EMERGENT-3【KarXT】Efficacy Compared to Current Drugs in Phase3

Introduction

Now that the results of KarXT’s second Phase 3 trial are in, I have a lot to think about. This trial is called EMERGENT-3.

Here is a link to the article I wrote about EMERGENT-1.
New Antipsychotics 1: KarXT Part2(Phase2 efficacy data)

Here is a link to the article I wrote about EMERGENT-2.
EMERGENT-2 / KarXT Efficacy Compared to Current Drugs in Phase3

There is also an article summarizing muscarinic agonists as a whole.
Innovative Schizophrenia Drugs【Summary part 1】Muscarinic Agonists

Effect Size

Some data on the results of EMERGENT-3 have been released. Of these, the “Effect size” has become the most important factor for this blog.

In the EMERGENT-3 study, the “Effect size” of KarXT came out to 0.60.

This value is lower than the “Effect size” of 0.75 in KarXT’s Phase 2 trial (EMERGENT-1), but comparable to the “Effect size” of 0.61 in KarXT’s first Phase 3 trial (EMERGENT-2).

The “Effect sizes” of other antipsychotics are calculated in what is called a “meta-analysis”. A meta-analysis is a synthesis of the results of hundreds of clinical trials and is higher in evidence than individual clinical trials.

In the table below, I will show the results of a meta-analysis conducted in 2019 by Maximilian Huhn et al.

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

Compare KarXT’s “Effect size” of 0.60 in EMERGENT-3 with the “Effect sizes” of other drugs in the meta-analysis.

The “Effect size” of 0.60 for KarXT in EMERGENT-3 is higher than 0.56 for olanzapine, which is in the higher group. This time KarXT was not as high as Amisulpride’s 0.73.

KarXT is more effective than olanzapine all three times in EMERGENT1-3.

Since olanzapine is a very good drug, I think it is clear that KarXT is also very effective in reducing the symptoms of the disease.

Results Data Table

The table below shows the results data from the EMERGENT-3 trial that has been published by Karuna.

5 weeks	Mean score reduction (KarXT)	Mean score reduction (Placebo)	Difference from Placebo	Effect size	p-value
PANSS Total	-20.6	-12.2	-8.4	0.60	<0.0001
PANSS Positive	-7.1	-3.6	-3.5	0.80	<0.0001
PANSS Negative	-2.7	-1.8	-0.8	0.23	<0.1224

The PANSS score was used to measure the efficacy of KarXT. For more information on PANSS, see this article.

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

Effects on Overall Symptoms (PANSS Total Score)

First, I will write about the “overall effectiveness” of KarXT. To see the “overall effectiveness,” just look at the “PANSS total score.

In the table below, I have included the “PANSS Total” results data for EMERGENT 1, 2, and 3.

PANSS Total	Mean score reduction (KarXT)	Mean score reduction (Placebo)	Difference from Placebo	Effect size	p-value
EMER GENT-1	-17.4	-5.9	-11.6	0.75	<0.0001
EMER GENT-2	-21.2	-11.6	-9.6	0.61	<0.0001
EMER GENT-3	-20.6	-12.2	-8.4	0.60	<0.0001

The results of “EMERGENT-3” are more similar to those of “EMERGENT-2” than those of EMERGENT-1.

That is to say, the “Mean score reduction” for the placebo drug in EMERGENT-3 was as large as -12.2, which is similar to EMERGENT-2.

Nevertheless, since the “Mean score reduction” for the KarXT was as large as -20.6, the “Difference from Placebo” was also slightly larger (-8.4).

Since the “Difference from Placebo” was larger, the “Effect size” was also slightly larger at 0.60. (“Effect size” was calculated by dividing the “Difference from placebo” by the “Standard deviation”)

EMERGENT-2 and 3 were able to achieve high results in terms of “Effect size”, even if the “Mean score reduction” for the placebo was large. This confirms that the efficacy of the study drug is indeed high.

Therefore, I think EMERGENT-3 was also a good result.

Effect on Positive Symptoms (PANSS Positive Score)

Next, let us focus on the effect of KarXT on “Positive symptoms”. The “PANSS Positive” outcome data for EMERGENT-1, 2, and 3 are shown in the table below.

PANSS Positive	Mean score reduction (KarXT)	Mean score reduction (Placebo)	Difference from Placebo	Effect size	p-value
EMER GENT-1	-5.6	-2.4	-3.2	0.59	<0.0001
EMER GENT-2	-6.8	-3.9	-2.9	?	<0.0001
EMER GENT-3	-7.1	-3.6	-3.5	0.80	<0.0001

For positive symptom, the “effect size” of KarXT in EMERGENT-3 is 0.80. This is much larger than the effect size of 0.59 at EMERGENT-1.

For the other antipsychotics, the “effect sizes” for positive symptoms are as shown in the following table.

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 effect size of 0.80 for positive symptoms of KarXT in EMERGENT-3 is higher than 0.69 for Amisulpride and 0.64 for Clozapine.

Effect on Negative Symptoms (PANSS Negative Score)

Next, let’s focus on KarXT’s effect on “Negative symptoms”.

The data for the PANSS negative score results for EMERGENT-1, 2, and 3 are shown in the table below.

