Xanomeline was first synthesized in 1997 in a collaboration between pharmaceutical firms
Eli Lilly and
Novo Nordisk with the goal of delaying cognitive decline in people with Alzheimer's disease. In a phase II study, significant improvements in cognition were observed in people with Alzheimer's along with surprising improvements in behavioral symptoms such as hallucinations, delusions, suspiciousness and agitation. In a follow-up placebo-controlled study in participants with schizophrenia, similar effects on symptoms of psychosis was observed with xanomeline. However, cholinergic-mediated side effects prevented advancement of xanomeline into phase III trials. Xanomeline was licensed to Karuna Therapeutics in 2012 and KarXT was subsequently created as a dual drug formulation by adding trospium. Trospium is a non-brain-penetrant and non-selective muscarinic receptor blocker that may ameliorate the peripheral side effects of xanomeline. In 2019, the EMERGENT-1 placebo controlled phase II clinical trial of KarXT in adults with schizophrenia met the primary endpoint of a change from baseline in the
positive and negative syndrome scale (PANSS) total score at week 5 vs. placebo. The results from the trial were subsequently published in the New England Journal of Medicine. In August 2022, Karuna Therapeutics announced that KarXT has achieved the primary endpoint in the phase III EMERGENT-2 trial and in March 2023, Karuna Therapeutics announced that KarXT had met its primary endpoint in the phase III EMERGENT-3, and that it was submitting the drug for approval by the US
Food and Drug Administration (FDA). The results from the EMERGENT-2 and EMERGENT-3 clinical trials were published in the LANCET and JAMA-Psychiatry respectively. In September 2023, Karuna announced that it has submitted the new drug application (NDA) for KarXT and in November 2023, the FDA began its review and set the
PDUFA date for September 2024. The FDA evaluated the effectiveness of xanomeline/trospium chloride for the treatment of schizophrenia in adults based on two studies with identical designs. Cobenfy is a trademark of Karuna Therapeutics. The EMERGENT-2 and EMERGENT-3 trials enrolled 470 adults with schizophrenia. The trials were conducted at 39 sites in the United States and Ukraine. There were 425 trial participants from the United States. The efficacy of the combination (which is a measure of how well the drug works) was evaluated in two clinical trials for 470 participants with schizophrenia, and safety was assessed in the two trials in a total of 504 participants with schizophrenia who received at least one dose of xanomeline/trospium chloride. The same trials were used to assess efficacy and safety. The number of participants representing efficacy findings differs from the number of participants representing safety findings due to different pools of study participants analyzed for efficacy and safety. In the trials, participants were randomly assigned to receive xanomeline/trospium chloride or placebo, and neither participants nor care providers knew which treatment was given during the trial. Symptoms of schizophrenia were measured using a clinician-administered measure of schizophrenia symptoms called the Positive and Negative Syndrome Scale (PANSS). The benefit of COBENFY was assessed in both trials by determining the improvement in schizophrenia symptoms (the difference in PANSS scores before and after five weeks of treatment). == Society and culture ==