Prolonging Residual Inhibition with Eglumegad

[DebInAustralia]

Might be of interest.

Here is the link:

1pAB6 – Long-lasting suppression of spontaneous firing in inferior colliculus neurons: implication to the residual inhibition of tinnitus

Of significance is the author's comments regarding the research already undertaken on residual inhibition and its ability to help science identify a group of drugs that can alter the suppression response, as well as the 'spontaneous firing of the auditory neurons responsible for tinnitus. These drugs will be further investigated in our future research to develop effective tinnitus treatments.'

I emailed the author, Prof. Galazyuk.

This is his response with relation to pharmaceutical developments for tinnitus.

The study has just started. We have preliminary results on animals indicating that the drug works to provide tinnitus relief for about two hours. We are planning to test this product on humans, but, even if successful, it will take several years until this drug will be approved by FDA.

The name of the drug is Eglumegad, which is a group 11 mGluR agonist.

 

[DebInAustralia]

Update 4 years later:

I touched base with Prof. Galazyuk recently.

He's submitting a grant proposal to the NIH to further his clinical trials.

Preliminary trials in animals showed relief from tinnitus for two hours using this compound (2016).

 

[Thuan]

I just read parts of Galazyuk's article. His proposed model of tinnitus certainly makes sense: an increased in spontaneous hyperactivity above a certain threshold is shifted from cochlea to central nervous system; thus we are stuck with tinnitus when the cochlea recovers. This is consistent with studies where the cochlear nerve is severed but tinnitus is not resolved nor improved. It's also consistent where some people with hearing loss do not have tinnitus because that hyperactivity has not shifted to the CNS or the hyperactivity has not reached above a certain threshold.

I wonder what Dr. Will Sedley's predictive tinnitus model thinks about this.

So the question is: how likely will healing the cochlea (regenerating damaged hair cells) resolve/improve tinnitus symptoms?

 

[DebInAustralia]

Further to this study, when asked about financing, here is Prof. Galazyuk's response:

Hi Deb,

We don't have exact budget yet, but with our rough estimation it will cost about $1,500,000. It will include the drug production and testing of 30-40 people during the trial. This is the Phase II clinical trial (the proof of concept). If successful we will need to move to the Phase III trial which would require of testing several thousand tinnitus patients. This trial would cost about 150 million dollars. However, if the Phase II trial is successful, raising this amount of money would not be so difficult, because all investors would likely to get their money back together with a significant profit.

Best

 

[WillBeNimble]

Phase II clinical trial

Wait, they did Phase 1 already? Or is this Phase 1/2?

 

[DebInAustralia]

Wait, they did Phase 1 already? Or is this Phase 1/2?

I think he's hoping to move to Phase 2 because he said earlier that they've already tested its efficacy in animals.

 

[WillBeNimble]

I think he's hoping to move to Phase 2 because he said earlier that they've already tested its efficacy in animals.

Phase 1 is safety. Normally, for issues like tinnitus, it becomes a Phase 1/2 trial for safety and efficacy. To move to just Phase 2 on humans without a safety is unlikely. He probably means Phase 1/2.

 

[Nick47]

thus we are stuck with tinnitus when the cochlea recovers. This is consistent with studies where the cochlear nerve is severed but tinnitus is not resolved nor improved

Then why do cochlear implants resolve or reduce tinnitus in many, even in a sound proofed room? And some cochlear nerve ablations do resolve tinnitus. So "stuck in the brain" seems nonsense.

Also an update from NEOMED Hearing research today:

mGluRs have definitely been implicated in tinnitus! The Galazyuk Lab is currently looking at mGluRs in the inferior colliculus as a potential therapeutic target for tinnitus.

Been a long time though...

 

[DebInAustralia]

Update:

I have received an email response from Alex Galazyuk regarding Eglumegad.

• Eglumegad activates group 2 metabotropic glutamate receptors - suppresses hyperactive neuronal activity.
• The director of a USA based pharmaceutical company (who suffers with bothersome tinnitus himself) has informed Alex in December 2023, that Eglumegad will hopefully be moving to a clinical trial (as Eli Lilly have expressed interest in leasing their drug for a clinical trial).
• Discussions during an internal meeting will occur January - February 2024.

I'll update when I hear anything further.

 

[Nick47]

I looked at Eglumegad a few days ago by coincidence.

To summarise:

This thread started 8 years ago now and it is frustrating that this is not, at the very least, in human clinical trials.

• It seems this treatment possibility was born out of research into the inferior colliculus.
• It found hyperactivity in this area of the brain and it has been postulated to occur because of increased activity in the cochlear nucleus. The inferior colliculus is the next part of the brain where sound is processed after it passes through the cochlear nucleus.
• The drug is an agonist of the Glut 2 neurotransmitter.
• It has been found to decrease tinnitus in animal models, albeit, only for 2 hours.

 

[BadNeighbors]

Even if this only undid the noise for 2 hours at a time, it'd be great to have a few hours of quiet each day.

 

[Nick47]

Maybe after years of R & D, it's time to invite Prof. Galazyuk onto the Tinnitus Talk Podcast, @Hazel, @Markku, and get him to summarise his findings, animal study results and where he is in relation to starting human clinical trials?

 

[Tomas80]

I looked at Eglumegad a few days ago by coincidence.

To summarise:

This thread started 8 years ago now and it is frustrating that this is not, at the very least, in human clinical trials.

• It seems this treatment possibility was born out of research into the inferior colliculus.
• It found hyperactivity in this area of the brain and it has been postulated to occur because of increased activity in the cochlear nucleus. The inferior colliculus is the next part of the brain where sound is processed after it passes through the cochlear nucleus.
• The drug is an agonist of the Glut 2 neurotransmitter.
• It has been found to decrease tinnitus in animal models, albeit, only for 2 hours.

