Introduction
I have something to say about the data from KarXT(Cobenfy)’s Phase 3 trial, and I think the results of KarXT’s Phase 3 were very good. For now, let’s table the results.
| Prior to KarXT administration | 5 weeks after KarXT administration | |
| Mean PANSS Total score | 98.3 points （markedly ill） | 77.1 points （moderately ill） |
About 95 points markedly ill
About 75 points moderately ill
About 58 points mildly ill
| Mean score reduction (KarXT) | Mean score reduction (Placebo) | Difference from Placebo | Effect size | p-value | |
| PANSS Total | -21.2 | -11.6 | 9.6 | 0.61 | <0.0001 |
| PANSS Positive | -6.8 | -3.9 | 2.9 | ? | <0.0001 |
| PANSS Negative | -3.4 | -1.6 | 1.8 | ? | =0.0055 |
| PANSS Marder | -4.2 | -2.0 | 2.2 | ? | =0.0022 |
The PANSS scale was used to measure the effectiveness of KarXT; for more information on PANSS, see this article.
Positive and Negative Syndrome Scale(PANSS, Scale used to measure efficacy)
By the way, I cannot focus on data about PANSS positive and PANSS negative in detail now because the data are not fully published.
Therefore, we will only consider the total PANSS data (the sum of positive, negative, and other symptoms) for which sufficient data are available. We will only look at the overall efficacy.
Effect size
More effective than olanzapine
Since the most important factor is the “Effect size“, let’s look at it first. As shown in the table above, the PANSS total effect size for KarXT is 0.61.
The “Effect sizes” of the PANSS total scores for other antipsychotics are shown in the following table from one meta-analysis.
| PANSS Total | Effect size | ||||
| Cloza pine | 0.89 | Sulpiride | 0.48 | Asena pine | 0.39 |
| Ami sulpride | 0.73 | Chlorpro mazine | 0.44 | Lurasi done | 0.36 |
| Olanza pine | 0.56 | Quetia pine | 0.42 | Caripra zine | 0.34 |
| Risperi done | 0.55 | Aripipra zole | 0.41 | Iloperi done | 0.33 |
| Paliperi done | 0.49 | Ziprasi done | 0.41 | Brexpipra zole | 0.26 |
| Haloperi dol | 0.47 | Sertin dole | 0.40 |
The total PANSS “Effect size” for KarXT in Phase 3 was 0.61, so it came out less effective than 0.89 for clozapine or 0.73 for amisulpride.
However, it was more effective than olanzapine‘s 0.56 and risperidone‘s 0.55.
Olanzapine is a very good drug, so KarXT may also be quite good in terms of efficacy, coming out as more effective than it.
Less effective than in Phase 2
But KarXT’s PANSS total effect size of 0.61 in the Phase 3 trial may seem considerably lower than KarXT’s effect size of 0.75 in the Phase 2 trial.
While it may be lower, this difference is due in part to the fact that the “Mean score reduction” of the placebo drug in Phase 3 was somewhat larger than average.
Rather, it can be said that the “Mean score reduction” for the placebo in the previous Phase 2 was quite small.
If the “Mean score reduction” of the placebo is large, as was the case in Phase 3, the “Difference from placebo” will become small. Then, the “Effect size” will also become smaller in conjunction.
In any case, the efficacy of KarXT may be high. It may be higher than olanzapine.
Mean Score Reduction
Next to the “Effect size“, I would like to point out that the “Mean score reduction” in PANSS total for KarXT is quite large in Phase 3.
The larger the negative number in the “Mean score reduction“, the greater the improvement in symptoms.
| PANSS Total | Mean score reduction (KarXT) | Mean score reduction (Placebo) | Difference from Placebo | Effect size |
| Phase3 | -21.2 | -11.6 | 9.6 | 0.61 |
| Phase2 | -17.4 | -5.9 | 11.6 | 0.75 |
The “Mean score reduction” of -21.2 in Phase 3 is the largest I have seen so far, larger of course than in Phase 2(-17.4).
