Frequency Therapeutics — Hearing Loss Regeneration

[Pink Noise]

Will FX-322 help with hearing loss incurred as result of Meniere's disease?

 

[FGG]

Will FX-322 help with hearing loss incurred as result of Meniere's disease?

Most Meniere's loss is low frequency, so maybe not initially with the first formulation for those losses. I am also not sure how stria vascularis damage effects the efficacy. My ototoxicity also effects the stria so this might be a problem for me too. I hope not but it is a worry.

 

[serendipity1996]

I can't envisage FX-322 costing upwards of $10k.

I'm fairly new to all this. Any idea what FX-322 might do for hyperacusis?

The simple answer is we really don't know at this point. It's complicated by the fact that hyperacusis is more of an 'umbrella' term and recently it's been argued that pain hyperacusis (aka noxacusis) and loudness hyperacusis are actually two distinct forms of the disorder with separate pathologies. I think the general consensus is that loudness hyperacusis would potentially benefit more from HC regeneration. One of the leading theories regarding noxacusis is that the type 2 nerve fibers in the ear, which behave like pain fibers, have become activated in response to noise that is not dangerously loud. So it's most likely a form of neuropathic pain although the underlying mechanisms haven't been conclusively proven yet. If that's the case then the answer will probably lie in finding a way to selectively block these fibers from generating a painful response to stimuli. So other avenues might show more promise for this, such as the reformulation of Retigabine.

 

[Joeseph Stope]

No, I mean I think it will help those with inner hair cell damage who have normal audiograms (which only show outer hair cell damage). I'm speculating that it may be especially useful for them.

I looked up embryologic development of the cochlea last night and it appears the IHCs also develop first. If they are preferentially recovered, I wonder if it's because OHCs apparently don't develop until after IHCs are in place.

It's so nice to have someone who understands the technology and the jargon so let me say how much I appreciate yourself and HootOwl. Somewhat related to this topic I recall back in the nineties when I first joined the "tinnitus club", that some doctor, otologist or ENT had actually gone and published a scientific paper on "The Angry Tinnitus Patient". No shit. I believe there was more than one paper published. Perhaps understandably so when the patient sees these angels walking around in their white coats and realizes that little can be done for him.
Ah yes, I have tinnitus and noise hyperacusis... maybe a little pain hyperacusis too. And a dip in my audiogram at a high pitch -- I seem to recall that it was around 6,000Hz or something like that or was it 6 KHz...

In which order do you thing that I should take these new therapies?

1st the Hough pill... but I'm way into the chronic category by now -- tinnitus onset in 1992.
2nd the Frequency Therapeutics?
3rd the Regain?

Early days yet with the 2b trials still underway but no harm in getting the opinion of someone in know.

Ah yes, HootOwl in one of his posts seemed as if he was hinting at going to attend some trial? Which one?

 

[reeseth]

Will FX-322 help with hearing loss incurred as result of Meniere's disease?

Something I hope myself, but no clue. I have bilateral.

 

[FGG]

It's so nice to have someone who understands the technology and the jargon so let me say how much I appreciate yourself and HootOwl. Somewhat related to this topic I recall back in the nineties when I first joined the "tinnitus club", that some doctor, otologist or ENT had actually gone and published a scientific paper on "The Angry Tinnitus Patient". No shit. I believe there was more than one paper published. Perhaps understandably so when the patient sees these angels walking around in their white coats and realizes that little can be done for him.
Ah yes, I have tinnitus and noise hyperacusis... maybe a little pain hyperacusis too. And a dip in my audiogram at a high pitch -- I seem to recall that it was around 6,000Hz or something like that or was it 6 KHz...

In which order do you thing that I should take these new therapies?

1st the Hough pill... but I'm way into the chronic category by now -- tinnitus onset in 1992.
2nd the Frequency Therapeutics?
3rd the Regain?

Early days yet with the 2b trials still underway but no harm in getting the opinion of someone in know.

Ah yes, HootOwl in one of her posts seemed as if she was hinting at going to attend some trial? Which one?