I'm a layman in this so it doesn't make sense to me that Eglumegad is a glutamate agonist. I thought that tinnitus was the result of overactive cells that needed to be calmed down. So I would expect a glutamate antagonist to work, not an agonist. Does anyone know?

 

[Hazel]

Maybe after years of R & D, it's time to invite Prof. Galazyuk onto the Tinnitus Talk Podcast, @Hazel, @Markku, and get him to summarise his findings, animal study results and where he is in relation to starting human clinical trials?

Ok, will do that now!

 

[Nick47]

Ok, will do that now!

Like not literally now.

I would expect a glutamate antagonist to work, not an agonist. Does anyone know?

Me too!

 

[StoneInFocus]

I'm a layman in this so it doesn't make sense to me that Eglumegad is a glutamate agonist. I thought that tinnitus was the result of overactive cells that needed to be calmed down. So I would expect a glutamate antagonist to work, not an agonist. Does anyone know?

Eglumegad is not a glutamate agonist, it is an agonist of the metabotropic glutamate receptor 2 (mGluR2). mGluR2 is a so called autoreceptor located at the presynaptic terminal. When glutamate, or an agonist like Eglumegad, binds to it, it decreases vesicular glutamate release. In that way it has a similar effect as Keppra, which reduces vesicle release through SV2A binding and blocking presynaptic calcium channels.

Interestingly enough, "previous research indicates that NAC increases extracellular glutamate, which is then thought to decrease neuronal glutamate release via activation of presynaptic mGluR2/3 receptors."

Unfortunately mGluR2 is not expressed in the inner ear.

 

[ithappens63]

Update:

I have received an email response from Alex Galazyuk regarding Eglumegad.

• Eglumegad activates group 2 metabotropic glutamate receptors - suppresses hyperactive neuronal activity.
• The director of a USA based pharmaceutical company (who suffers with bothersome tinnitus himself) has informed Alex in December 2023, that Eglumegad will hopefully be moving to a clinical trial (as Eli Lilly have expressed interest in leasing their drug for a clinical trial).
• Discussions during an internal meeting will occur January - February 2024.

I'll update when I hear anything further.

@DebInAustralia, have there been any further updates on this?

 

[Joeseph Stope]

I know I might come across as ignorant, but could someone kindly explain what "residual inhibition" is? It seems like there's a real need for a dictionary or glossary on tinnitus-related terms.

 

[IYIiKe]

I know I might come across as ignorant, but could someone kindly explain what "residual inhibition" is? It seems like there's a real need for a dictionary or glossary on tinnitus-related terms.

I'm assuming it's when a sound occurs and the tinnitus diminishes. Mine does this when I drop an Allen wrench on a tile. My tinnitus goes away completely for about half a second, then comes back.

 

[RunningMan]

Some people don't experience residual inhibition, but I do. This was discussed in Tinnitus Talk Podcast, Episode 21: Can Sound Silence Tinnitus? When I play a series of high-pitched tones at different frequencies with brief intervals of silence in between, I notice my tinnitus volume dropping during those moments of silence. It doesn't disappear completely, but after the tones stop, it returns to its baseline level within 30 seconds to a minute.

I also experience some residual inhibition with masking sounds, but only if the volume is high enough to trigger it. However, it's less noticeable on the fly than with the short, separated tones and brief silences.

 

[Joeseph Stope]

@IYliKe & @RunningMan, thank you.

 

[Nick47]

If dorsal cochlear nucleus (DCN) modulation is just the first of many pathways involved in the perception of tinnitus, wouldn't more animal studies help identify other potentially non-invasive options? So far, all I've found are some basic animal studies focusing on DCN lesioning. Is this because the upstream auditory networks are challenging to pinpoint and vary individually?

This thread...

Inferior colliculus, which is upstream from the DCN.

 

[Joeseph Stope]

In layman's terms, some tinnitus patients notice that their tinnitus briefly pauses after an external noise occurs. The goal, then, is to try and extend this pause for as long as possible – ideally, to make it permanent.

As for me? I seem to have permanent tinnitus. Every few years, I notice it shifting slightly, but otherwise, it's constant.

Well, as they say – Godspeed.

 

[IYIiKe]

In layman's terms, some tinnitus patients notice that their tinnitus briefly pauses after an external noise occurs. The goal, then, is to try and extend this pause for as long as possible – ideally, to make it permanent.

As for me? I seem to have permanent tinnitus. Every few years, I notice it shifting slightly, but otherwise, it's constant.

Well, as they say – Godspeed.

It's pretty wild when I hear recreations of various tinnitus sounds. It's somewhat reassuring since very few of us experience the typical single tone that most people imagine when they think of tinnitus. Instead, there's often a blend of sounds like conflagrations or wave-like distortions that overlay more prominent tones.

It would be intriguing if it weren't so unfortunate, knowing that others also struggle with their unique bundle of misery.

I only experience a brief moment of inhibition, just a millisecond, where my tinnitus fades while a specific high-pitched noise occurs, only to return immediately afterward. I wonder if this response is due to a compound that triggers an inhibition or gating mechanism. Animal studies seem to support this possibility.

I know @Nick47 has mentioned setting up single-site testing for cases like this, where a patient can create this inhibition so it can be measured.

I'm cautiously optimistic that understanding the science behind inhibition and gating could lead to a treatment for various forms of tinnitus, even for those without residual inhibition. It might just require a stronger stimulus to activate the gating mechanism.

I'm also located in Ohio, where NEOUMED is based. Hopefully, a future trial will take place here so I can participate, though that might just be wishful thinking.