Investigational Antipsychotic Demonstrates Efficacy Without Blocking Dopamine Receptor


Investigational agent KarXT is a first-in-class muscarinic receptor agonist demonstrating antipsychotic efficacy and safety in short- and long-term clinical trials.

Raymond Orton_AdobeStock

Raymond Orton_AdobeStock

The investigational agent KarXT (xanomeline-trospium chloride) demonstrated antipsychotic efficacy in a recently published short-term, phase 3 randomized clinical trial,1 and over a 52-week open-label extension2 presented at the 2024 Annual Congress of the Schizophrenia International Research Society (SIRS) in Florence, Italy.

KarXT (Karuna Therapeutics, subsidiary of Bristol Myers Squibb) shows evidence of antipsychotic effect without the direct dopamine D2 receptor blockade of currently available antipsychotics. The xanomeline component of KarXT is an agonist at muscarinic M1 and M4 receptors, with antipsychotic effect likely arising with altered dopamine regulation from changes in synaptic acetylcholine concentrations.3

The putative dopamine regulation is distinct from direct dopamine D2 receptor blockade and ostensibly from concomitant adverse effects such as extrapyramidal symptoms (EPS) and hyperprolactinemia.

Samatha Yohn, PhD, of Karuna Therapeutics and colleagues explain in a review3 that activation of M1 receptors on cholinergic cortical inhibitory interneurons reduces excitatory tone of dopamine circuitry in the ventral tegmental area (VTA), and that M4 receptor activation leads to reduced dopamine cell firing in both the VTA and nucleus accumbens (NAc).

Although early work modulating postsynaptic M1 receptors focused on mitigating cognitive deficits associated with loss of cholinergic neurons in Alzheimer disease, subsequent elucidation of 5 muscarinic receptor subtypes and the interaction of M1 and M4 in particular with dopamine neural circuits implicated in psychosis, informed the current development.

“As shown in this review, there is remarkable convergence of preclinical and clinical evidence for the potential for muscarinic acetylcholine receptor activators to become a new molecular class for the treatment of schizophrenia,” Yohn and colleagues wrote.3

The KarXT product is a combination of the muscarinic xanomeline and the peripherally active muscarinic receptor antagonist, trospium, formulated together to exert therapeutic central effects while mitigating cholinergic adverse effects such as vomiting, nausea, and diarrhea.

In the 5-week trial1 assessing antipsychotic effect and safety in patients with schizophrenia who were experiencing acute psychosis, the dose started at 50mg xanomeline/20mg trospium twice daily for the first 2 days, and then was changed to 100mg xanomeline/20mg trospium twice daily for days 3 though 5. Flexible dosing began on day 8, with optional increases to maximum of 125mg xanomeline/30mg trospium twice daily.

David Walling, PhD, a co-investigator in the trial and chief clinical officer of the CenExel Hassman Research Institute, discussed the challenge of establishing ceiling dosage of the muscarinic/antimuscarinic agent with Psychiatric Times®, particularly in light of “real-world” antipsychotic dosing, which is often increased without apparent toxicity in pursuit of improved therapeutic response.

“At this time, and with a new class of medications, it is difficult to know what exactly the upper limits may be,” Walling commented. “I think that we can infer from the preclinical data, as well as the studies in humans, that there are likely dose-limiting side effects—in particular some of the gastrointestinal side effects such as nausea.”

As to whether there are dose-response data emerging for KarXT, which are generally unavailable for currently marketed antipsychotics, Walling responded, “at this time, there is probably not. During the research process, you largely focus on those studies that are requirements for regulatory approval. They can be quite costly to run, so the studies that expand dosing—both up and down—are often done after the initial required studies.”

Efficacy and Safety in Short- and Long-Term Trials

The 5-week, double-blind, randomized, placebo-controlled trial of KarXT (EMERGENT-3) involved 256 participants with schizophrenia who were experiencing acute psychosis assigned (1:1) to KarXT treatment or to placebo.

The trial was conducted at 18 inpatient facilities in the United States and 12 in Ukraine (enrolled prior to the February 2022 Russian invasion), between April 2021 and December 2022. It follows the EMERGENT-2 phase 3 trial of the same design but without the Ukraine sites, as an additional safety and efficacy registrational trial to support the New Drug Application (NDA).

