Karuna’s experimental schizophrenia drug succeeds in advanced study

If approved by the FDA, the Boston biotech’s medicine would be the first new type of treatment for the disease in decades.

There hasn't been a new type of treatment for schizophrenia in decades.lolloj - stock.adobe.com

Karuna Therapeutics said Monday that its experimental drug to treat schizophrenia significantly reduced symptoms of the disease, including hallucinations and social withdrawal, in an advanced clinical study.

Boston-based Karuna plans to submit the drug to the Food and Drug Administration by mid-2023, meaning it could be approved later next year or in early 2024. If that happens, it would be the first new type of schizophrenia medicine in decades.

“It’s hard to understate what a scientific achievement this is, and I think it’s going to be a big deal for patients as well,” said Dr. Joshua Tolkien Kantrowitz, director of the Columbia Schizophrenia Research Center. “It looks to be highly efficacious and so far looks pretty tolerable without the more significant side effects we see in current schizophrenia treatments, such as weight gain.”

Karuna estimates that there are 21 million people living with schizophrenia worldwide, and analysts predict the drug could ultimately reap the firm billions of dollars in sales. The company’s stock rose more than 70 percent on the news of the trial data. Karuna also plans to begin testing the drug in an advanced clinical trial of people with psychosis related to Alzheimer’s disease within the next two months.

The news comes just a few weeks after Cambridge-based Biogen announced that it would stop developing its own schizophrenia drug after it failed to improve cognitive impairment in an intermediate study. A number of smaller companies, including Lexington-based Concert Pharmaceuticals, have also had schizophrenia drugs fail in the past few years.

Drugs approved for treating schizophrenia, such as Abilify, Seroquel, and Zyprexa, all work by blocking the receptors of an important brain chemical called dopamine. These drugs can reduce disordered thoughts, delusions, hallucinations, and other forms of psychosis. Iterations of that approach have been around since the 1950s.

But the drugs come with many side effects, including drowsiness and weight gain. They also don’t address symptoms of schizophrenia, such as the inability to feel pleasure and social withdrawal. In fact, many existing treatments that reduce psychosis actually make those symptoms, such as social withdrawal, worse.

“New drugs are absolutely needed,” said Daniel Fulford, a clinical psychologist and associate professor of neuropsychiatric disorders at Boston University. People treated with current drugs often feel sedated or unmotivated and can have trouble focusing or retaining information, he added.

Karuna’s treatment, dubbed KarXT, doesn’t block dopamine receptors like current medicines do. Instead, it stimulates the so-called muscarinic receptors, which cells use to communicate in parts of the brain involved in cognition, memory, and motivation.

During a call with investors on Monday, the company said that in a Phase 3 study of about 250 adults, people who got the drug for five weeks scored an average of 21.2 points lower on a scale commonly used to measure the severity of schizophrenia. People who received a placebo pill scored 11.6 points lower on average.

Experts said that improvement was in line with what would be expected for an antipsychotic drug, and that it was impressive for a compound that works on different parts of the brain than existing drugs. Although it is likely not a big enough effect to completely replace existing drugs, it could help some patients.

“For some people who are very ill, even some small improvement can be very significant,” said Dr. Oliver Freudenreich, co-director of the MGH Psychosis Clinical and Research Program. “Every patient that is unhappy with the response to the current treatment is going to want to try it,” he added.

“I would be shocked if it replaces the current dopamine-blocking drugs. I think it’s just one more option that people would have,” Freudenreich said.

The pill is a combination of two drugs: xanomeline and trospium chloride. Eli Lilly and Company, the Indianapolis-based pharma giant, originally tested xanomeline in people with Alzheimer’s in the 1990s. Although the compound failed to improve memory, it reduced symptoms of psychosis in people with Alzheimer’s.

Despite those intriguing results, the drug caused side effects that included nausea and vomiting, and Lilly stopped developing the drug. Karuna is giving xanomeline a second chance by pairing it with trospium chloride to counteract the gastrointestinal side effects. Trospium chloride, which was approved for treating an overact bladder, blocks muscarinic receptors outside of the brain to cancel out the actions of xanomeline.

Commercial antipsychotics that block dopamine have been available since the 1950s, said Dr. Deepak Cyril D’Souza, director of the Schizophrenia Neuropharmacology Research Group at Yale University. “All the drugs that we currently have on the market are based on a similar mechanism,” he said. If Karuna’s drug becomes approved, it would represent the first new approach for a schizophrenia drug in more than half a century.

Freudenreich said that although KarXT doesn’t seem to have the same side effects as current antipsychotics, most people who received the drug still experienced some side effects. And he cautioned that many side effects can’t be detected in a five-week study. Long term use of existing drugs causes people with schizophrenia to gain weight and increases their risk of dying from heart disease, he said. “Long term studies are really much more important.”