Journey Through FDA Approval for Schizophrenia

Medically Reviewed by Brunilda Nazario, MD on December 19, 2024
6 min read

If you have schizophrenia, you will need to take medication for life. Schizophrenia drugs work well. But many carry unpleasant side effects such as weight gain, high cholesterol, high blood sugar, and even involuntary muscle movements.

A new medication, Cobenfy, has recently been approved by the FDA to treat schizophrenia. This means that it’s now available to patients throughout the United States. It doesn’t seem to have some of the same troubling side effects of older schizophrenia medications. But you may worry that it doesn’t work as well or isn’t safe. 

There’s some reassuring news, though. The drug development process from the lab to the pharmacy takes a lot of careful work, testing, and teamwork among scientists, doctors, and others to make sure new drugs are both safe and effective. 

Here’s a closer look at the journey of Cobenfy, which got FDA approval in September 2024 to treat adults with schizophrenia. We'll see how it was made and why it's potentially helpful for patients like you. 

The discovery that Cobenfy helped to treat schizophrenia was an accident. Researchers had initially studied the drug to treat Alzheimer’s. 

Cobenfy is a combination of two medications, xanomeline and trospium chloride. They target certain brain receptors known as cholinergic receptors that are important for learning and memory. 

Xanomeline was developed by drug company Eli Lilly in the 1990s for Alzheimer’s disease. It activates muscarinic receptors in the brain, which are a type of cholinergic receptor. Studies showed it improved cognition and behavioral symptoms of Alzheimer’s like delusions and hallucination. But one paper found that about half of patients dropped out of clinical trials because of serious side effects like fainting and bad diarrhea. As a result, researchers decided to stop their studies.

A few years later, Lilly researchers wondered if xanomeline could help patients with schizophrenia. Normally, they would test a new drug in a laboratory, and in animals, to make sure it was safe before they tried it in humans. But they’d already done that in their initial trials for Alzheimer’s. So doctors at Indiana University enrolled 20 people with schizophrenia in a clinical trial and found that those given the drug experienced improvement in symptoms like delusions and hallucinations. It also helped them think and function better. Since these patients were younger, they tolerated the drug better than older adults. They still had side effects, though, so Lilly decided to shelve xanomeline.

Before researchers try a drug in humans, they test it in animals to ensure it’s safe and works well. These tests help scientists understand how a drug works and if there might be any problems. 

Lilly had done early safety studies of xanomeline before it began its clinical trials for Alzheimer’s. At around the same time, studies of xanomeline showed it reduced symptoms of schizophrenia in rats. This made scientists comfortable to use it in a clinical trial for schizophrenia. 

After Lilly lost interest in xanomeline, another drug company, Karuna, decided to test it. They thought that if they combined it with another medication, trospium chloride, it would help to reduce side effects. This drug blocks the activation of muscarinic receptors, so researchers thought it might help reduce some of xanomeline’s side effects. Trospium chloride was approved by the FDA in 2004 to treat overactive bladder. Since it had already been proven to be safe in humans, there was no need to do any laboratory or animal testing for it. Scientists were ready to try the combination in humans.

The next step was to test a xanomeline-trospium chloride combination in people. Karuna named this drug KarXT. The goal was to ensure that the medication was safe and did what it was supposed to do: relieve schizophrenic symptoms. 

There were three phases of studies, known as clinical trials. Here are the different phases.

Small tests (phase I). At first, just a few people tried KarXT to see if it was safe. In one study, doctors looked at 59 healthy volunteers who didn’t have schizophrenia. They gave them either a placebo (a pill with no medicine) or a dose of KarXT that was gradually increased over five days. The study found that patients tolerated this combo well. About a third of patients said they noticed side effects like dry mouth, but they got better with time. 

Bigger tests (phase II). Later, people who had schizophrenia tried KarXT for five weeks to see if it helped them and was still safe. People who had developed significant cognitive problems with schizophrenia, like trouble with memory and focus, showed a lot of improvement on this drug. Most people also tolerated KarXT well. There were side effects like nausea and dry mouth, but they usually went away after a week or two. No one dropped out of the trial because of side effects. 

Biggest tests (phase III). Researchers were finally ready to try KarXT in lots of people. They did two big studies: EMERGENT-2 and EMERGENT-3. These looked at adults aged 18-65 who had schizophrenia whose symptoms had gotten so bad that they needed to be hospitalized. Patients who got KarXT saw more improvements in symptoms like paranoia, hallucination, and trouble with focus and memory than those who took a placebo. 

Doctors also watched the patients closely to make sure no one got hurt. The most common side effects were GI ones like constipation, heartburn, nausea, vomiting, and diarrhea. Some people also got a headache, felt dizzy, or had an increase in blood pressure. Most of these symptoms got better or went away completely after a week or two on the drug.

After phase III clinical trials, the information goes to the FDA. This is the government agency whose experts decide if a new drug is good enough to use. 

Karuna, the drug company, had to submit a form called a New Drug Application (NDA) to the FDA. It tells a medication’s full story. It includes everything, from early animal trials to phase III studies. Companies also have to include information on how they want to label the drug and what they plan to do long-term to monitor its safety. 

The FDA review process usually takes several months. While KarXT was under review,  another drug company, Bristol Myers Squibb, bought Karuna. They changed KarXT’s name to Cobenfy and announced they would soon start to study it for people with Alzheimer’s.

The FDA approved Cobenfy to treat schizophrenia in adults on Sept. 26, 2024. It based its approval on Cobenfy’s five-week phase III clinical trials. 

Even after a medicine is approved, scientists keep watching to make sure it's still safe and works well. This is especially important for medications like Cobenfy, which got FDA approval based on studies that were only done for five weeks. 

As of late 2024, 134 people on Cobenfy have been followed for 52 weeks. The medicine appears to be safe. Over 60% of patients reported at least one side effect, like nausea, vomiting, constipation, dry mouth, or heartburn. Most got better or went away over time, although about 15% of people dropped out of the trial because of side effects. Doctors will continue to follow people on Cobenfy closely to make sure no new side effects or safety concerns develop. 

Cobenfy also still appears to be effective to reduce schizophrenia symptoms even after a year of use. One worrisome side effect of many schizophrenia medications is weight gain. People on Cobenfy appear less likely to gain weight than people on other drugs for schizophrenia. About two-thirds of patients on the medicine for a year actually lose weight. 

If your doctor recommends that you try Cobenfy, you may be nervous to take a new drug. Scientists, doctors, and experts have worked together to make sure it's an effective medicine for people who need it. 

If you have questions or worries about Cobenfy or any other medicine, it's OK to ask your doctor or pharmacist. They're there to help and make sure you feel comfortable with your treatment.