EMERGENT-1【KarXT】Efficacy Compared to Current Drugs in Phase 2

Introduction

In this article, I write about KarXT by Karuna, the new drug in development that I am most excited about at the moment.

In the previous article, I wrote about xanomeline, the main ingredient of KarXT. I also wrote about the side effects of KarXT and the development status of KarXT. Click here for a link to the previous article.

New Antipsychotics 1: KarXT Part1(Side Effects, Phase, Xanomeline)

In this article, I consider the efficacy of KarXT in terms of Phase 2 clinical trial results.

Efficacy (Clinical Trial Results)

The efficacy of KarXT for schizophrenia was measured in a Phase 2 trial using the PANSS (The Positive and Negative Symptom Scale).

The results showed a high degree of efficacy, with “clinically meaningful improvement” as well as “statistically significant improvement.”

For more information on PANSS and clinical trial data items (Difference from placebo, p-value, Effect size, etc.), please refer to these articles.

Positive and Negative Syndrome Scale(PANSS, Scale used to measure efficacy)

How to Judge the Efficacy of an Investigational Drug for Schizophrenia(coming soon!)

The results of the PANSS data measured over 35 days are shown in the table below,

with data presented for “Mean score”, “Mean reduction from Day0”, “difference from the placebo”, “95% confidence interval”, “P-value”, and “Effect size“.

	Prior to KarXT administration	5 weeks after KarXT administration
Mean PANSS Total score	97.7 points （markedly ill）	80.3 points （moderately ill）

Week5 (Day35)	PANSS Total score	PANSS Positive score	PANSS Negative score
Mean reduction from Day0	-17.4	-5.6	-3.2
Mean placebo reduction	-5.9	-2.4	-0.9
Difference (95%CL)	-11.6 (-16.1~-7.1)	-3.2 (-4.8~-1.7)	-2.3 (-3.5~-1.1)
P-value	p<0.0001	p<0.0001	p<0.001
Effect size	0.75	0.59	0.56

In this article, we will only look at the bottom row of KarXT’s efficacy data, the “effect size“.

Total effect (total of positive, negative, and other symptoms)

The effect size of the PANSS Total for KarXT in the Phase 2 study is 0.75. This would be a value that would be considered quite effective.

However, it should be noted that this is only one trial, so the evidence is still weak.

Stronger evidence comes from a meta-analysis, which combines the results of hundreds of clinical trials. The effect sizes of the PANSS Total for the other drugs calculated in the meta-analysis are shown in the table below.

A meta-analysis that includes KarXT has not yet been done. Since I have no choice, I will compare the effect sizes from the Phase 2 study of KarXT with the effect sizes from the meta-analysis of the other drugs.

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

To repeat, the Total PANSS effect size in the Phase 2 study of KarXT was 0.75.

As shown in the table above, the effect size of the PANSS Total for clozapine was 0.89 in the meta-analysis, making KarXT the next highest. This is higher than Amisulpride‘s 0.73 and olanzapine‘s 0.56.

Effects on Positive Symptoms

We have now looked at the overall efficacy of KarXT. Next, let us look at the efficacy of KarXT focusing only on positive symptoms.

The effect size of the PANSS positive score for KarXT has not been published, but I calculated it by hand and found it to be 0.59.

The effect sizes for PANSS-positive scores for other drugs are as follows

PANSS Positive	Effect size
Ami sulpride	0.69	Haloperi dol	0.49	Lurasi done	0.33
Cloza pine	0.64	Asena pine	0.47	Caripra zine	0.30
Risperi done	0.61	Ziprasi done	0.43	Iloperi done	0.30
Chlorpro mazine	0.57	Quetia pine	0.40	Brex piprazole	0.17
Olanza pine	0.53	Sertin dole	0.40
Paliperi done	0.53	Ari piprazole	0.38

The value of 0.59 for KarXT is lower than 0.69 for Amisulpride, 0.64 for Clozapine, and 0.61 for Risperidone, but higher than 0.53 for Olanzapine.

Effects on Negative Symptoms

Next, let us look at the effect of KarXT on negative symptoms only.

The effect size of KarXT on the PANSS negative score was calculated manually to be 0.56.

The effect sizes for PANSS negative scores for other drugs are as follows

PANSS Negative	Effect size
Cloza pine	0.62	Paliperi done	0.37	Haloperi dol	0.29
Ami sulpride	0.50	Chlorpro mazine	0.35	Lurasi done	0.29
Olanza pine	0.45	Ari piprazole	0.33	Brex piprazole	0.25
Asena pine	0.42	Ziprasi done	0.33	Iloperi done	0.22
Sertin dole	0.40	Cari prazine	0.32
Risperi done	0.37	Quetia pine	0.31

KarXT‘s value of 0.56 is second only to clozapine‘s 0.62. It is also higher than Amisulpride‘s 0.50 and olanzapine‘s 0.45.

Conclusion

Comment

Again, KarXT has been the most promising drug so far.

When looking at whether a new drug is good or bad, the higher the PANSS total effect size, the better.

However, I think it is more important to have a high PANSS negative effect size with an adequate PANSS positive effect size.

In addition, improvement in cognitive function and low side effects are also important.

KarXT may meet most of these criteria.

I hope to see other drugs that are not only effective on the PANSS total, but also effective on negative symptoms, effective in improving cognitive function, and with fewer side effects.

Aug. 12, 2022 note: Results of Phase 3 study of KarXT are now available.
EMERGENT-2 / KarXT Efficacy Compared to Current Drugs in Phase 3

March. 31, 2023 note: Results of Phase 3 study of KarXT are now available.
EMERGENT-3 / KarXT Efficacy Compared to Current Drugs in Phase3

Click here for links to related articles.
New Antipsychotics 1: KarXT Part1(Side Effects, Phase, Xanomeline)

New Antipsychotics 2: Emraclidine(Phase1b efficacy data)

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