The participants aged 18 to 65 years had experienced an acute exacerbation or relapse of psychotic symptoms necessitating admission or continued hospitalization, with onset of fewer than 2 months or fewer than 2 weeks of hospitalization for the exacerbation at the time of screening. Participants had not had lithium therapy for at least 2 weeks before baseline (study day 1) and were free of all oral antipsychotic medications for the longer of 5 half-lives or 1 week, and for 12 weeks after an injectable depot antipsychotic (24 weeks for Invega Trinza).

Walling and colleagues reported that at week 5, the KarXT group had a significantly reduced PANSS total score (the primary end point) compared with placebo (-20.6 vs -12.2; least squares [LS] mean difference -8.4 [95%CI -12.4 to -4.3]). In secondary end points, the reduction in the PANSS positive subscale in the KarXT group was -7.1 compared with -3.6 with placebo (LS -3.5; -4.7 to -2.2). Differences in the prespecified PANSS negative subscale score did not meet statistical significance at week 5.

“The studies that are published here were focused on individuals who were experiencing an acute episode—as such, negative symptoms were secondary,” Walling noted. “To truly examine negative symptoms, a study has to have inclusion/exclusion criteria that enrich for this population.”

The investigational agent was considered well tolerated, with similar discontinuation rates due to treatment-emergent adverse events (TEAEs) in both groups. The most common TEAEs occurring at higher rates in the KarXT group were nausea, dyspepsia, vomiting, and constipation. There were no clinically meaningful changes from baseline to week 5 on any of the extrapyramidal motor symptoms scales between groups. KarXT was not associated with weight gain or somnolence compared with placebo.

In the 52-week open-label extension4 of both the EMERGENT-2 and -3 trials, all participants were offered treatment with the active agent. In the analysis of pooled efficacy data, designated EMERGENT-4, more than 75% of the 110 participants attained at least 30% reduction in PANSS total score, regardless of whether initially assigned to the active treatment or placebo group. Improvement from baseline continued through 52 weeks of treatment for all participants.

Long-term safety data gathered from both the EMERGENT-4 and a separate open-label, 52-week safety study (EMERGENT-5) were pooled in a separate study5 presented at the 2024 SIRS meeting, with lead author Ronald Marcus, MD, senior vice president of clinical development at Bristol Myers Squibb. In a total of 718 participants, the overall discontinuation rate was 53.1%, and the rate of discontinuation due to TEAEs was 14.9%.

The most commonly reported TEAEs leading to treatment discontinuation were nausea (3.9%) and vomiting (3.5%). KarXT was not associated with weight gain, with clinically meaningful changes in movement disorder scale scores, or with significant changes related to prolactin over the 52 weeks.

“These findings, together with the long-term efficacy results showing improvements in efficacy measures across the 52-week trials, support the potential of KarXT, if approved, to be the first in a new class of antipsychotic medications based on muscarinic receptor agonism and a well-tolerated alternative to currently available antipsychotics,” Marcus and colleagues concluded.5

Dr Bender reports on medical innovations and advances in practice and edits presentations for news and professional education publications. He previously taught and mentored pharmacy and medical students, and he provided and managed pharmacy care and drug information services.


1. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trialJAMA Psychiatry. Published online May 1, 2024.

2. Kaul I, Cohen EA, Miller AC, et al. Maintenance of efficacy of KarXT (xanomeline and trospium) in schizophrenia. Poster F264. Presented at the Annual Congress of the Schizophrenia International Research Society (SIRS). April 3 to 7, 2024.

3. Yohn SE, Weiden PJ, Felder CC, Stahl SM. Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinicTrends Pharmacol Sci. 2022;43(12):1098-1112.

4. Kaul I, Cohen EA, Miller AC, et al. Maintenance of efficacy of KarXT (xanomeline and trospium) in schizophrenia. Poster F264. Presented at the Annual Congress of the Schizophrenia International Research Society. April 3 to 7, 2024.

5. Marcus R, Kakar R, Miller AC, et al. Long-term safety of KarXT (xanomeline and trospium) in schizophrenia. Poster F74. Presented at the Annual Congress of the Schizophrenia International Research Society (SIRS). April 3 to 7, 2024.

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