Reviewing Cholinergic Adverse Events with KarXT in EMERGENT-2

At the American Psychiatric Association 2023 Annual Meeting, Rishi Kakar, MD, presented a post hoc analysis of procholinergic and anticholinergic adverse events (AEs) among patients with schizophrenia in the phase 3 EMERGENT-2 study undergoing treatment with KarXT.

KarXT is the combination of xanomeline and trospium, a muscarinic receptor agonist and peripherally restricted muscarinic receptor antagonist, respectively, and itis intended to mitigate AEs linked to peripheral muscarinic receptor activation without sacrificing the efficacy of xanomeline.

According to Dr. Kakar, the majority of AEs related to KarXT were mild and transient, occurred within the first two weeks of treatment, and were consistent with xanomeline and trospium activity observed at muscarinic receptors. In EMERGENT-2 itself, authors noted KarXT met the primary end point, improved secondary end points, and was generally well tolerated.

This post hoc analysis included 251 patients with schizophrenia with acute psychosis, of which 126 received KarXT and 125 received placebo for five weeks. Dr. Kakar and colleagues assessed onset, duration, and severity of common procholinergic and anticholinergic treatment-emergent AEs (TEAEs) and calculated number needed to harm (NNH) for each TEAE, defined as one divided by the difference in TEAE rate between the KarXT and placebo groups.

In the KarXT group, 31.0% and 33.0% of patients experienced at least one procholinergic or anticholinergic TEAE, respectively, compared with 8.0% and 19.2% of patients in the placebo group. The most common TEAEs that occurred in ≥5% of the KarXT group and at a more than two-times incidence versus the placebo group were:

  • Nausea (19.0% vs 5.6%)
  • Vomiting (14.3% vs 0.8%)
  • Constipation (21.4% vs 10.4%)
  • Dyspepsia (19.0% vs 8.0%)

The median TEAE duration was 1.0 days for vomiting and up to 6.5 days for dyspepsia. Additionally, authors noted that approximately one-third of vomiting TEAEs were a single episode of emesis and that few patients discontinued treatment due to AEs. NNH for KarXT versus placebo was eight for nausea, eight for vomiting, 10 for constipation, and 10 for dyspepsia.

Ultimately, Dr. Kakar and colleagues suggested “KarXT has the potential to be the first in a new class of treatments for people with schizophrenia based on muscarinic receptor agonism and a promising alternative to direct dopamine D2 receptor antagonists.”