American Society of Clinical Psychopharmacology Annual Meeting
American Society of Clinical Psychopharmacology Annual Meeting
Source/Disclosures
Source:

Brannan S, et al. Poster 74. Present at: American Society of Clinical Psychopharmacology Annual Meeting; May 29-30, 2020 (virtual meeting).

Disclosures: The authors report being employees or associates of Karuna Therapeutics.
June 09, 2020
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KarXT appears effective, safe among hospitalized patients with schizophrenia

Source/Disclosures
Source:

Brannan S, et al. Poster 74. Present at: American Society of Clinical Psychopharmacology Annual Meeting; May 29-30, 2020 (virtual meeting).

Disclosures: The authors report being employees or associates of Karuna Therapeutics.
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An antipsychotic with a novel mechanism of action appeared effective and safe among hospitalized patients with schizophrenia, according to data presented at the American Society of Clinical Psychopharmacology Annual Meeting.

The antipsychotic, KarXT (Karuna Therapeutics), is based on the selective muscarinic acetylcholine M1/M4 receptor agonist xanomeline.

“There is a substantial unmet need for a differentiated antipsychotic treatment option that not only has improved efficacy, but also a manageable side effect profile,” Stephen Brannan, MD, chief medical officer of Karuna Therapeutics, told Healio Psychiatry. “Antipsychotic treatments have undergone relatively modest innovation compared with first-generation drugs developed in the 1950s, which has meant very little advancement around the treatment choices that health care providers can offer their patients. Individuals with schizophrenia are often faced with a decision between managing their debilitating symptoms or experiencing serious side effects from their treatment that may be intolerable enough for them to discontinue.”

In prior randomized controlled trials — a large trial in Alzheimer’s disease and a small, proof-of-concept trial in schizophrenia — xanomeline showed antipsychotic efficacy. However, significant dropout rates because of cholinergic adverse events in the Alzheimer’s disease trial led to discontinuation of xanomeline development, Brannan and colleagues noted. In the KarXT formulation, xanomeline was combined with the FDA-approved peripheral anticholinergic drug trospium to reduce the adverse events associated with xanomeline.

Brannan and colleagues conducted the current randomized, double-blind, placebo-controlled, 5-week inpatient trial among 182 patients with schizophrenia aged 18 to 60 years who exhibited exacerbation of psychotic symptoms requiring hospitalization. The researchers randomly assigned patients 1:1 to KarXT or placebo and titrated KarXT dosing to minimize transient cholinergic adverse events. Change from baseline to 5 weeks in Positive and Negative Syndrome Scale (PANSS) total score for KarXT compared with placebo served as the primary endpoint. Key secondary endpoints included change from baseline to 5 weeks in PANSS-positive subscale, PANSS-negative subscale, PANSS Marder negative symptom factor score and Clinical Global Impressions-Severity (CGI-S) for KarXT compared with placebo. The researchers conducted statistical analyses using the modified intent-to-treat analysis set and a mixed-effects model for repeated measures.

Results showed a statistically significant change of 11.6 points from baseline to 5 weeks in PANSS total score compared with placebo, with significant separation starting at first PANSS total score assessment after baseline at 2 weeks and continuing through the study’s duration. Further, KarTX treatment was associated with statistically significant changes from baseline to 5 weeks compared with placebo in pre-specified analyses of PANSS positive subscore, PANSS negative subscore and PANSS Marder negative factor, as well as in a CGI-S score post hoc analysis. The researchers also observed statistically significant separation from placebo regarding change from baseline to 5 weeks in CGI-S score frequency count.

KarXT appeared safe and well tolerated, with similar discontinuation rates in the treatment and placebo groups, as well as similar rates of overall treatment-emergent adverse events and discontinuation linked specifically to such events. Constipation, nausea, dry mouth, dyspepsia and vomiting were the most common adverse events. All treatment-emergent adverse events were mild or moderate in severity, except for one serious adverse event of increased schizophrenia symptoms among the KarXT group. The researchers reported no discontinuation linked to cholinergic or anticholinergic adverse events, and the majority of the most common of these events associated with KarXT treatment decreased over the course of the study.

“We are encouraged by these findings and the potential to offer people with schizophrenia a differentiated treatment option with a novel mechanism of action that may have a superior efficacy, as well as tolerability profile relative to currently available antipsychotics,” Brannan told Healio Psychiatry. “This new mechanism also shows potential to effectively treat the condition and lessen the debilitating side effects associated with the current standard of care. We look forward to evaluating KarXT in future phase 3 studies.”