EFFICACY OF KARXT ON NEGATIVE SYMPTOMS IN ACUTE SCHIZOPHRENIA: AN ANALYSIS OF POOLED DATA FROM 3 TRIALS

Abstract Background KarXT is an investigational M1 /M4 preferring central muscarinic receptor agonist and has shown efficacy as a monotherapy treatment for people with schizophrenia who are experiencing acute psychosis. Across three phase 2/3 trials, participants treated with KarXT had significant improvements in PANSS total (primary endpoint) and positive symptoms compared to placebo. In two of the three trials, significant improvement for negative symptoms in the KarXT group was observed. Although improvement of negative symptoms in studies of acute psychosis may be secondary to the improvement in dominant positive symptoms, it is possible that KarXT has a direct treatment benefit for negative symptoms as well. To further investigate this, post hoc analyses of pooled data from these three studies explored the possible efficacy of KarXT in a subset of participants with moderate/severe negative symptoms of schizophrenia. Methods Data were pooled from a phase 2 (NCT03697252) and two phase 3 (NCT04659161, NCT04738123) inpatient trials of KarXT in people with schizophrenia experiencing acute psychosis that used identical 5-week randomized, double-blind, placebo-controlled designs. A subset of participants with prominent negative symptoms were identified. MMRM analyses were used to evaluate changes from baseline to week 5 in PANSS-Marder Negative Symptoms in the full pooled sample and prominent negative symptoms subgroup. In addition, we evaluated whether changes in negative symptoms were related to changes in other symptoms, including positive symptoms. Finally, MMRM analyses explored KarXT effects on the two PANSS negative symptom subdomains of expressive and experiential deficits. Results In the full pooled sample from three studies (n = 640), PANSS-Marder Negative Symptom scores showed significantly greater improvement in those treated with KarXT (n = 314) than placebo (n = 326; Estimate = -1.97, SE =.40, p <.0001; Cohen’ s d =.42). Of the pooled sample, 10% (n = 64) met criteria for having prominent negative symptoms at baseline. Within this subgroup, PANSS-Marder Negative Symptom scores revealed significantly larger improvement in those treated with KarXT (n = 29) versus placebo (n = 35; Estimate = -4.71 SE = 1.16, p <.0001; Cohen’ s d = 1.18), even after accounting for changes in positive symptoms, depression/anxiety, disorganization, or hostility. Significant KarXT benefits were also seen for both reduced experiential and expressive deficits in the full sample (ES, d =.52 vs..22, respectively) and in the prominent negative symptom subgroup (d = 1.08 vs..84, respectively). Conclusion In the subgroup of participants with acute psychosis and moderate/severe negative symptoms, KarXT was associated with significant improvement in negative symptoms versus placebo with an even greater benefit than in the full study sample that remained significant after accounting for changes from baseline in positive symptoms, depression/anxiety, disorganization, or hostility. Collectively, these findings are consistent with the possibility that KarXT directly impacts negative symptoms in acutely psychotic individuals. Notably, KarXT impacted both reduced experience and reduced expression subdomains. Further investigation of the effects of KarXT on negative symptoms in a larger sample of stable outpatients with dominant negative symptoms is warranted.