, he adds.

“The picture of schizophrenia in the public mind is that of a person who ends up homeless or incarcerated or in a nursing home, and that is not representative of the vast majority of people with this illness,” Dr. Srihari says. “Rapid access to existing and empirically supported treatments can help most people recover in all the diverse ways possible in human development, and all deserve full participation in society.”

A lot depends on “humane and acceptable care”—meaning care that is not fragmented or poorly delivered—especially early, but for all stages of this illness, he says. Whether Cobenfy should be part of that treatment is a conversation each individual should have with their doctor, based on the risks and benefits in their situation, he adds.