As long as it's safe, I plan to take whichever comes out first because I suspect I (and a lot of us) have mixed pathology in the cochlea.

Not sure about Regain though because I have likely ototoxic damage to my support cells as it is so I wouldn't want to deplete them further. This is personal preference. We will hopefully get a lot more data about that when the trial data is released.

@HootOwl indicated that she applied for Frequency.

 

[MRItechssuck]

As long as it's safe, I plan to take whichever comes out first because I suspect I (and a lot of us) have mixed pathology in the cochlea.

Not sure about Regain though because I have likely ototoxic damage to my support cells as it is so I wouldn't want to deplete them further. This is personal preference. We will hopefully get a lot more data about that when the trial data is released.

@HootOwl indicated that she applied for Frequency.

I think you had mentioned you aren't doing Lenire and waiting for the regenerative medicine, correct?
Two months ago, I thought the non-invasive devices were the less risky... not so sure after recent reports.

 

[Mentos]

Will FX-322 restore synaptic connections in the intact hair cells?

 

[FGG]

I think you had mentioned you aren't doing Lenire and waiting for the regenerative medicine, correct?
Two months ago, I thought the non-invasive devices were the less risky... not so sure after recent reports.

Of the bimodal devices, the Minnesota device is the one I am most interested in. I'm not very sold on Lenire and I'm not sure I'm the best candidate for it, either.

 

[Christopher805]

As long as it's safe, I plan to take whichever comes out first because I suspect I (and a lot of us) have mixed pathology in the cochlea.

Not sure about Regain though because I have likely ototoxic damage to my support cells as it is so I wouldn't want to deplete them further. This is personal preference. We will hopefully get a lot more data about that when the trial data is released.

My tinnitus and hyperacusis (loudness) is also the result of ingesting an ototoxin. In my case it was neomycin. I've had both since May 2019. I have no hearing loss up to 8,000 kHz. What treatment(s) would hold promise for me? Also, thank you for recommending getting an expanded audiogram in an earlier post to me.

 

[FGG]

My tinnitus and hyperacusis (loudness) is also the result of ingesting an ototoxin. In my case it was neomycin. I've had both since May 2019. I have no hearing loss up to 8,000 kHz. What treatment(s) would hold promise for me? Also, thank you for recommending getting an expanded audiogram in an earlier post to me.

I think ototoxins are pretty poorly studied in humans but it looks like neomycin destroys both inner and outer hair cells. Maybe synapses too?

You may need a combination of therapies or maybe just FX-322. All of these drugs are primarily tested on noise-induced injury so we may have to wait and see. My only worry with ototoxicity is how many of our support cells are destroyed and/or whether other structures (e.g.. Stria Vascularis or even brainstem structures) are involved. I'm very much hoping all of us with antibiotic ototoxicity can at least get *some* improvement and i think we can. I don't think that is at all an unreasonable assumption.

Eventually (e.g., Chen's research or possibly Decibel's LATS inhibitor acquisition) they should be able to regenerate support cells too. But that may be a decade away. Without imaging inside the cochlea anyone is just guessing based on rodent studies what these drugs did in our individual cochleas. I plan to try all the regeneration drugs that are safe, personally and see what helps.

 

[FGG]

Will FX-322 restore synaptic connections in the intact hair cells?

Yes but it will not repair synapses in areas of undamaged hair cells.

 

[Ozwel]

I'm reading a lot of information on this board... Can anyone remind me when to expect the next announcement related to results? I think I remember next September is supposed to be the end of the current testing phase isn't it?

 

[Lucifer]

I'm reading a lot of information on this board... Can anyone remind me when to expect the next announcement related to results? I think I remember next September is supposed to be the end of the current testing phase isn't it?

End of September will be the next announcement about Phase 2a results and whether they will go directly to Phase 3.

There is an event sometime in June but I'm not too sure the date or time and if they will announce anything or not at the event.

 

[Christopher805]

I think ototoxins are pretty poorly studied in humans but it looks like neomycin destroys both inner and outer hair cells. Maybe synapses too?

