KarXT reduces symptom severity in schizophrenia

Key takeaways:

• The EMERGENT 2 and EMERGENT-3 trials included 508 adults with schizophrenia and acute psychosis.
• KarXT significantly reduced symptoms at week 2, with results remaining consistent through week 5.

MIAMI BEACH, Fla. — Treatment with KarXT reduced symptom severity for those with schizophrenia and acute psychosis compared with placebo, according to research presented at the American Society of Clinical Psychopharmacology annual meeting.

“The trial designs are exactly the same, very typical for antipsychotics,” Stephen K. Brannan, MD, chief medical officer at Karuna Therapeutics, said in his presentation.

Since KarXT met its primary endpoint in reduction of Positive and Negative Syndrome Scale (PANSS) scores, improved other key secondary efficacy measures and was generally well-tolerated in a 5-week, randomized, double-blind, placebo-controlled phase 2 study (EMERGENT-1), researchers wished to further test its safety and efficacy in two phase 3 trials.

Brannan and colleagues initiated two 5-week, randomized, double-blind, placebo-controlled studies in adults with schizophrenia and acute psychosis in an inpatient setting. For both EMERGENT-2 (n = 252) and EMERGENT-3 (n = 256), participants had recent worsening of positive symptoms requiring hospitalization, a PANSS total score of 80 or above as well as a Clinical Global Impression–Severity (CGI-S) score of four or higher. They were randomized 1:1 to KarXT or placebo, with the former dosing started at 50 mg xanomeline/20 mg trospium twice daily for the first 2 days of the study, upped to 100 mg/20 mg at days 3 to 7, then maximized at 125 mg/30 mg at days 8 to 35. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score with additional efficacy endpoints of changes from baseline to week 5 in PANSS positive, PANSS negative and PANSS Marder negative factor subscale scores.

In EMERGENT-2, KarXT demonstrated a 9.6-point reduction in PANSS total score compared with placebo at week 5 (-21.2 KarXT vs. -11.6 placebo), while also registering significant reductions in PANSS positive subscale score (-6.8 vs. -3.9), PANSS negative subscale score (-3.4 vs. -1.6) and PANSS Marder negative factor subscale score (-4.2 vs -2.0). Similar effects were observed in EMERGENT-3, with improvements in both PANSS and CGI-S beginning in week 2 and maintained through the end of the trial.

Pooled data from EMERGENT 1-2-3 found KarXT generally well tolerated, with treatment-emergent adverse events occurring in 5% or fewer of participants. The most common TEAEs with KarXT were mild to moderate in severity and occurred in 18.5% or fewer of the study population. Data additionally showed KarXT was not associated with common side effects of current therapies such as motor symptoms, weight gain, prolactin elevation or somnolence.

“Our exploratory analyses suggest a possible procognitive effect of KarXT,” Brannan said.