【Emraclidine】Efficacy Compared to Current Drugs in Phase1b

Introduction

Cerevel’s Emraclidine(CVL-231) is the same type of drug as Neurocrine’s NBI-1117568 and Karuna’s KarXT.

These muscarinic agonists have become the type of drug I am most excited about at the moment. So I will be preparing more articles on them.

Click here for links to articles on NBI-1117568 and KarXT.

New Antipsychotics 3: NBI-1117568 (Neurocrine’s M4 agonist) (coming soon!)

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

I will write about these drugs, as data from Phase 2, Phase 3, and other clinical trials become available.

In this article, I would like to write about Phase 1b of Emraclidine.

Efficacy Data (Clinical Trial Results)

The efficacy of Emraclidine was measured using the PANSS (Positive and Negative Symptom Scale).

For more information on PANSS and clinical trial data (p-value, difference from placebo, 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!)

In Phase 1b, the Mean reduction in PANSS score for Emraclidine 30mg, Difference from placebo, Effect size, and p-value, came out as follows

6 weeks	Mean score reduction (Emracli dine)	Mean score reduction (placebo)	Difference from Placebo	Effect size	p- value
PANSS Total	-19.5	-6.77	-12.7	0.68	0.023
PANSS Positive	-6.8	-2.5	-4.27	0.72	0.016
PANSS Negative	-3.0	+0.1	-3.07	0.80	0.009
PANSS General psycho pathology	?	?	-4.92	0.52	0.085

Overall Efficacy

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 Emraclidine is 0.68. This value of 0.68 is quite high.

In one meta-analysis, the PANSS Total “Effect sizes” for other antipsychotics were as follows

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 value of 0.68 for Emraclidine is lower than clozapine and Amisulpride, but higher than olanzapine‘s 0.56.

It is also lower than KarXT’s Phase 2 of 0.75, but higher than KarXT’s Phase 3 of 0.61. So far, Emraclidine may be comparable to KarXT.

However, the 0.68 effect size of Emraclidine is still weak evidence since it is only the result of one trial. It could be higher or lower in other clinical trials.

Effect on Positive Symptoms

Next, I will focus on the effect of Emraclidine on positive symptoms.

The effect size of the PANSS positive score for Emraclidine 30mg is 0.72.

The effect sizes for PANSS positive scores for other drugs are 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

Emraclidine‘s 0.72 effect size is the highest, surpassing Amisulpride‘s 0.69 and Clozapine‘s 0.64.

The reason why the effect size of Emraclidine on positive simptoms was so high this time may be due to the fact that the decrease (improvement) in the PANSS positive score of the placebo was smaller.

But at any rate, the efficacy of Emraclidine on positive symptoms is sufficient and likely high.

Effect on negative symptoms

Next, I will focus on the effect of Emraclidine on negative symptoms.

The effect size of the PANSS negative score for Emraclidine 30mg is 0.80.

The PANSS negative score effect sizes 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

Emraclidine‘s effect size of 0.80 is the highest, significantly higher than Clozapine‘s 0.62.

However, in this trial, there was no decrease (improvement) in the PANSS negative score for the placebo drug; on the contrary, the PANSS negative score for the placebo-treated patients increased (worsened). (+0.1)

This would make the effect size of Emraclidine very large. In the next and subsequent trials, the effect size of 0.80, a very large effect size, will probably not be achieved.

Still, it may be in the group with the highest effect size on negative symptoms.

Development Status

Emraclidine is being developed in the United States by Cerevel. In the U.S., Phase 2 is scheduled to begin in mid-2022. Data will be released in the first half of 2024.

As of November 26, 2022, it appears that the Phase 2 clinical trial has not yet begun.

Side Effects

Adverse events were generally similar to placebo.

Gastrointestinal side effects, extrapyramidal symptoms, and weight gain were comparable to placebo; unlike KarXT, fewer gastrointestinal side effects may be an advantage.

Headache was the most common side effect, occurring in 28% of patients. Nausea was the next most common, occurring in 7% of patients.

Regarding serious adverse events, one patient had a coronavirus infection, and one patient had overdose. One patient had worsening symptoms of schizophrenia.

Regarding cardiovascular side effects of concern, there was no increase in blood pressure and only one patient had an increase in heart rate, which was comparable to placebo.

Adverse events that occurred in more than 2% of patients are shown in the following table.

Headache	28%
Nausea	7%
Back pain	6%
Dizziness	6%
Dry mouth	6%
Somnolence	6%
Pruritus	4%

Summary

Comment

I think the efficacy of Emraclidine in Phase 1b is generally higher. In particular, I think the efficacy on negative symptoms is too high. This is because the placebo improvement was quite small.

I am not sure if it will be as high in subsequent trials, but it still seems to be in the high range, and it would be nice if we could see efficacy similar to that of KarXT.

In terms of side effects, it does not have the gastrointestinal side effects that KarXT has, and unlike the D2 blockers currently in use, it has little weight gain or extrapyramidal symptoms. For some people, it could be a very useful drug.

I will closely monitor the results of Phase 2 and Phase 3.

Links to related articles are available below. KarXT is a muscarinic agonist like Emraclidine.

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

New Antipsychotics 1: KarXT Part2(Phase2 EMERGENT-1)

EMERGENT-2 / KarXT Efficacy Compared to Current Drugs in Phase3

EMERGENT-3 / KarXT Efficacy Compared to Current Drugs in Phase3

References

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891890/
• https://www.globenewswire.com/news-release/2021/06/29/2254559/0/en/Cerevel-Therapeutics-Announces-Positive-Topline-Results-for-CVL-231-in-Phase-1b-Clinical-Trial-in-Patients-with-Schizophrenia.html
• https://pubmed.ncbi.nlm.nih.gov/36528376/