21 Drugs for Cognitive and Negative Symptoms of Schizophrenia in 2024 【Revised 2024.5.20】

This article can be read in about 31 minutes.

Introduction

This article summarizes new drugs in development that may help with cognitive dysfunction and negative symptoms of schizophrenia.

Perhaps not all of the drugs in development that I present will be approved for marketing. It is uncertain whether drugs for cognitive dysfunction and negative symptoms will really materialize.

It would be very wonderful if even a few of them reach the market, but there may be quite a few drugs that will end up being discontinued from development because they cannot show efficacy.

If a drug shows positive results in a Phase 3 clinical trial and is likely to be marketed, I will post the data and other information in a blog post.

This article may have become somewhat technical. Common readers may just want to look at the summary and comment at the end of the article and be done with it.

Below you will find sections on monoamine receptor modulators, glutamate receptor modulators, acetylcholine receptor modulators, other modulators, and a summary.

Monoamine Receptor Modulators

First, I will write about drugs that act on monoamine receptors such as serotonin receptors, histamine receptors, and dopamine receptors.

ASP-5736

ASP-5736 is a selective serotonin 5HT5A receptor inhibitor. It is a drug that inhibits serotonin 5HT5A receptors.

In animal studies, it improved cognitive dysfunction, working memory, learning by vision, and It also improved hyperactivity state in mice similar to positive symptoms.

As a single agent or as an adjunctive drug, it may be able to treat positive symptoms and cognitive dysfunction without side effects.

Status of development is unknown.

Usmarapride (SUVN-4010)

Usmarapride is a serotonin 5HT4 receptor partial agonist.

Effects on cognitive function were observed in animal studies.

Phase 2 has been completed in the U.S. as of 2021.

Samelisant

Samelisant is a histamine 3 receptor inverse agonist. It essentially inhibits histamine H3 receptors.

In animal studies, it increased acetylcholine levels in the cerebral cortex and improved cognitive function.

In the U.S., a Phase 2a trial is planned as of 2019.

ASP-4345

ASP4345 is a positive allosteric modulator of the dopamine D1 receptors. It enhances D1 receptor function by binding to allosteric sites of the dopamine D1 receptors.

It enhances the function of D1 receptors in the prefrontal cortex, which is closely related to working memory and other functions.

Clinical trial in human has shown clinically meaningful improvement. A Phase 2 trial in the U.S. was completed in October 2019.

Glutamate Receptor Modulators

Next, I will write about drugs that act on glutamate receptors. The drugs act on two types of glutamate receptors: NMDA receptors and metabotropic glutamate receptors 5 (mGluR5).

BI425809 (Iclepertin)

BI425809 is a cognitive enhancer. This drug has been designated a “breakthrough therapy” by the FDA.

It is a GlyT1 inhibitor (glycine transporter 1 inhibitor). GlyT1 inhibitors enhance NMDA receptor function by increasing glycine at synapses.

Phase 3 trial is underway in Japan. It may be the first drug for the treatment of cognitive dysfunction.

In a Phase 2 study, 509 patients with schizophrenia were treated for 12 weeks to evaluate the efficacy of the drug on cognitive function.

The efficacy was measured by the total score of the composite Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) after 12 weeks of treatment.

The results showed an effect size of “0.34” in the 10 mg group. There is a possibility of a mild improvement in cognitive function. In particular, there was a large improvement in working memory testing.

A look at some of the cognitive enhancers in development showed an average effect size of “0.28“; BI425809’s effect was only slightly higher than that.

Although it is not expected to be effective enough to restore overall cognitive function to the pre-symptomatic level, it is expected to improve working memory.

RL-007

RL007 is a drug that acts on acetylcholine receptors, GABA B receptors, and NMDA receptors.

In a Phase 2a study in the U.S., it showed clinically meaningful improvements in overall cognitive function and in episodic memory.

A larger, more rigorous Phase 2 study is planned.

2023 note: Phase 2b trial started in the U.S. in December 2022; results are expected in the first half of 2024.

Plazinemdor (CAD-9303)

Plazinemdor is an positive allosteric modulator of NMDA receptors that enhances NMDA receptor function by binding to allosteric sites of the NMDA receptor.

It is intended to improve cognitive dysfunction and negative symptoms.

