Innovative Schizophrenia Drugs【Summary part 1】Muscarinic Agonists

Introduction
Atypical Antipsychotics
Muscarinic agonists (Muscarinic acetylcholine receptor agonists)
KarXT, Cobenfy (M1/M4 agonists)
Emraclidine (M4 allosteric agonist)
NBI-1117568 (M4 agonist)
ML-007 (M1/M4 agonist)
ANAVEX3-71 (M1 agonist & sigma 1 agonist)
Comment
References

Introduction

In this article and the next, I will summarize innovative schizophrenia drugs that will be released in the future. I will write a sort of summary of some articles in my blog.

First, this article will write about a type of new drug called muscarinic agonists.

Atypical Antipsychotics

Currently, atypical antipsychotics are the most commonly used drugs for schizophrenia. Problems with atypical antipsychotics include the following

Insufficient effects on negative symptoms and cognitive dysfunction
Weight gain
Extrapyramidal symptoms
Positive symptoms are not suppressed in about 20% to 30% of patients.

Muscarinic agonists (Muscarinic acetylcholine receptor agonists)

Muscarinic agonists(Muscarinic acetylcholine receptor agonists) have been developed as schizophrenic drugs that may solve the above problems.

Atypical antipsychotics are essentially dopamine blockers. They treat illness by blocking dopaminergic activities in the brain.

Direct blockade of dopamine leads to a variety of side effects.

Muscarinic agonists, on the other hand, activate acetylcholine activities in the brain. This indirectly reduces dopaminergic activities in the brain, thereby treating the disease.

As a result, muscarinic agonists may solve or reduce many of the problems associated with atypical antipsychotics.

KarXT, Cobenfy (M1/M4 agonists)

One of the muscarinic agonists is KarXT(Cobenfy), that will be available during 2024. KarXT is also an M1/M4 agonist.

KarXT agonizes the M1 and M4 subtypes of muscarinic acetylcholine receptors in the brain. Therefore, it is called an M1/M4 agonist.

KarXT has shown efficacy over olanzapine three times in clinical trials to date. Olanzapine itself is a very good drug in terms of efficacy. It is noteworthy that KarXT has shown efficacy over and above Olanzapine.

In the KarXT trials, it caused only as much weight gain and extrapyramidal symptoms as placebo. I think it is safe to say that they are almost nonexistent.

A “post-hoc analysis” was conducted after the Phase 2 trial and showed that KarXT improved cognitive dysfunction. The effects of muscarinic agonists, including KarXT, on cognitive function are promising.

However, KarXT has concerns about side effects, such as nausea, indigestion, vomiting, constipation, diarrhea, and other gastrointestinal side effects.

KarXT may be more effective than olanzapine, with little or no weight gain or extrapyramidal symptoms, and may be effective in improving cognitive dysfunction.

Five Advantages of Taking KarXT (Cobenfy)/ A Summary Article for Beginners

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

EMERGENT-1 / New Antipsychotics 1: KarXT Part2(Phase2 efficacy data)

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

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

Emraclidine (M4 allosteric agonist)

In addition to KarXT, muscarinic agonists include Emraclidine. Emraclidine is also called M4 allosteric agonist.

Emraclidine binds to the allosteric site of the M4 subtype of muscarinic acetylcholine receptor, thereby promoting its receptor activation.

In this way, it activates acetylcholinergic activities in the brain.

Unlike KarXT, Emraclidine has had few gastrointestinal side effects in a clinical trial.

If KarXT is not good for digestive side effects for you, Emraclidine might be a better choice.

The efficacy of Emraclidine in the clinical trial has been about as good as KarXT. Perhaps, Muscarinic agonists in general may be highly effective.

A Phase 2 trial is currently underway in the U.S., and Phase 2 data is expected to be released in the first half of 2024. I will report the result on this blog when it is available.

Emraclidine may be as effective as KarXT and may not have the same gastrointestinal side effects that have been a concern with KarXT.

New Antipsychotics 2: Emraclidine(Phase1b efficacy data)

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

NBI-1117568 (M4 agonist)

Neurocrine Biosciences is developing a muscarinic agonist, NBI-1117568.

NBI-1117568 is a muscarinic agonist that acts on the M4 subtype of the muscarinic acetylcholine receptor in the brain. Therefore, it is also called an M4 agonist.

According to Neurocrine, NBI-1117568 is a highly specific drug, different from both KarXT and Emraclidine.

NBI-1117568 is also claimed to be superior to KarXT and Emraclidine in terms of efficacy and side effects.

A Phase 2 trial is currently underway in the U.S., and Phase 2 is expected to be completed in 2024.

According to Neurocrine, NBI-1117568 is different from both KarXT and Emraclidine. NBI-1117568 is claimed to outperform them in terms of efficacy and side effects.

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

ML-007 (M1/M4 agonist)

ML-007 is an M1/M4 agonist like KarXT. It is said that M1 agonists are more effective than M4 agonists for cognitive impairment.

KarXT and ML-007 are M1 agonists in addition to M4 agonists. I would like to focus on ML-007 as well.

I have not been able to find much information on ML-007, but I heard that Phase 1 was completed in August 2022.

ML-007 is an M1/M4 agonist, the same as KarXT, so I’m looking forward to its effectiveness in improving cognitive function.

ANAVEX3-71 (M1 agonist & sigma 1 agonist)

Finally, I will write about ANAVEX3-71, which is both an M1 agonist and a sigma 1 receptor agonist.

ANAVEX3-71 differs from other muscarinic agonists in that it agonizes sigma 1 receptors.

By activating sigma 1 receptors, it is said to be able to restore the body’s homeostasis and neuroplasticity of the brain. It is also said to prevent inflammation of the brain.

In animal experiments, it has been shown to prevent cognitive decline.

As of May 2023, ANAVEX3-71 is in a Phase 2 trial in the U.S. for the treatment of schizophrenia.

ANAVEX3-71 also acts on sigma 1 receptors. This drug may also be different.

Comment

Again, muscarinic agonists

May be effective for negative symptoms and cognitive dysfunction.
May have little or no weight gain or extrapyramidal symptoms.
May be effective in treatment-resistant schizophrenia.
May be more effective than olanzapine.

Atypical antipsychotics may shorten the lifespan of schizophrenic patients, especially due to the side effect of weight gain.

Muscarinic agonists may help many schizophrenic patients, including the fact that weight gain is less likely to occur.

By the way, I personally think that muscarinic agonists could be used in combination with atypical antipsychotics and TAAR1 agonists such as Ulotaront.

These drugs have different mechanisms of action. I have heard that medicines with different mechanisms of action are suitable for combination therapy. The combination therapies may increase efficacy and reduce side effects.

I think there is some literature on the combination therapies of these drugs, and KarXT is also aiming to be indicated as an adjunct to existing medicines. I will keep an eye out for more information on the combination therapies.

I would like to report on the users’ impressions after they are launched. I would be happy if you could use them as a reference.

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