You may need a combination of therapies or maybe just FX-322. All of these drugs are primarily tested on noise-induced injury so we may have to wait and see. My only worry with ototoxicity is how many of our support cells are destroyed and/or whether other structures (e.g.. Stria Vascularis or even brainstem structures) are involved. I'm very much hoping all of us with antibiotic ototoxicity can at least get *some* improvement and i think we can. I don't think that is at all an unreasonable assumption.

Eventually (e.g., Chen's research or possibly Decibel's LATS inhibitor acquisition) they should be able to regenerate support cells too. But that may be a decade away. Without imaging inside the cochlea anyone is just guessing based on rodent studies what these drugs did in our individual cochleas. I plan to try all the regeneration drugs that are safe, personally and see what helps.

Hello FGG,

Thank you for the very informative response. Much appreciated. I pray that the damage to my ears is only limited to OHC. I pray you are right with thinking we can get some improvement from these new discoveries. I am holding on to your words "I don't think that is at all an unreasonable assumption". That makes me smile with hope. I also pray the firms you listed can regenerate support cells... just in case but I hope they are not needed. Based on your estimate I'll be 70 years old. LOL. Again, thank you for the invaluable information. I pray that TOMORROW is TODAY for a viable cure for us all. It's time well overdue.

 

[MrCrybaby]

I think ototoxins are pretty poorly studied in humans but it looks like neomycin destroys both inner and outer hair cells. Maybe synapses too?

You may need a combination of therapies or maybe just FX-322. All of these drugs are primarily tested on noise-induced injury so we may have to wait and see. My only worry with ototoxicity is how many of our support cells are destroyed and/or whether other structures (e.g.. Stria Vascularis or even brainstem structures) are involved. I'm very much hoping all of us with antibiotic ototoxicity can at least get *some* improvement and i think we can. I don't think that is at all an unreasonable assumption.

Eventually (e.g., Chen's research or possibly Decibel's LATS inhibitor acquisition) they should be able to regenerate support cells too. But that may be a decade away. Without imaging inside the cochlea anyone is just guessing based on rodent studies what these drugs did in our individual cochleas. I plan to try all the regeneration drugs that are safe, personally and see what helps.

I believe in one of the preclinical FX-322 tests they used cochlea that were removed from the mice then soaked in antibiotic to kill the hair cells then soaked in FX-322 to regrow them successfully. Based on that anecdote ototoxicity patients may have cause to be optimistic.

 

[Ben S]

No clue, not their target. Might help marginally but I have a feeling hyperacusis is more rooted in damage of the nerve rather than in the hair cells.

Hmm, damage to the synapses or the spiral ganglions? Or both?

 

[Lucifer]

I believe in one of the preclinical FX-322 tests they used cochlea that were removed from the mice then soaked in antibiotic to kill the hair cells then soaked in FX-322 to regrow them successfully. Based on that anecdote ototoxicity patients may have cause to be optimistic.

I did not know they actually did this. Do you have a link about it?

 

[MrCrybaby]

Hmm, damage to the synapses or the spiral ganglions? Or both?

Actually, the current leading theories for hyperacusis are OHC loss for loudness hyperacusis, and damaged OHC that stimulate the pain nerve due to their dysfunction for pain hyperacusis. Based on this the drug has the potential to improve hyperacusis, particularly loudness.

 

[Mentos]

Yes but it will not repair synapses in areas of undamaged hair cells.

That's a pity in case synaptopathy is the reason for tinnitus, this may not help these individuals. Hough Ear Institute pill seems to be more potent for these patients

 

[FGG]

I believe in one of the preclinical FX-322 tests they used cochlea that were removed from the mice then soaked in antibiotic to kill the hair cells then soaked in FX-322 to regrow them successfully. Based on that anecdote ototoxicity patients may have cause to be optimistic.

Agree. And I definitely have some optimism. They used gentamycin I believe.

