SAFETY AND EFFICACY OF KARXT IN PATIENTS WITH SCHIZOPHRENIA IN THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED EMERGENT TRIALS

Abstract Background A high unmet medical need exists for more effective, better tolerated treatments for schizophrenia with novel mechanisms of action. All currently approved treatments for schizophrenia have dopamine D2 receptor blocking activity; the efficacy and tolerability limitations of these therapies are well known. KarXT is a novel combination of the dual M1/M4 preferring muscarinic receptor agonist xanomeline and the peripherally restricted anticholinergic trospium chloride. KarXT is designed to preserve the beneficial central nervous system effects of xanomeline, while mitigating the adverse events observed previously due to peripheral muscarinic receptor activation. In a 5-week, randomized, double-blind, placebo-controlled, phase 2 study (EMERGENT-1; NCT03697252), KarXT met the primary endpoint of a significant reduction in Positive and Negative Syndrome Scale (PANSS), improved other key secondary efficacy measures, and was generally well tolerated. Methods EMERGENT-2 (NCT04659161) and EMERGENT-3 (NCT04738123) were 5-week, randomized, double-blind, placebo-controlled phase 3 trials of KarXT in people with schizophrenia with acute psychosis in an inpatient setting. Key inclusion criteria were recent worsening of positive symptoms warranting hospitalization, Positive and Negative Syndrome Scale (PANSS) total score >80, and Clinical Global Impression– Severity (CGI-S) score >4. Eligible participants were randomized 1:1 to KarXT or placebo. KarXT dosing (mg xanomeline/mg trospium) started at 50 mg/20 mg twice daily (BID) and increased to a maximum of 125 mg/30 mg BID. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Other efficacy endpoints included change from baseline to week 5 in PANSS positive, PANSS negative, and PANSS Marder negative factor subscale scores. Results In the EMERGENT trials, KarXT consistently demonstrated significant and clinically meaningful reductions in Positive and Negative Syndrome Scale (PANSS) score and was generally well tolerated. KarXT demonstrated a significant improvement in other secondary outcome measures, including CGI and PANSS positive subscales, across clinical trials. PANSS negative subscale and PANSS Marder negative factor achieved statistical significance compared with placebo at study endpoint in EMERGENT-1 and 2 and only at week 4 in EMERGENT-3. The most common (>5%) treatment-emergent adverse events with KarXT were all mild to moderate in severity and were not associated with common problematic side effects of current therapies such as motor symptoms, weight gain, prolactin elevation, or somnolence. Conclusions If approved, KarXT has the potential to be first in a new class of schizophrenia treatments based on muscarinic receptor agonism and a promising alternative to direct dopamine D2 receptor antagonists and partial agonists.