'Amazing' Phase 3 Results for Novel Schizophrenia Combo Drug

Liam Davenport

October 20, 2022

VIENNA — The investigational agent xanomeline-trospium (KarXT, Karuna Therapeutics) achieves significant and clinically meaningful improvements in schizophrenia symptom scores without causing problematic adverse effects, new research suggests.

Results from the phase 3 EMERGENT-2 trial, which included more than 250 patients with schizophrenia, showed that those who received xanomeline-trospium for 5 weeks achieved a significant reduction in Positive and Negative Syndrome Scale (PANSS) total scores of more than nine points compared with their peers who received placebo. In addition, the improvements started at week 2.

Alongside significant reductions in both positive and negative symptoms, the results suggest the agent was well tolerated, with treatment-emergent adverse events (TEAEs) largely mild to moderate and transient in nature.

Lead investigator Christoph U. Correll, MD, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York, told Medscape Medical News that the upcoming EMERGENT-3 study will have a "European component" and that the "readout is expected most likely in the first quarter of next year."

Correll suggested that if leads to "two positive studies and reasonable safety," the novel agent may become part of the "next generation of antipsychotics that are not related to postsynaptic dopamine blockade."

The findings for EMERGENT-2, presented here at the 35th European College of Neuropsychopharmacology (ECNP) Congress as a poster and as an oral presentation, were an update of topline results released earlier this year.

Novel Compound

Xanomeline-trospium is a novel compound that combines the dual M1/M4-preferring muscarinic receptor agonist effect of xanomeline with the peripherally restricted muscarinic receptor antagonist effect of trospium.

A previous phase 2 trial that compared the drug with placebo in almost 200 patients suggested it significantly reduced psychosis symptoms, leading to the current phase 3 trial.

Correll noted that xanomeline-trospium reduces psychosis via a "bottom up and top down approach."

He said that on one hand, M4 agonism decreases acetylcholine in the ventral tegmental area and the associated stratum, "which then decreases dopamine levels from the bottom up," while the M1 agonism stimulates GABA and decreases dopamine from the "top down."

M1 agonism, however, also stimulates the cholinergic system peripherally, "which can give you nausea, vomiting, and also some blood pressure and pulse" problems, Correll said.

That was the limitation when this approach was studied by Lilly as a treatment for patients with Alzheimer's disease, but the addition of trospium means "you're buffering somewhat the cholinergic peripheral effects," he said.

While that can conversely lead to dyspepsia, dry mouth, and constipation, Correll noted that the adverse effects of the novel agent are "mitigated by titration," with patients taking up to 8 days to reach the full dose.

The result is that the drug was "overall tolerated, and the effect sizes were quite astounding," he reported.

Intermittent, Time Limited TEAEs

The current trial included 252 patients aged 18–65 years (mean age, 45 years) who were confirmed to have schizophrenia and who had recently experienced a worsening of psychotic symptoms that warranted hospitalization. Three quarters of the participants were men, and a similar proportion were Black. Approximately one quarter were White.

All were randomly assigned in a 1:1 ratio to receive either xanomeline-trospium or placebo following a 2-week screening period.

Xanomeline and trospium were titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily, and patients were treated for a total of 5 weeks. Efficacy and safety analyses were conducted in those who had received at least one dose of the study drug.

At the end of the treatment period, xanomeline-trospium was associated with a significant 9.6-point reduction in PANSS total scores relative to placebo; scores fell by 21.2 points with the active treatment, vs 11.6 points with placebo (P < .0001).

The significant improvement in PANSS total score began at week 2 (P < .05) and continued to accrue over the course of the study.

Xanomeline-trospium was also associated with significant reductions in PANSS positive subscale scores in comparison with placebo (P < .0001), as well as with reductions in PANSS negative subscale scores (P < .01) and PANSS Marder negative subscale scores (P < .01).

Although 75.4% of patients who received xanomeline-trospium experienced a TEAE, in comparison with 58.4% of the placebo group, very few experienced a serious TEAE (just 1.6% in both groups).

TEAEs leading to discontinuation occurred in 7.1% of the active-treatment group, vs 5.6% of the placebo group. The overall discontinuation rates from the trial were 25% and 21%, respectively.

The most common TEAEs with xanomeline-trospium were constipation (21.4%), dyspepsia (19.0%), nausea (19.0%), vomiting (14.3%), and headache (13.5%).

The results showed that cholinergic TEAEs typically began within the first 2 weeks of treatment and were "intermittent and time limited in nature," the investigators note. Moreover, average blood pressure levels were "similar" between the xanomeline-trospium and placebo groups "at each time point throughout the trial," they add.

Correll reported that whereas the EMERGENT studies are testing xanomeline-trospium as a monotherapy, the ARISE program will be examining it as an "augmentation" treatment. "And that's relevant because, let's face it, patients do not switch" treatments, he said.

He suggested that if xanomeline-trospium is able to have a synergistic effect with other drugs, "we might be able to treat people who are currently not benefiting enough from postsynaptic dopamine blockade to maybe get a little bit closer" to the benefits seen with clozapine, which "also has problematic side effects."

"Really Revolutionary"

Following the oral presentation of the study by co-author Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, Massachusetts, the results were warmly received.

Session co-chair Mark Weiser, MD, chairman at the Department of Psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, said the agent is "really revolutionary in the field.

"It's a non-dopamine compound which helps for schizophrenia, so we're all very optimistic about it," Weiser added.

Nevertheless, he asked Brannan whether the occurrence of gastrointestinal adverse effects with xanomeline-trospium led to "functional unblinding of the study."

Brannan answered that the investigators were "really worried about this prior to EMERGENT-1" but that formal testing suggested it was not a problem.

Brannan said that although this has not yet been formally tested for the current trial, he believes that it is "highly unlikely" that functional unblinding occurred, inasmuch as the "percentages are about in the same range as we saw in EMERGENT-1."

Speaking to ECNP Congress Daily in a conference roundup video, session co-chair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt, Frankfurt am Main, Germany, also highlighted the study.

He said that along with a study of dexmedetomidine sublingual film for agitation associated with schizophrenia or bipolar disorder that was also presented in the session, the current trial is "pivotal."

Reif noted that the effect size shown with xanomeline-trospium was "really amazing."

"We are in a really exciting time in treating mental disorders," he said. "Industry is finally investing again, and really has new compounds that will make it to the market."

Karuna plans to submit a new drug application with the US Food and Drug Administration for KarXT in mid-2023. The drug is also in development for the treatment of psychiatric and neurologic conditions other than schizophrenia, including Alzheimer's disease.

The study was funded by Karuna Therapeutics. Correll has reported relationships with Karuna, as well as AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pfizer, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Viatris, Otsuka, and UpToDate. Brannan is an employee of Karuna Therapeutics.

35th European College of Neuropsychopharmacology (ECNP) Congress: Abstracts P.0193 and S07.05. Presented October 16, 2022.

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