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Xanomeline and trospium chloride is the first in a new class, offering a new approach with selectively targeting M1 and M4 receptors.
The FDA approved xanomeline and trospium chloride (Cobenfy, previously KarXT; Bristol Myers Squibb) for the treatment of schizophrenia in adults. The medication is the first in a new class, offering a new approach by selectively targeting M1 and M4 receptors in the brain without blocking D2 receptors.1
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“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” Rishi Kakar, MD, chief scientific officer and medical director at Segal Trials, said in a news release. “The approval of Cobenfy is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, COBENFY offers a new option to manage this challenging condition.”1
The approval is supported by data from the EMERGENT clinical program, including 3 placebo-controlled efficacy and safety trials and 2 open-label trials that evaluated the long-term safety and tolerability of the oral medication for up to 1 year. The EMERGENT clinical program included EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123).1
EMERGENT-3 was a phase 3, multicenter, randomized clinical trial used to confirm the results reported in EMERGENT-1 and EMERGENT-2. A total of 256 individuals were included with a mean age of 43.1 years, 74.6% were male, and 60.9% were Black or African American. Patients received xanomeline and trospium chloride (maximum dose of xanomeline 125 mg/trospium 30 mg) or the placebo for 5 weeks. The primary end point was change from baseline to week 5 PANSS total score, with secondary outcomes including change from baseline to week 5 PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of individuals with at least a 30% reduction in PANSS total score.2
In EMERGENT-3, xanomeline and trospium chloride demonstrated clinically meaningful and statistically significant 8.4-point reduction in Positive and Negative Syndrome Scale (PANSS) compared with the placebo at 5 weeks. The drug also demonstrated a reduction in both positive and negative symptoms, measured by PANSS positive, PANSS negative, and PANSS negative Marder factor subscales, which were the secondary outcomes of the study. There was a 3.5-point reduction in PANSS positive score.3
Trial Name: A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3)
ClinicalTrials.gov ID: NCT04738123
Sponsor: Karuna Therapeutics
Study Completion Date: December 2022
Investigators noted that the prespecified PANSS negative subscale score did not meet statistically significance at week 5, but the least-square mean changed form baseline in PANSS negative subscore and PANSS Marder negative factor score did achieve statistical significance at week 4.2
For safety, investigators found that the drug was generally well tolerated, with the overall discontinuation rate of 37% compared with 29% with the placebo. The most common treatment emergent adverse events (TEAEs) were constipation, diarrhea, dyspepsia, headache, hypertension, insomnia, and nausea. TEAE occurred in 70% in the drug arm and 50% in the placebo arm, with discontinuation rates due to TEAS being 6% and 5%, respectively.3