However, the “Effect size” of Phase 2 is larger than that of Phase 3 because the “Mean score reduction” of the “placebo” in Phase 2 was too small (-5.9).
That is to say, the “Effect size” of Phase 3 is smaller than that of Phase 2, even though the “Mean score reduction” of Phase 3 is larger than that of Phase 2.
When judging effectiveness, the “Mean score reduction” can be used as a reference, but the “Effect size” is stronger as evidence.
Nevertheless, in my opinion, we should pay attention to both “Mean score reduction” and “Effect size. If both are high, we can certainly judge that the effectiveness is high. (I may write more about this in another article.)
In Phase 3 of KarXT, both “Mean score reduction” and “Effect size” are pretty good, so we can safely say that the effectiveness is indeed high.
(In Phase 2, the part of the “Mean score reduction” was not as large.)
Adverse Events (Side Effects)
Finally, I will write about adverse events.
Serious adverse events included suicidal ideation, appendicitis, and worsening of schizophrenia. However, it is not known whether they are related to the administration of KarXT.
Adverse events that occurred in more than 5% of patients treated with KarXT were.
Constipation, uncomfortable abdominal symptoms such as stomach pain and lethargy, nausea, vomiting, headache, increased blood pressure, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea.
All of these adverse events were mild to moderate.
For Emraclidine, another muscarinic agonist, the adverse events that occurred in more than 5% of patients were.
Headache, nausea, back pain, increased creatine phosphokinase in blood, dizziness, dry mouth, and drowsiness.
Compared to Emraclidine, KarXT still seems to have more gastrointestinal side effects.
However, KarXT seemed to cause little sedation, drowsiness, weight gain, or extrapyramidal symptoms.
KarXT is generally safe and well tolerated, but may still have more gastrointestinal side effects.
For those who have severe gastrointestinal side effects, muscarinic agonists such as Emraclidine or NBI-1117568 could be used.
Conclusion
- The efficacy of KarXT may be higher than that of olanzapine.
- In the Phase 3 study, unlike the Phase 2 study, there was a greater improvement in symptoms with the placebo drug. Nonetheless, the results showed that KarXT was highly effective, which certainly increased the likelihood that it is highly effective.
- KarXT may have generally mild side effects, but with regard to gastrointestinal side effects, some people may get them.
Comment
The results of the KarXT Phase 3 trial have further increased the possibility that muscarinic agonists are, indeed, highly effective. We can also look forward to NBI-1117568 from Neurocrine and Emraclidine from Cerevel.
In the future, if no strange side effects are found, muscarinic agonists may even be given preference over the atypical antipsychotics currently in use.
This is because atypical antipsychotics have troublesome side effects, such as weight gain.
In order for muscarinic agonists to be used more, they may also need to be effective against negative symptoms and cognitive dysfunction. Muscarinic agonists are also promising in this area.
An application for approval of KarXT is expected to be submitted to the FDA in mid-2023. If all goes well, it should receive marketing approval and be available in the U.S. in 2024.
Links to related articles are available below.
There is an article summarizing KarXT(Cobenfy).
Five Advantages of Taking KarXT (Cobenfy)/ A Summary Article for Beginners
New Antipsychotics 1: KarXT Part1(Side Effects, Phase, Xanomeline)
New Antipsychotics 1: KarXT Part2(Phase2 EMERGENT-1)
EMERGENT-3 / KarXT Efficacy Compared to Current Drugs in Phase3
New Antipsychotics 2: Emraclidine(Phase1b efficacy data)
【NBI-1117568】Detailed analysis of Phase 2 results data/More effective than olanzapine
References
- http://soseiheptares.blogspot.com/2022/08/karxtp3.html
- https://www.clinicaltrialsarena.com/news/karuna-karxt-schizophrenia-trial/
- https://investors.karunatx.com/node/8656/pdf
- https://www.thelancet.com/article/S0140-6736(19)31135-3/fulltext
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