【Emraclidine】Efficacy Compared to Current Drugs in Phase1b

This article can be read in about 16 minutes.

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.

【NBI-1117568】Detailed analysis of Phase 2 results data/More effective than olanzapine

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.

Results of the Phase 2 trials of emulacridine are also available.
Emraclidine/Phase 2 trial failed/Muscarinic drugs not highly effective?

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 weeksMean
score
reduction

(Emracli
dine)
Mean
score
reduction

(placebo)
Difference
from
Placebo
Effect
size
p-
value
PANSS
Total
-19.5-6.77-12.70.680.023
PANSS
Positive
-6.8-2.5-4.270.720.016
PANSS
Negative
-3.0+0.1-3.070.800.009
PANSS
General
psycho
pathology
??-4.920.520.085

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 TotalEffect size” for Emraclidine is 0.68. This value of 0.68 is quite high.

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

PANSS
Total
Effect
size
Cloza
pine
0.89Sulpiride0.48Asena
pine
0.39
Ami
sulpride
0.73Chlorpro
mazine
0.44Lurasi
done
0.36
Olanza
pine
0.56Quetia
pine
0.42Caripra
zine
0.34
Risperi
done
0.55Aripipra
zole
0.41Iloperi
done
0.33
Paliperi
done
0.49Ziprasi
done
0.41Brexpipra
zole
0.26
Haloperi
dol
0.47Sertin
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.

The overall efficacy of Emraclidine may be lower than clozapine and Amisulpride, but higher than olanzapine, and may be comparable to KarXT.

If higher than olanzapine, it would be very effective.

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

In Phase 1b, the efficacy of Emraclidine on positive symptoms was high and was the top efficacy. The efficacy for positive symptoms is sufficient and likely to be 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
0.62Paliperi
done
0.37Haloperi
dol
0.29
Ami
sulpride
0.50Chlorpro
mazine
0.35Lurasi
done
0.29
Olanza
pine
0.45Ari
piprazole
0.33Brex
piprazole
0.25
Asena
pine
0.42Ziprasi
done
0.33Iloperi
done
0.22
Sertin
dole
0.40Cari
prazine
0.32
Risperi
done
0.37Quetia
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.

In Phase 1b, the effect of Emraclidine on negative symptoms came out on top, far exceeding that of clozapine.

This is likely due to the lack of improvement in the placebo drug. I will look closely at the next and subsequent trials to see if the efficacy of Emraclidine on negative symptoms is really high.

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.

Headache28%
Nausea7%
Back pain6%
Dizziness6%
Dry mouth6%
Somnolence6%
Pruritus4%
Blood creatine phosphokinase increased 6%

Summary

  • Muscarinic agonists such as Emraclidine, NBI-1117568, and KarXT are the most promising so far.
  • The overall efficacy of Emraclidine may be lower than that of clozapine and Amisulpride, but higher than that of olanzapine. It may be very effective. As of now, it may be in line with KarXT.
  • The results of the current study suggest that the efficacy of Emraclidine for positive symptoms is the highest in the table and may be sufficient.
  • The results of the current study show that Emraclidine’s efficacy for negative symptoms is the highest in the table, but since there was no improvement with the placebo drug, it is not known if it is actually that high.
  • Side effects were mild, with cardiovascular and gastrointestinal side effects, extrapyramidal symptoms, and weight gain comparable to placebo.
  • Phase 2 is scheduled to begin in mid-2022 in the US. Data will be released in early 2024.

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.

Emraclidine/Phase 2 trial failed/Muscarinic drugs not highly effective?

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

【NBI-1117568】Detailed analysis of Phase 2 results data/More effective than olanzapine

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