Positive Phase 3 Results for Novel Schizophrenia Drug

News

The investigational agent xanomeline-trospium (KarXT, Karuna Therapeutics), which combines a muscarinic receptor agonist with an anticholinergic agent, helps improve psychosis symptoms, and is not associated with weight gain or sedation in adults with schizophrenia, new research shows.

Top-line results from the phase 3 EMERGENT-2 trial showed a significantly greater reduction from baseline on Positive and Negative Syndrome Scale (PANSS) total scores for those receiving the active drug than for those receiving placebo, meeting its primary endpoint.

The findings “underscore the potential for KarXT, with its novel and unique mechanism of action, to redefine what successful treatment looks like for the 21 million people living with schizophrenia worldwide, and potentially usher in the first new class of medicine for these patients in more than 50 years,” Steve Paul, MD, chief executive officer, president, and chairman of Karuna Therapeutics, said in a press release.

Primary Outcome Met

About 20% to 33% of patients with schizophrenia do not respond to conventional treatments, the company noted. Many have poor functional status and quality of life despite lifelong treatment with current antipsychotic agents.

Unlike current therapies, KarXT doesn’t rely on the dopaminergic or serotonergic pathways. It comprises the muscarinic agonist xanomeline and the muscarinic antagonist trospium, and is designed to preferentially stimulate muscarinic receptors in the central nervous system.

As reported at the time by Medscape Medical News, results from a phase 2 trial of almost 200 patients with schizophrenia were published last year in the New England Journal of Medicine. The findings showed that those who received xanomeline-trospium had a significantly greater reduction in psychosis symptoms than those who received placebo.

In the current phase 3 EMERGENT-2 trial, investigators included 252 adults aged 18-65 years who were diagnosed with schizophrenia and were experiencing symptoms of psychosis. Patients were randomly assigned to receive either a flexible dose of xanomeline-trospium or placebo twice daily.

The primary endpoint was change from baseline in the PANSS total score at week 5. Results showed a statistically significant and clinically meaningful 9.6-point reduction in the PANSS total score in participants taking the active drug compared with those taking placebo (-21.2 vs -11.6, respectively; P < .0001; Cohen’s d effect size, 0.61).

In addition, there was an early and sustained significant reduction of schizophrenia symptoms, as assessed by the PANSS total score, starting at week 2. This reduction was maintained through all trial timepoints.

Safety Profile

The novel drug also met key secondary endpoints. In the active treatment group, there was a significant reduction on the PANSS subscales in both positive symptoms of schizophrenia, such as hallucinations or delusions, and negative symptoms, such as difficulty enjoying life or withdrawal from others.

Overall, the agent was generally well tolerated. The treatment-emergent adverse events (TEAEs) rate for xanomeline-trospium and placebo was 75% vs 58%, respectively.

The most common TEAEs for the active treatment were all mild-to-moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea.

As in prior trials, an increase in heart rate was also associated with the active treatment and decreased in magnitude by the end of the current study.

Discontinuation rates related to TEAEs were similar between xanomeline-trospium (7%) and placebo (6%), as were rates of serious TEAEs (2% in each group) — which included suicidal ideation, worsening of schizophrenia symptoms, and appendicitis.

Notably, the drug was not associated with common problematic adverse events of current therapies, such as weight gain, sedation, and movement disorders.

Karuna plans to submit a New Drug Application with the US Food and Drug Administration for KarXT in mid-2023. In addition to schizophrenia, the drug is in development for the treatment of other psychiatric and neurological conditions, including Alzheimer’s disease.

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