Rishi Kakar, MD: EMERGENT Trials, FDA Accepts Xanomeline-Trospium Application

Karuna Therapeutics announced on November 29, 2023 that the US Food and Drug Administration (FDA) accepted the New Drug Application for xanomeline-trospium (KarXT). If approved—which will be decided by September 26, 2024—the drug will be the first new pharmacological approach to treating schizophrenia since the 1970s.^1,2

The pivotal EMERGENT trials demonstrated the clinical significance of xanomeline-trospium, which acts as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system. The EMERGENT program included 5 trials, the first 3 comparing xanomeline-tospium with a placebo to test efficacy and safety and 2 trials to evaluate the long-term safety of the drug.

In an interview with HCPLive, Rishi Kakar, MD, discussed the implications of the findings from the EMERGENT trials and what xanomeline-trospium’s pending FDA approval could mean for patients with schizophrenia.

“The data is really encouraging,” Kakar said. “It's very encouraging to see that across three different studies, KarXT did show that difference across the timeframe where the study was conducted.”

Despite already available medications for schizophrenia, Kakar pointed out there persists a “very large unmet need in the community” for additional schizophrenia treatment. Right now, 30% of patients do not have a response to the current medications, and 50% only have a partial response or experience high side effects to the point where they might not consistently take their medications.

“This particular compound of KarXT is unique and is potentially really differentiated from the others,” Kakar said.

He explained xanomeline-trospium affects brain chemicals responsible for symptoms of schizophrenia differently than other medication. Currently, schizophrenia treatments directly regulate the dopamine receptor. Repeatedly, investigators—trying to find a new schizophrenia treatment—attempted new ways to modulate the dopamine receptor to see if symptoms change.

“KarXT is very unique in that way, in that it is a muscarinic drug—it only indirectly modulates those dopamine and other neurotransmitters responsible for symptoms of schizophrenia,” Kakar said, "and in that is where I think there is a potential reason to have optimism where there is the side effect burden that we spoke about for those patients who are experiencing them arising from those dopamine drugs.”

Current schizophrenia treatment has led to adverse effects of weight gain, somnolence, movement disorders. Since KarXT focuses on a different receptor profile altogether, the drug was not associated with these adverse effects.

Kakar stressed the importance of having an agent like KarXT. Drugs intended for schizophrenia treatment have stayed quite similar over the years, but KarXT targets a different part in the brain chemistry, directly looking at the part of the brain where the dopamine is.

“One of the important things to really highlight is the fact that KarXT as a really novel molecule does have a unique way of potentially treating the patients with schizophrenia,” Kakar said. “It’s time for change, it’s time to look at different ways of looking at it, it’s time to really address the symptom burden as a whole and see how can we look at the reduction in the symptoms in a different way.”

^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 November 30, 2023.}
2. ^{Karuna Therapeutics Announces U.S. Food and Drug Administration Accepts New Drug Application for KarXT for the Treatment of Schizophrenia. Karuna Therapeutics. November 29, 2023. https://investors.karunatx.com/news-releases/news-release-details/karuna-therapeutics-announces-us-food-and-drug-administration. Accessed November 30, 2023.}