Data on schizophrenia drug suggests potential progress in treatment

Next year, doctors might finally have something new to offer people who suffer from schizophrenia: a much-needed drug that can better improve their symptoms without the side effects that too often cause them to stop taking their medications.

The latest round of late-stage data on a drug in development by Karuna Therapeutics, released on Monday, reinforces its potential to offer desperately needed progress for a brain disorder that affects about 1% of people in the U.S.

Karuna’s news is a bit of a revival story. One component of the treatment, called xanomeline, has been around since the early 1990s, when scientists at Eli Lilly & Co. started exploring its use to treat the cognitive and behavioral symptoms of Alzheimer’s disease and, later, schizophrenia.

Small studies suggested the drug could have a marked effect on those symptoms, but it was dropped from development because people couldn’t tolerate its side effects. The problem was that the drug didn’t act only on receptors that carry messages between nerve cells in the brain but interacted with ones throughout the whole body, causing people who took it to be nauseated and vomit.

Typically, the next step would have been to go back to design a new molecule that retains the good parts of the drug while avoiding its nasty gastrointestinal side effects. But xanomeline came along when the currently available anti-psychotics, which mainly work by slowing down dopamine signaling in the brain, were coming on to the market. With other drugs quickly achieving blockbuster sales status and scientists convinced it would be folly to try to engineer out the bad bits of xanomeline, companies abandoned that drug and others like it.

That is, until many years later when Karuna took a different tack. Rather than try to build a new drug from scratch, what if it combined xanomeline with a drug that could dampen the side effects? It turns out such a drug already existed. A drug for overactive bladder syndrome called trospium blocks muscarinic receptors outside the brain, thereby mostly limiting xanomeline’s effects to the brain.

This week’s data provides more evidence that the approach is working. Schizophrenia encompasses a constellation of symptoms, and the study achieved its primary goal of demonstrating that the Karuna drug could decrease ones like paranoia, delusions and hallucinations. Just as important, it not only helped people without the tough side effects of xanomeline on its own but also avoids the weight gain or drowsiness associated with all the currently available classes of schizophrenia drugs — side effects that often cause people to stop taking those treatments.

This new batch of data wasn’t a total slam dunk. The company’s stock traded down on Monday, seemingly because investors were unhappy with a continuing sign that some patients on the drug experienced elevated blood pressure, though the magnitude of the effect diminished during the trial.

In this trial, the drug also failed to have a statistically significant effect on qualities that are diminished in people with schizophrenia compared with those without the disease, such as emotional and verbal engagement with the world, motivation and the ability to experience pleasure.

These caveats don’t mean the drug won’t win approval from the Food and Drug Administration, which is expected in the second half of 2024.

But it does leave an opening for other treatments in development that take a different approach to tinkering with the activity of muscarinic receptors.

Maybe Karuna’s drug doesn’t end up being the right choice for everyone, but helping even a fraction of the population could make a huge difference in the lives of hundreds of thousands of people. And ultimately, it moves the needle closer to drugs that can holistically and safely treat all the symptoms of schizophrenia.