In the U.S., a Phase 1 study was completed in November 2021.

BMS-955829

BMS955829 binds to allosteric sites of the metabotropic glutamate receptors 5 and enhances the function of the receptors. It is an mGluR5 allosteric agonist.

In animal studies, strong improvements in cognitive and executive function were observed.

Development status is unknown.

Pomaglumetad methionil

Pomaglumetad methionil agonizes metabotropic glutamate receptor 2 and metabotropic glutamate receptor 3. It is called mGluR2/3 agonist.

Clinical trials have failed to show efficacy. However, it was found to be ineffective for chronic patients but may work for patients in the early stages of the disease.

A Phase 1 trial is currently underway by Denovo Biopharma in the U.S.

Acetylcholine Receptor Modulators

In this section, drugs that act on nicotinic acetylcholine receptors are listed first, followed by drugs that act on muscarinic acetylcholine receptors.

SKL-15508

SKL15508 is an alpha 7 nicotinic acetylcholine receptor agonist.

It improved cognitive function in animal studies. When used in combination with existing drugs, there were synergistic effects. The combinations are expected to improve overall symptoms and mitigate side effects.

Phase 2a trial is ongoing in the U.S. as of 2016. No development progress has been reported as of 2021.

VQW-765

VQW765 is another alpha7 nicotinic acetylcholine receptor agonist.

It may be effective for cognitive impairment and dyskinesia.

Phase 2 trials are currently ongoing in France, Germany, Italy, and the U.S.

ML-007

ML-007 is the same type of drug as Emraclidine, NBI-1117568 and KarXT. It is an agonist of both M1 and M4 receptors.

So I expect it to have an effect on cognitive function and negative symptoms.

It may work for schizophrenia and dyskinesia. Phase 1 trial has been initiated in the U.S. by Mapwright.

2023 Note: A Phase 1 trial for schizophrenia and dyskinesia was completed in August 2022. The trial was apparently successful with no serious side effects.

ANAVEX3-71

ANAVEX3-71 is an M1 muscarinic acetylcholine receptor 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 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 January 2024, the drug is in Phase 2 trials in the U.S. for the treatment of schizophrenia.

VU0467154

VU0467154 is a positive allosteric modulator of muscarinic acetylcholine M4 receptors.

It may be effective for cognitive dysfunction and schizophrenia.

Still in preclinical trials, not yet in Phase 1.

Other modulators

In this section, I will write about other drugs with various mechanisms of action.

Luvadaxistat

Luvadaxistat is a D-amino acid oxidase inhibitor.

D-amino acid oxidase causes the breakdown of D-serine, which is important for brain function. Luvadaxistat “inhibits” this function.

A Phase 2 study in the U.S. did not show improvement in negative symptoms, but did show improvement in cognitive function.

In Japan, it is also in Phase 2 trial as TAK-831.

NaBen

NaBen is also a D-amino acid oxidase inhibitor.

In clinical trials, it has shown some or no improvement in cognitive function.

Some clinical trials have shown improvement, particularly in processing speed and visual memory. Another trial showed improved cognitive function when combined with sarcosine (a glycine transporter 1 inhibitor).

NaBen is currently in a Phase 2/3 study in the U.S. for an indication as an adjunct to antipsychotic medications.

MK-8189

MK-8189 is a phosphodiesterase 10A inhibitor.

In animal studies, it has been shown to improve cognitive dysfunction in schizophrenia.

It is currently in Phase 2 trials in the United States.

Osoresnontrine(BI-409306, SUB-166499)

Osoresnontrine is a phosphodiesterase 9A inhibitor.

In animal studies, it has been shown to improve memory.

It is currently in Phase 2 trials in the United States.

KYN-5356

KYN-5356 is a kynurenine-oxoglutarate transaminase inhibitor.

It is a drug that treats only the cognitive dysfunction of schizophrenia and looks promising.

It is currently in Phase 1 trials in the United States.

GPR139 agonist (NBI-1065846, TK-041)

NBI-1065846 agonizes the orphan G protein-coupled receptor 139. It is called GPR139 agonist.

It is intended for application in schizophrenia and cognitive dysfunction. It is not known if development is ongoing.

