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Hi and hello from Boston, Massachusetts. Oliver Freudenreich, or Dr. F, here for the Psychopharmacology Institute. In this Quick Take, I will talk about a very exciting experimental antipsychotic that is far advanced in clinical trials and may even be approved this year by the American FDA. The company, Karuna Therapeutics, just published the results from one of their registration trials for their experimental drug called KarXT. This may be a good time to review this drug and the clinical trial that goes with it to bring you up to speed with drug development in the schizophrenia field.
Let me start with some background. All currently approved antipsychotics directly target the dopamine system. They are all dopamine antagonists, and they affect not only psychosis circuits but also neural circuits related to motor function. As a result, all currently available antipsychotics can cause a host of other side effects, including extrapyramidal symptoms, and you always have to worry about tardive dyskinesia as a potentially irreversible motor problem. It turns out that medications that target the cholinergic system can function as antipsychotics. More specifically, muscarinic acetylcholine receptor agonists, or muscarinic agonists for short, seem to be able to indirectly modulate those dopaminergic circuits that we believe are responsible for psychosis while sparing the motor circuit. You would expect efficacy from such a drug but a different side-effect profile and, notably, no motor side effects.
Using cholinergic agonists to treat psychosis was discovered over 25 years ago purely by serendipity. At that time, researchers studied the cholinergic agonist xanomeline—which is spelled with an “x” at the beginning—for the treatment of Alzheimer’s disease. In these trials, they observed that xanomeline reduced psychosis in Alzheimer’s. Unfortunately, this never really went anywhere because xanomeline has poor tolerability. It also affects the peripheral cholinergic system, so you get severe GI problems, including nausea and vomiting, which prevents its long-term use. We have learned a lot since then, and we know much more about cholinergic pharmacology. We know, for example, that xanomeline is a so-called M1/M4-preferring muscarinic agonist, and it seems that this M1/M4 agonism is critical for antipsychotic action, maybe by modulating dopamine via top–down and bottom–up mechanisms, with M1 being the one for the top–down regulation and M4 for the bottom–up regulation.
The manufacturer has co-formulated xanomeline with the peripheral muscarinic antagonist called trospium to block the activation of peripheral muscarinic receptors and the related severe cholinergic side effects. Trospium is available in the United States for the treatment of overactive bladder, the main symptom being urinary incontinence. It does not cross the blood–brain barrier, so it only acts peripherally and should not hinder the therapeutic central action of xanomeline, which you don’t want to block. This co-formulated medication is called KarXT, which helps you remember what’s in the pill. Kar stands for the company name, Karuna; X stands for the muscarinic agonist, xanomeline; and T stands for the peripheral antagonist, trospium.
This Lancet publication summarizes the results of 1 of the company’s phase 3 trials, which goes by the acronym EMERGENT-2. They already published an earlier phase 2 trial, which was positive. Hopefully, they will also soon publish the results of a second phase 3 trial, which is completed but has yet to be published. This EMERGENT-2 trial is a typical registration trial. What does that mean? It is placebo controlled, as required by the FDA, and uses the reduction of acute psychosis as the primary efficacy endpoint. In this case, and very typical for schizophrenia trials, they used the PANSS to measure this reduction in psychosis. It is also a typical short-term trial lasting only a few weeks.
They randomized 252 patients from 22 centers in the United States. The key message is that they found that KarXT was effective for psychosis after 5 weeks of treatment. The study met its endpoint of a reduction in PANSS total score with an effect size of 0.61. Now, 0.61 is considered a medium effect size and is good for this type of acute registration trial. It is a difference that you will see clinically. Let me emphasize this differently. Many drugs fail at this phase 3 stage because results from earlier, usually smaller phase 2 trials cannot be replicated once you study the drug in more typical and perhaps less-selected populations.
In this trial, the side effects were interesting because they differed from the usual side effects seen with antidopaminergic agents. They observed side effects commonly associated with the cholinergic system, particularly gastrointestinal problems, such as nausea and vomiting. Additionally, there were other side effects affecting the heart, such as hypertension. We will need to monitor these effects over the long term to understand their significance. What they discovered aligns with the mechanism of action; thus, no signal for motor side effects was observed. We will, however, have to wait for the results from longer so-called extension trials, like their EMERGENT-4 and EMERGENT-5 trials, to truly appreciate the real-world side-effect profile for KarXT, particularly when administered chronically.
I hope you excuse my enthusiasm, but in my 30 years as a psychiatrist, there has been very little progress in new medication treatments for schizophrenia coming to market. I started working in the field when risperidone was approved in 1993, so all I had in my active career was basically clozapine, which is an old drug, and antidopaminergic antipsychotics based on chlorpromazine.
Here is the bottom line for today. KarXT is a new cholinergic antipsychotic that appears to be effective for psychosis and seems to be well-tolerated, at least as judged by this phase 3 trial. Given that there already is 1 other positive trial, the company has asked the FDA to review KarXT for regulatory approval, with a likely verdict coming at the end of 2024. If approved, it will be interesting to see what other symptom clusters of schizophrenia, like cognition or negative symptoms, can be targeted with cholinergic medication. There are also several other muscarinic agonists under development. Xanomeline may just be the beginning of a new phase of treatment for patients with schizophrenia.
Abstract
Efficacy and Safety of the Muscarinic Receptor Agonist KarXT (Xanomeline-Trospium) in Schizophrenia (EMERGENT-2) in the USA: Results from a Randomised, Double-Blind, Placebo-Controlled, Flexible-Dose Phase 3 Trial
Inder Kaul, Sharon Sawchak, Christoph U Correll, Rishi Kakar, Alan Breier, Haiyuan Zhu, Andrew C Miller, Steven M Paul, Stephen K Brannan
Background: New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis.
Methods: EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161).
Findings: From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]).
Interpretation: In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia.
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Reference
Kaul, I., Sawchak, S., Correll, C. U., Kakar, R., Breier, A., Zhu, H., Miller, A. C., Paul, S. M., & Brannan, S. K. (2024).
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The Lancet, 403
(10422), 160-170.
