KarXT is effective in schizophrenic patients experiencing acute psychosis

Results from the phase 3 EMERGENT-2 study showed that, in schizophrenic patients experiencing acute psychosis, treatment with KarXT (xanomeline-trospium) induced a clinically meaningful and statistically significant improvement in total Positive and Negative Syndrome Scale (PANSS) score versus placebo.

Although antipsychotics that are approved for schizophrenia work primarily by antagonising D2 dopamine receptors, evidence suggests that the muscarinic-cholinergic system is also involved in the pathophysiology of schizophrenia [1]. Xanomeline, the active component of KarXT, is a functional agonist of M1 and M4 muscarinic receptors; trospium was added to xanomeline to limit adverse events related to the activation of peripheral muscarinic receptors [2,3]. Recently, results from the double-blind, phase 2 EMERGENT-1 study (NCT03697252) showed promising clinical activity of KarXT in patients with schizophrenia [3]. Dr Stephen Brannan (Karuna Therapeutics, MA, USA) presented the results of the subsequent phase 3 EMERGENT-2 study (NCT04659161) [4].

EMERGENT-2 enrolled 252 patients with schizophrenia experiencing acute psychosis (baseline PANSS score of 80 to 120). Participants were 1:1 randomised to receive KarXT (up to 125 mg xanomeline/30 mg trospium daily) or placebo for 5 weeks. The primary endpoint was PANSS score change from baseline.

Treatment with KarXT induced a clinically meaningful and statistically significant improvement in total PANSS score in 5 weeks compared with placebo (-21.2 vs -11.6; P<0.0001). At all timepoints from week 2 to week 5, KarXT was more effective than placebo. In line with this, KarXT was more effective in improvement of both PANSS positive subscale score, PANSS negative subscale score, and PANSS Marder negative factor at week 5.

KarXT was well tolerated with 1.6% serious treatment-emergent adverse events and 7.1% discontinuations. The most common adverse events –constipation, nausea, and vomiting– were in line with the cholinergic mode of action of xanomeline, and were mild and time-limited. In contrast to many other antipsychotic drugs, KarXT did not induce adverse events like extrapyramidal symptoms, sedation, weight gain, metabolic disturbances, or hyperprolactinemia, all of which contribute to poor medication adherence and relapses of psychosis.

Based on these results, Dr Brannan concluded that “KarXT is a potential new therapeutic option for schizophrenic patients experiencing acute psychosis.”

1. Erskine D, et al. Drug Discov Today. 2019;24:2307–2314.
2. Thorn CA, et al. Chem Neurosci. 2019;10:3910–3910.
3. Brannan SK, et al. N Engl J Med 2021;384:717–726.
4. Brannan SK, et al. Safety and efficacy of KarXT (xanomeline–trospium) in patients with schizophrenia: results from a phase 3, randomised, double-blind, placebo-controlled trial (EMERGENT-2). Abstract S07.05, ECNP Congress 2022, 15–18 October, Vienna, Austria.

 

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Posted on 28 November, 2022