Development is ongoing for the treatment of anhedonia in depression. Phase 2 data will be available in the U.S. in 2023.

GPR52 agonist

There is a class of drugs called GPR52 agonists that are also being developed by Nxera.

By activating (stimulating) GPR52 receptors, they indirectly enhance D1 receptor signaling in the prefrontal cortex and inhibit D2 receptor signaling in striatum.

By doing so, it improves negative symptoms, cognitive dysfunction, and positive symptoms.

However, as yet, only animal studies have been conducted. A human Phase 1 clinical trial of HTL0048149, a GPR52 agonist from Nxera, is expected to be conducted in the near future.

Summary

Summary of Development Stages

The development stages of all drugs in this article are summarized below. All drugs are in development in the U.S. except those with country names in red.

————————————–

In preclinical testing
VU0467154

————————————–

Phase 1 in progress
Pomaglumetad methionil, KYN-5356, HTL0048149

Phase 1 completed
Plazinemdor, ML-007

————————————–

Phase 2 in planning
Samelisant

Phase 2 in progress
VQW-765 (France, Germany, Italy, U.S.A.), SKL-15508, TAK-831 (Japan), RL-007, Luvadaxistat, ANAVEX3-71, NaBen, Osoresnontrine, MK-8189

Phase 2 completed
Usmarapride, ASP-4345

————————————–

Phase 3 in progress
BI425809 (Japan, U.S.A.)

————————————–

Unknown
ASP-5736, BMS-955829, NBI1065846

Summary of mechanism of action

In case you are interested, the mechanism of action is also summarized.

Monoamine Receptor Modulators

  1. ASP-5736 (selective serotonin 5HT5A receptor inhibitor)
  2. Usmarapride (serotonin 5HT4 receptor partial agonist)
  3. Samelisant (histamine 3 receptor inverse agonist)
  4. ASP-4345 (positive allosteric modulator of D1 receptors)

Glutamate Receptor Modulators

  1. BI425809 (glycine transporter 1 inhibitor)
  2. RL-007 (acetylcholine, GABA B, NMDA, receptor modulator)
  3. Plazinemdor (positive allosteric modulator of NMDA receptors)
  4. BMS-955829 (mGluR5 allosteric agonist)
  5. Pomaglumetad methionil (mGluR2/3 agonist)

Acetylcholine Receptor Modulators

  1. SKL-15508 (alpha 7 nicotinic acetylcholine receptor agonist)
  2. VQW-765 (alpha7 nicotinic acetylcholine receptor agonist)
  3. ML-007 (muscarinic acetylcholine M1/M4 receptor agonist)
  4. VU0467154 (positive allosteric modulator of muscarinic acetylcholine M4 receptors)
  5. ANAVEX3-71 (M1 muscarinic acetylcholine receptor agonist and sigma 1 receptor agonist)

Other modulators

  1. Luvadaxistat, TAK-831 (D-amino acid oxidase inhibitor)
  2. NaBen (D-amino acid oxidase inhibitor)
  3. Osoresnontrine (phosphodiesterase 9A inhibitor)
  4. MK-8189 (phosphodiesterase 10A inhibitor)
  5. KYN-5356 (kynurenine-oxoglutarate transaminase inhibitor)
  6. NBI-1065846 (GPR139 agonist)
  7. HTL0048149 (GPR52 agonist)

Comment

I don’t think this article is able to present all of the cognitive impairment drugs in development. I may add new ones as I discover them.

As far as I know, there are only two drugs in development in Japan that are specially intended for cognitive dysfunction. BI425809 is in phase 3 and TAK-831 is in phase 2.

In the U.S., there are about 20 drugs. I do not know how many of these will go on sale.

I wish BI425809 and TAK-831 the best of luck.

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References

Pimavanserin

ASP-5736

Usmarapride（SUVN-4010）

Samelisant

ASP-4345

BI425809

PF-03463275

RL-007

Plazinemdor（CAD-9303）

EM-036

BMS-955829

SKL-20540

SKL-15508

VQW-765

ML-007

HTL-9936

VU0467154

Luvadaxistat

Davunetide（CP-201、AL-108、NAP）

NBI-1065846（TK-041）

GPR52 agonist

selective Kv3 ion channel modulator（AUT00206）

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