Introduction
In this article and the next, I will write about KarXT(Cobenfy) by Karuna, the new drug in development that I am most excited about at the moment.
In this article, I will write about xanomeline, the main ingredient of KarXT. I will also write about the side effects of KarXT and the development status of KarXT.
In the next article, I will consider the efficacy of KarXT in light of the Phase 2 clinical trial results. Click here for a link to the next article.
New Antipsychotics 1: KarXT, Part 2 (Efficacy data for positive & negative symptoms)
KarXT is a muscarinic agonist, and similar drugs include Neurocrine’s NBI-1117568 and Cerevel’s Emraclidine.
Drugs that act on those muscarinic receptors are also highly promising. Click here for a link to an article I wrote about those drugs.
New Antipsychotics 2: Emraclidine (CVL-231, Cerevel)
【NBI-1117568】Detailed analysis of Phase 2 results data/More effective than olanzapine
Xanomeline Effects
Xanomeline
In addition to the active ingredient xanomeline, KarXT contains an ingredient called trospium.
Trospium is simply mixed in to mitigate the gastrointestinal side effects that xanomeline has.
So, in this section, I will first write about the most important ingredient of KarXT, xanomeline.
Effects on Alzheimer’s Disease
Xanomeline was first tested for effectiveness in Alzheimer’s disease patients in a large clinical trial published in 1997.
There, it worked particularly well for hyperarousal, distrust, delusions, agitation, and hallucinations, while also improving emotional numbness and behavioral disturbances.
These very symptoms were also common in schizophrenic patients.
This surprising discovery led to the belief that xanomeline could also be used to treat schizophrenia.
Effects on Schizophrenia (animal studies)
In some “animal studies” in the early 2000s, xanomeline also showed effects similar to those of clozapine.
To put it a little more technically, it suppressed dopamine activity in the mesolimbic dopamine pathway, did not interfere with dopamine activity in the nigrostriatal dopamine pathway, and increased dopamine activity in the prefrontal cortex.
In short, simply put, like clozapine, it has been shown to work well for both positive and negative symptoms and may be less likely to cause extrapyramidal symptoms. Animal studies have shown that.
Effects on Schizophrenia (Human Clinical Trials)
One clinical trial “in humans” published in 2008 measured the efficacy of xanomeline on “positive” and “negative” symptoms.
Efficacy was measured by the Positive and Negative Symptom Scale (PANSS), which showed significant improvement. The efficacy of the drug on “schizophrenia in humans” was confirmed.
In addition, a pilot study published in 2008 investigated the effects on “cognitive dysfunction” in schizophrenic patients.
The strongest improvements were seen in word learning and working memory function.
No significant improvements were seen in attention or information processing speed, but significant improvements were seen in list learning, story recall, memory retention, and a reverse number reading test.
Although this one pilot study alone may not be definitive about the effects of xanomeline on cognitive function, it may provide some hope.
Clinical trials on humans have also shown that xanomeline improves positive and negative symptoms and cognitive dysfunction.
Then, xanomeline and trospium were mixed by Karuna and became KarXT. Thus, the problem of xanomeline’s severe gastrointestinal side effects was softened.
P.S. A “post-hoc analysis” of the KarXT Phase 2 trial confirmed the efficacy of KarXT in cognitive dysfunction.
In Phase 2, an iPad-based tool called CBB (Cogstate Brief Battery) was used to measure five items: attention, processing speed, executive function, word learning, and working memory.
The effect size on cognitive function for “all patients” treated with KarXT was 0.20, with no statistically significant effect.
However, when the patients with less impaired cognitive function were excluded, and when the extreme and unreliable data were excluded, the effect size was 0.79, a fairly high effect size.
Generally, an effect size of 0.2 is considered small, 0.5 medium, and 0.8 large. Therefore, an effect size of 0.79 is large.
KarXT may not be very effective for patients without much cognitive impairment, but it may be highly effective for normal patients who are commonly seen.
Side Effects
Side effects are minimal and well tolerated. Somnolence (sedation), extrapyramidal symptoms, and weight gain are not different from placebo.
The average weight change over the 5-week period was an increase of 1.5 kg. This was about the same as placebo.
Gastrointestinal side effects are a concern, but appear to have been mild or moderate. Constipation, nausea, dry mouth, indigestion, and vomiting were only somewhat common.
One patient had worsening psychiatric symptoms.
Side effects that appeared in more than 2% of the Phase 2 trials are shown in the table below. Bolded in blue are gastrointestinal side effects.
| Constipation | 17% | Increased weight | 3% | |
| Nausea | 17% | Tachycardia | 3% | |
| Dry mouth | 9% | Sedation | 2% | |
| Dyspepsia | 9% | Diarrhea | 2% | |
| Vomiting | 9% | Agitation | 2% | |
| Headache | 7% | Insomnia | 2% | |
| Somnolence | 6% | Decreased appetite | 2% | |
| Akathisia | 3% | Hyperhidrosis | 2% | |
| Dizziness | 3% |
Development Status
KarXT is being developed in the United States by Karuna Therapeutics.
Two Phase 3 results will be available in 2022, and I will report on efficacy data and other information on this blog.
It is said that the drug will be approved in the U.S. by the end of 2024 at the earliest. Clinical trials have not yet started in Japan.
Note added 9/27/2024: KarXT has been approved for September 2024; it will be available during 2024.
When KarXT goes on sale in the U.S. in 2024, users may post their impressions on Reddit and other sites. I would like to watch those impressions and other information. I will report those information in some blog posts.
KarXT is also highly anticipated as it is intended to be applied to negative and cognitive symptoms.
Furthermore, it may be effective for treatment-resistant (refractory) patients. In that case, they say it will be used as an adjunct to other drugs.
Conclusion
- Xanomeline was studied for its effect on Alzheimer’s disease, and its potential for schizophrenia was discovered.
- Xanomeline’s effects on positive and negative symptoms of schizophrenia were confirmed in clinical trials on humans.
- It has also been shown to improve cognitive function in one pilot study.
- Xanomeline was mixed with trospium by Karuna to solve the problem of severe gastrointestinal side effects and became KarXT.
- The side effects of KarXT were mild, with extrapyramidal symptoms and weight gain comparable to those of placebo. However, there could be some gastrointestinal side effects.
- It will be approved in the U.S. as early as 2024.
Comment
Continued in Part 2, considering the efficacy of KarXT based on the results of the Phase 2 trial. Link here.
New Antipsychotics 1: KarXT Part 2 (Efficacy data for positive & negative symptoms)
There is an article summarizing KarXT(Cobenfy).
Five Advantages of Taking KarXT (Cobenfy)/ A Summary Article for Beginners
References
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891890/
- https://www.nejm.org/doi/full/10.1056/NEJMoa2017015
- https://investors.karunatx.com/static-files/c09991a8-81fa-4ab9-aa15-8f200d73f3d1
コメント