PANSS Negative	Mean score reduction (KarXT)	Mean score reduction (Placebo)	Difference from Placebo	Effect size	p-value
EMER GENT-1	-3.2	-0.9	-2.3	0.56	p<0.001
EMER GENT-2	-3.4	-1.6	-1.8	?	p=0.0055
EMER GENT-3	-2.7	-1.8	-0.8	0.23	p<0.1224

In EMERGENT-3, the “p-value” for negative symptoms is p<0.1224 and it is not less than 0.05. It means that there was no effect (statistically speaking) on negative symptoms.

The effect size is also low at 0.23.

The “effect sizes” of other antipsychotics are shown in the table below.

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

The 0.23 effect size for negative symptoms for KarXT in EMERGENT-3 is comparable to 0.22 for iloperidone and 0.25 for Brexpiprazole. It is near the bottom of the list.

Adverse Events (Side Effects)

Next, I will write about adverse events (side effects).

In the EMERGENT-3 trial, the percentage of patients who discontinued KarXT for any reason was 37%. The percentage of patients who discontinued the placebo drug was also high, at 29%.

The following table lists the discontinuation rates for other drugs, to the best of my knowledge.

Investigational Drug	Discontinuation Rate
Lumateperone(Phase3)	14.7%
Ulotaront(Phase2)	21.7%
KarXT(EMERGENT-1)	20%
KarXT(EMERGENT-2)	25%

KarXT’s discontinuation rate of 37% for EMERGENT-3 is much higher than what is shown in the table above.

As I have just said, 37% of all patients discontinued KarXT. 6% of all patients discontinued due to adverse events (side effects).

The rate of patients who stopped other medicines due to adverse events (side effects) is shown in the table below.

Investigational Drug	Discontinuation Rate due to adverse events
Lumateperone(Phase3)	1.3%
Ulotaront(Phase2)	8.3%
KarXT(EMERGENT-1)	2%
KarXT(EMERGENT-2)	7%
Emraclidine(Phase1b)	7%

The 6% discontinuation rate of KarXT due to adverse events is not low compared to other drugs, but is not extremely high.

By the way, the “percentage of patients who experienced side effects” with KarXT, whether they discontinued the drug or not, is as high as 70%.

The overall treatment-emergent adverse event (TEAE) rates for other drugs are shown in the following table.

Investigational Drug	Treatment-emergent adverse events (TEAEs)
Lumateperone(Phase3)	64.7%
Ulotaront(Phase2)	45.8%
KarXT(EMERGENT-1)	54%
KarXT(EMERGENT-2)	75%

In EMERGENT-3, the incidence of side effects was lower than that of EMERGENT-2(75%). However, it is higher than the rates of EMERGENT-1(54%), Ulotaront(45.8%), and Lumateperon(64.7%).

Next, let’s look at “what side effects” were more common. In EMERGENT-3, the side effects that occurred in more than 5% of patients were as follows.

nausea, dyspepsia, vomiting, constipation, diarrhea, hypertension, headache, insomnia

As expected, KarXT frequently has gastrointestinal side effects, including nausea, dyspepsia, vomiting, constipation, and diarrhea.

Hypertension was also a concern, occurring in 6% of patients. It is said that a special study will be conducted to confirm the safety of the drug for hypertension.

PS: A safety trial was carried out, and there did not appear to be any problems with high blood pressure.

But despite the weakness of the high gastrointestinal side effects, KarXT has fewer “extrapyramidal symptoms” and “weight gain”. Both were about the same level as the placebo and were low in EMERGENT-3, too.

By the way, one “serious adverse event” occurred. Gastroesophageal reflux disease occurred to a serious degree.

Incidentally, in EMERGENT-2, there were “serious adverse events” such as suicidal ideation, worsening of schizophrenia, and appendicitis. Gastroesophageal reflux disease also occurred in EMERGENT-2 but was not serious.

Development Status

The FDA will look at the efficacy and safety of the EMERGENT 1, 2, and 3 studies, as well as the EMERGENT 4 and 5 studies, to determine whether to grant marketing authorization to KarXT. They will also consider a trial on hypertension.

The EMERGENT-4 and EMERGENT-5 trials are “long-term studies,” lasting about a year, and are currently underway.

Karuna plans to submit an application, for marketing approval of KarXT, in mid-2023.
If approved in the U.S., Karuna expects to launch KarXT in the second half of 2024.

Summary

Comment

Although the EMERGENT-3 trial did not show efficacy in negative symptoms, I think the trial was a success overall.

There were some other drugs that were approved by the FDA, even if some of the trials did not show efficacy. So, I do not think that KarXT has any problems in terms of efficacy.

If the EMERGENT-4 and 5 studies and the study on hypertension do not raise any safety issues, I think the FDA will approve it in the U.S. in the next year or so.

KarXT is likely to be an excellent drug, and I think it will be approved easily by the FDA in the US.

Links to related articles are available below.

Article written about EMERGENT-1.
New Antipsychotics 1: KarXT Part2(Phase2 EMERGENT-1)

Article written about EMERGENT-2.
EMERGENT-2 / KarXT Efficacy Compared to Current Drugs in Phase3

Article written about Emraclidine. Emraclidine is a muscarinic agonist like KarXT.
New Antipsychotics 2: Emraclidine(Phase1b efficacy data)

There is also an article summarizing muscarinic agonists as a whole.
Innovative Schizophrenia Drugs【Summary part 1】Muscarinic Agonists

References

• https://www.clinicaltrialsarena.com/news/karuna-karxt-primary-endpoint/
• https://www.biospace.com/article/latest-trial-data-for-karuna-s-karxt-make-investors-antsy-/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891890/