Every antibiotic is a little different and some even affect ion channels in the brainstem. I do think ototoxic victims will get some improvement for sure but I think they are excluding ototoxicity in these initial studies for a reason and even Hough alluded to this in their podcast: kopke said the population is too heterogeneous to study in a trial.

 

[FGG]

That's a pity in case synaptopathy is the reason for tinnitus, this may not help these individuals. Hough Ear Institute pill seems to be more potent for these patients

True. If synaptopathy is the cause, those individuals will need a synaptopathy drug.

 

[Pink Noise]

@FGG how do we know what is the cause? Would we just have to try and hope with the treatments? Less invasive one first and then try FX-322 afterwards?

 

[FGG]

@FGG how do we know what is the cause? Would we just have to try and hope with the treatments? Less invasive one first and then try FX-322 afterwards?

I think the only thing standard testing can tell us is if we have OHC damage (if you have an extended audiogram). And, even then, you could have notches in between testing frequencies. If you have speech in noise difficulty, you likely have synaptopathy (though apparently new studies show IHC damage can do this, too) but it doesn't rule it out if you don't because you might not have synaptopathy in the most important speech range. The truth is, apart from OHC damage in tested frequencies, there is no good way to know. I think regenerative medicine will help with this because we will see which drugs help with what distortions. But for this first wave, we are looking like the population to help figure this out.

I think it's up to the individual what they are willing to try. That's why the safety data is important, too. Thankfully, so far FX-322 appears very safe after phase 1.

 

[Joly]

I had an acoustic trauma in August 2019. It got worse by taking ototoxic drugs (Doliprane) and with TRT.

How do you know where the damage is?

You talk about other structures (for example, Stria Vascularis or even brainstem structures), can these cause tinnitus?

There is no research on these causes at the moment?

FX-322 relates only to the synapses or OHCs and IHCs if I understood correctly?

You are talking about synaptopathy which can be resolved with Hough Ear Institute's treatment. However, when the treatment is in the market, it might not work for me, since it seems to be for the acute phase only.

How can Thanos Tzounopoulos' treatment for tinnitus help?

 

[Tweedleman]

You are talking about synaptopathy which can be resolved with Hough Ear Institute's treatment. However, when the treatment is in the market, it might not work for me, since it seems to be for the acute phase only.

This is my worry, too. Will we be out of luck by the time the pill becomes available "mid-decade?"

 

[FGG]

I had an acoustic trauma in August 2019. It got worse by taking ototoxic drugs (Doliprane) and with TRT.

How do you know where the damage is?

You talk about other structures (for example, Stria Vascularis or even brainstem structures), can these cause tinnitus?

There is no research on these causes at the moment?

FX-322 relates only to the synapses or OHCs and IHCs if I understood correctly?

You are talking about synaptopathy which can be resolved with Hough Ear Institute's treatment. However, when the treatment is in the market, it might not work for me, since it seems to be for the acute phase only.

How can Thanos Tzounopoulos' treatment for tinnitus help?

I don't believe there is a way for sure to know where the damage is apart from if you happen to have OHC damage evident on the audiogram. Part of the problem is that, before regenerative medicine, it didn't matter in terms of treatment so there was no reason to develop testing.

I mentioned the stria because some ototoxins directly effect it. E.g.. Macrolides and Cisplatin/Carboplatin.

Most ototoxins have not been studied enough to say conclusively where the damage is in the cochlea but OHC and IHC are the usual players in terms of most damage it seems. To complicate it, the ototoxic studies that do exist may be species dependent too. Noise injury seems more predictable across species. Likely one reason all regenerative therapies are being tested on noise first. I know absolutely nothing about Doliprane toxicity, specifically, sorry.

I have not heard the stria can cause tinnitus directly but it may make healing of some structures (e.g.. IHC) more difficult.

From a correspondence with a researcher at Autifony, the brainstem has some plasticity in the auditory centers and she is hopeful it can compensate for some if the direct ototoxic damage, if occurs (aminoglycosides +/- macrolides can bind to KV3.1 ion channels in the brainstem from some studies). I am hoping fixing the cochlea will address any ototoxic damage there, too, after my brain stem adjusts.

