How Karuna's schizophrenia med KarXT went from a 'serendipitous clinical finding' to the FDA in 25 not-so-short years

Andrew Miller, Ph.D., remembers pacing around his basement on a Sunday evening in November 2019 the night before his company, Karuna Therapeutics, was about to reveal to the world that the schizophrenia med KarXT had aced a phase 2 trial, “chomping at the bit” to share the data.

“We got what we needed and now we're going to share it with the world and now we're going to see a lot about how meaningful this can be,” he recalled thinking.

Things move slow in the biopharma world, so while that one phase 2 moment—where KarXT was found safe and effective—was momentous, the clinical journey has rolled on for Karuna, culminating in last week’s filing of an FDA application to treat schizophrenia.

Miller, co-founder of Karuna, onetime CEO and now chief operating officer, detailed the long journey to get KarXT developed, from raiding Eli Lilly’s storeroom all the way to the FDA, in an interview with Fierce Biotech. He understands the huge moment this represents for patients with schizophrenia—who have only ever had one single class of drugs to rely on to treat their condition.

“From a biopharmaceutical industry perspective, people follow success. Investors follow success. Companies follow success—and, in schizophrenia, we haven't had the opportunity to launch a new class of product,” Miller said. “We haven't had the opportunity to see how much of a difference that can make and hopefully we're on the cusp of doing that.”

Compare the treatment options for depression, where there are eight different classes of drugs from SSRIs, SNRIs, monoamine oxidase inhibitors, NMDA antagonists and so on. If one doesn’t work or causes burdensome symptoms, a patient can try another. But that’s not the case when you have schizophrenia. While there are different types of antipsychotics—clozapine, risperidone and olanzapine are a few of the options—they are universally known for their adverse side effects such as weight gain, movement disorders and somnolence.

People follow success. Investors follow success. Companies follow success—and in schizophrenia, we haven't had the opportunity to launch a new class of product." — Andrew Miller, Karuna

“What's best for patients is there's more ideas, more options, more things being tested, and we can be part of building success and what psychiatric drug development looks like and help inspire others,” Miller said. “We'd love to be at the forefront of that.”

A serendipitous finding

Only about 20% of people with schizophrenia are considered “well treated,” according to Miller, while 50% have a partial response to the medication and 30% have a minimal response. There’s a lot of room for improvement and new targets.

Typical antipsychotics block the dopamine pathway in the prefrontal cortex of the brain, which is responsible for executive functioning and wakefulness, among other important functions. KarXT instead is a dual M1/M4 muscarinic agonist that acts in the same region of the brain but lines up better with where cognitive function and psychosis are, according to Miller. The therapy is more targeted and has shown a low rate of predominantly gastrointestinal side effects that were mild to moderate in trials with few discontinuations.

“We have a good understanding of the pharmacology of dopamine and serotonin based agents, where they give efficacy, where they give side effects, and then we just have a completely different pharmacology,” Miller explained. “We understand enough about the basic biology to say, 'here's why we're seeing these antipsychotic benefits and pro-cognitive benefits but also why we see some of the side effects we see as well.'”

Karuna Andrew Miller
Andrew Miller, Ph.D. (Karuna Therapeutics)

The “serendipitous clinical finding” in patients with Alzheimer’s disease that led to KarXT came in a paper published 25 years ago by Eli Lilly. The company found a cognitive benefit with a compound called xanomeline, which focused on the M1 muscarinic acetylcholine receptors. Unfortunately, they also had a high rate of side effects including nausea, vomiting and diarrhea when the muscarinic receptors were tampered with.

At the same time, Lilly made a “completely surprising discovery” of xanomeline’s antipsychotic benefits, which was tested further in a small-scale schizophrenia study but ultimately never advanced due to the tolerability issues. There was a 50% discontinuation rate among the trial participants. Other companies tried to tap the muscarinic pathway as well.

“Muscarinic receptors could represent a new class of medicines, but the side effect and tolerability considerations really didn't allow any of the molecules to be successfully developed. And xanomeline, that's really what made it the furthest,” Miller said.

That’s where Miller came into the picture, about 13 to 14 years ago, by balancing out xanomeline’s efficacy in the central nervous system with another compound called trospium that could tamp down the side effects in the peripheral tissues. Miller said he became fascinated by muscarinic receptors and xanomeline specifically because there was a clinical record of an antipsychotic benefit already on the books. When testing medicines for psychiatric illness, scientists can’t really make an animal model to show efficacy like you can for, say, cancer.

“Having that human signal that there was something real and effective here, solving the side effect considerations seemed like a much more tractable problem to go after,” Miller said.

Once the idea to make a combination was formed, the intellectual property was licensed from Lilly and placed under the umbrella of Karuna Therapeutics. Then, the real work began: finding the right drug to pair with xanomeline. Miller calls this a “quite frankly, pretty laborious process” to find the right molecule. The team evaluated more than 7,000 potential combinations, finally landing on trospium.

“[We’ve] kind of been going hot and heavy since then, all systems go," Miller said. “We've had I think the good fortune of having a string of very positive clinical data readouts, which is also not the easiest thing to do in schizophrenia and psychiatry, generally.”

Miller describes those clinical wins as “pretty tremendous, personally and professionally.” He’s not necessarily surprised by the outcomes, though, as Karuna focused heavily on clinical methodology and execution throughout the clinical process to ensure success, building risk mitigation into the process.

KarXT met the primary endpoints in all three completed trials. In the first of two phase 3 readouts in August 2022, Karuna showed that treated patients had a nearly 10-point drop on the Positive and Negative Syndrome Scale for Schizophrenia, a measure of severity for the condition. The second readout earlier this year found that the drug-induced an 8.4-point reduction on the scale compared to placebo at Week 5.

While there was an impact on the negative symptoms, Miller said Karuna still has some work to do if it wants to get an FDA approval especially for those symptoms, which encompass an absence of normal behaviors such as a lack of communication or social interaction. Positive symptoms include hallucinations and delusions, which are hallmarks of the condition. There is currently no approved treatment specifically for the negative symptoms.

For now, the company has sought an FDA nod for treating schizophrenia. Miller knows schizophrenia treatment is personalized for each patient, with care providers often using different combinations at different doses. He couldn’t say whether the focus will be new patient starts or encouraging patients to switch, but he hopes Karuna has provided a good basis of data that healthcare providers can use to make an informed decision. Karuna is also testing KarXT in Alzheimer's-related psychosis. 

Karuna itself is now in the process of transitioning into a commercial organization. Bill Meury, an executive who had previously served as chief commercial officer at Allergan, was brought on as president and CEO in December 2022. “It is a big transition,” Miller admits. The company now has about 300 employees. If KarXT is approved as planned, the launch could take place in the second half of 2024, according to Miller.

"I've been on this journey for a really long time, and I hope to be continuing on this journey for a very long time,” Miller said. “It's not commonplace to have the opportunity to see something go from conception to development to being in the hands of patients, and I certainly feel super blessed to have been a part of this.

“I really can't think of anything else that I'd rather be doing.”