Andrew Miller, PhD: Inventor of KarXT Discusses Pivotal EMERGENT-2 Data

Last month, the U.S. Food and Drug Administration accepted the xanomeline-trospium (KarXT) New Drug Application (NDA) for the treatment of adults with schizophrenia.¹

If approved by the FDA, xanomeline-trospium will be the first pharmacological approach to treating schizophrenia since the breakthroughs of injectable fluphenazine enanthate and fluphenazine decanoate (the more popular option) in the 1970s. ²

Xanomeline-trospium acts as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system, and clinical trials significantly demonstrated improvements in positive, negative, and cognitive symptoms of schizophrenia. Unlike previous treatments of schizophrenia which directly block dopamine receptors, xanomeline-trospium does not.

Investigators studied xanomeline-trospium in the 5-trial EMERGENT program, assessing for efficacy and safety, as well as long-term safety in placebo-controlled trials. The New England Journal of Medicine published EMERGENT-1 results a couple years ago, and The Lancet just published the peer-reviewed results on December 14.³

HCPLive recently interviewed lead investigator of the EMERGENT trials, Rishi Kakar, MD, who talked about the encouraging data, and how xanomeline-trospium was a unique compound due to the fact it does not block dopamine receptors.⁴

In an interview with HCPLive, Andrew Miller, PhD, co-founder of Karuna Therapeutics, co-author of the study published in The Lancet, and inventor of KarXT, discussed the significant findings.

“When you look across all three of the studies, the data is very consistent, and consistent in that it shows a clear statistical and clinically meaningful benefit on the primary endpoint, which is a measure of total symptoms, the positive and negative syndrome score,” Miller said.

The team observed only mild to moderate gastrointestinal adverse events. Also, adverse events associated with current dopamine-based treatments—such as extrapyramidal symptoms, motor symptoms, metabolic or weight effects, sedation, somnolence—were not present.

“It’s very gratifying for us to see the publication of those data, both from a data quality perspective, but also… the recognition that these studies are very important in demonstrating the potential benefits and profile of KarXT,” Miller said.

Miller pointed out, if xanomeline-trospium gets approved, they can launch the “first new class of medicine” with muscarinic receptor agonists used for schizophrenia treatment. The FDA will decide if xanomeline-trospium gets approved or not by September 2024.

“And so, I think we really have a tremendous opportunity in front of us to really think about how we impact care in patients living with schizophrenia, as well as their caregivers and care partners,” Miller said. “I really couldn’t be more excited about…trying to get this out in the hands of patients.”

References

1. ^{Derman, C. FDA Accepts Xanomeline-Trospium Drug Application for Schizophrenia Treatment. HCPLive. November 29, 2023. https://www.hcplive.com/view/fda-xanomeline-trospium-drug-application-schizophrenia-treatment. Accessed December 21, 2023.}
2. ^{Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia. J Clin Psychiatry. 2010;71(9):1115-1124. doi:10.4088/JCP.10r06264yel}
3. ^{Derman, C. Peer-Reviewed EMERGENT-2 Trial Data Supports Xanomeline-Trospium for Schizophrenia. HCPLive. December 15, 2023. https://www.hcplive.com/view/peer-reviewed-emergent-2-trial-data-supports-xanomeline-trospium-schizophrenia. Accessed December 21, 2023.}
4. ^{Derman, C. Rishi Kakar, MD: EMERGENT Trials, FDA Accepts Xanomeline-Trospium Application. HCPLive. December 1, 2023.https://www.hcplive.com/view/rishi-kakar-md-emergent-trials-fda-accepts-xanomeline-trospium-application. Accessed December 21, 2023.}