FX-322 will not repair synapses that are damaged without hair cell damage at the same location. They have said as much in their Q and A. If you have both at the same location, both will be fixed, though, as the new hair cell grows new synapses.

Hough has said they suspect their synapse drug to work chronically. However, they don't appear to be testing that in their upcoming phase 2. Maybe in a phase 2b? 2021? That's just a guess.

Pipeline is about to start phase 1 testing for PIPE-505, though. That is a synaptopathy drug that is also patented for tinnitus. I don't believe you have to be acute for that drug.

Otonomy has a synaptopathy drug in phase 2 at the moment, OTO-413. I don't believe they recruited only acute cases.

Thanos Tzounopoulos' approach seems to be on silencing channels that help relay the tinnitus signal. I don't know much about his progress so far. An update would be great.

 

[serendipity1996]

I don't believe there is a way for sure to know where the damage is apart from if you happen to have OHC damage evident on the audiogram. Part of the problem is that, before regenerative medicine, it didn't matter in terms of treatment so there was no reason to develop testing.

I mentioned the stria because some ototoxins directly effect it. E.g.. Macrolides and Cisplatin/Carboplatin.

Most ototoxins have not been studied enough to say conclusively where the damage is in the cochlea but OHC and IHC are the usual players in terms of most damage it seems. To complicate it, the ototoxic studies that do exist may be species dependent too. Noise injury seems more predictable across species. Likely one reason all regenerative therapies are being tested on noise first. I know absolutely nothing about Doliprane toxicity, specifically, sorry.

I have not heard the stria can cause tinnitus directly but it may make healing of some structures (e.g.. IHC) more difficult.

From a correspondence with a researcher at Autifony, the brainstem has some plasticity in the auditory centers and she is hopeful it can compensate for some if the direct ototoxic damage, if occurs (aminoglycosides +/- macrolides can bind to KV3.1 ion channels in the brainstem from some studies). I am hoping fixing the cochlea will address any ototoxic damage there, too, after my brain stem adjusts.

FX-322 will not repair synapses that are damaged without hair cell damage at the same location. They have said as much in their Q and A. If you have both at the same location, both will be fixed, though, as the new hair cell grows new synapses.

Hough has said they suspect their synapse drug to work chronically. However, they don't appear to be testing that in their upcoming phase 2. Maybe in a phase 2b? 2021? That's just a guess.

Pipeline is about to start phase 1 testing for PIPE-505, though. That is a synaptopathy drug that is also patented for tinnitus. I don't believe you have to be acute for that drug.

Otonomy has a synaptopathy drug in phase 2 at the moment, OTO-413. I don't believe they recruited only acute cases.

Thanos Tzounopoulos' approach seems to be on silencing channels that help relay the tinnitus signal. I don't know much about his progress so far. An update would be great.

Regarding Thanos Tzounopoulous' work, there don't appear to be many updates forthcoming but this company is also working on a reformulated version of retigabine primarily for epilepsy although I think they had listed tinnitus as one of their indications.

https://www.xenon-pharma.com/product-pipeline/xen1101-for-epilepsy/

 

[mrbrightside614]

Guys, we keep having to go back over information for every individual case that has just been discussed pages ago. Everyone should be able to glean all the information they need from the last 10 pages or so.

 

[FGG]

Guys, we keep having to go back over information for every individual case that has just been discussed pages ago. Everyone should be able to glean all the information they need from the last 10 pages or so.

I wish we could sticky the following:

Apart from OHC damage that is found on an audiogram, there is no good way to tell what you might have damaged in your cochlea.

and

It looks like Frequency will repair OHC, IHC and only synapses *if* they are associated with a damaged IHCs, otherwise a synaptopathy drug (e.g.. Pipeline, Otonomy, Hough pill) would be needed.

They have said it should reach over 3500 Hz. It is unknown if a reduced or any effect will be reached sub 3500 Hz with version 1.0 of FX-322.