Frequency Therapeutics — Hearing Loss Regeneration

[mrbrightside614]

I should add that I think we will all need a combination of hair cell and synapse regeneration, and imo the order is going to end up being important. A drug that regenerates your IHC synapses isn't going to work if your IHC is gone.

FX-322 is supposed to regenerate the lost IHC's and said IHC's supposedly make such synaptic connections— we wouldn't be observing any hearing loss improvement if they were simply rendered vestigial components.

 

[Caveman]

My thought is you do FX-322 first, then do clean up with Pipeline/OTO-413. Good news is that order is how the drugs will be arriving to market.

What are the chances of PIPE-505 and OTO-413 receiving fast-track designation, in your estimation?

 

[MrCrybaby]

I believe if you have IHC damage/death then these reconnections happen after treatment because IHC are the site of synaptopathy. A newly regenerated IHC should have new synapses to go along with it. This is what allows the dendrites to reconnect.

If you have mainly OHC damage/death then it remains to be seen if FX can regrow synapse or nerve fibers to connect with an already intact IHC. I could not glean the answer from their papers, and my email went unanswered in this regard.

My current understanding is that it does not but it's hard to tell.

To clarify, this means that FX-322 will regrow both hair cell types but some may be left "unplugged"?

 

[mrbrightside614]

To clarify, this means that FX-322 will regrow both hair cell types but some may be left "unplugged"?

No, the IHC's should be regrown and should make synaptic connections, otherwise we would fail to see the improvement in hearing as we've seen in the trials. I don't believe anyone knows if OHC regeneration is taking place.

 

[FGG]

No, the IHC's should be regrown and should make synaptic connections, otherwise we would fail to see the improvement in hearing as we've seen in the trials. I don't believe anyone knows if OHC regeneration is taking place.

I think you have it backward. OHC regrowth equals audiogram changes. That's what Frequency is targeting but it may help IHC's too depending on how you read their paper.

Now if you have damaged synapses without hair cell damage, that's a different drug.

 

[MrCrybaby]

I think you have it backward. OHC regrowth equals audiogram changes. That's what Frequency is targeting but it may help IHC's too depending on how you read their paper.

Now if you have damaged synapses without hair cell damage, that's a different drug.

Ohhhh, I get it now. Thanks!

 

[mrbrightside614]

I think you have it backward. OHC regrowth equals audiogram changes. That's what Frequency is targeting but it may help IHC's too depending on how you read their paper.

Now if you have damaged synapses without hair cell damage, that's a different drug.

Cochlear synaptopathy is far less common, no? I may have mixed the verbiage up because of "inner EAR hair cell" and not inner hair cells. I'm not well versed on their distinguishing factors, so thank you for clarification.

 

[FGG]

Cochlear synaptopathy is far less common, no? I may have mixed the verbiage up because of "inner EAR hair cell" and not inner hair cells. I'm not well versed on their distinguishing factors, so thank you for clarification.

Even googling "inner hair cell" gives you info on "inner ear hair cells" instead. Just adds to the confusion. Images and diagrams helped me with this.

Cochlear synaptopathy is probably more common than problematic hair loss. Anyone who more has trouble hearing conversation in noisy places than they used to has at least some synaptopathy.

 

[HootOwl]

Cochlear synaptopathy is far less common, no? I may have mixed the verbiage up because of "inner EAR hair cell" and not inner hair cells. I'm not well versed on their distinguishing factors, so thank you for clarification.

No worries my dude, it's a lot of terminology. Synaptopathy is believed to be far more common than previously thought due to Liberman's extensive research on the topic, showing that the A1 nerve fibers and synapses connecting to IHCs are extremely susceptible to noise trauma (they will die before OHC) and that you can have severe synaptopathy without any change in your audiogram, hence "hidden hearing loss". The damage "hides" behind a normal audiogram.

 

[JohnAdams]

Cochlear synaptopathy is probably more common than problematic hair loss. Anyone who more has trouble hearing conversation in noisy places than they used to has at least some synaptopathy.

Agreed. People can lose hair cells without getting tinnitus. This leads me to believe that most of tinnitus is from cochlear synaptopathy.

 

[FGG]

Agreed. People can lose hair cells without getting tinnitus. This leads me to believe that most of tinnitus is from cochlear synaptopathy.

I still think some data (testimonials?) prompted Frequency to add tinnitus to their experimental arm. I tend to think damage to any part of the audio system can cause the "phantom sound" of tinnitus.

 

[d'Wooluf]

I still think some data (testimonials?) prompted Frequency to add tinnitus to their experimental arm.

For the sake of everyone here I hope you're right.

 

[Lucifer]

I still think some data (testimonials?) prompted Frequency to add tinnitus to their experimental arm. I tend to think damage to any part of the audio system can cause the "phantom sound" of tinnitus.

I know they started testing for tinnitus for Phase 2a but surely they must of have participants in Phase 1b that had tinnitus and said it was reduced or gone. Do we really need to wait till end of September to tell us if tinnitus was reduced or not?

 

[mrbrightside614]

No worries my dude, it's a lot of terminology. Synaptopathy is believed to be far more common than previously thought due to Liberman's extensive research on the topic, showing that the A1 nerve fibers and synapses connecting to IHCs are extremely susceptible to noise trauma (they will die before OHC) and that you can have severe synaptopathy without any change in your audiogram, hence "hidden hearing loss". The damage "hides" behind a normal audiogram.

This condition gets more sinister by the day. I don't have much problem hearing in noisy environments (or so I think?) so I'm hoping my damage is limited to the hair cells. But this foundation is shaky at best.

If there is registered damage at high frequencies, surely then OHC loss could be the culprit for high frequency tinnitus?

 

[FGG]

This condition gets more sinister by the day. I don't have much problem hearing in noisy environments (or so I think?) so I'm hoping my damage is limited to the hair cells. But this foundation is shaky at best.

If there is registered damage at high frequencies, surely then OHC loss could be the culprit for high frequency tinnitus?

My opinion is assuming you don't have TMJ, a brainstem injury, blood flow issues or are/were on meds that cause nerve dysfunction, structural damage anywhere in the cochlea can cause the "phantom sounds" of tinnitus. Whether hair cells or synaptopathy, the signal at some point is not getting through.

An analogy: you can lose feeling in your feet from diabetic neuropathy or from a spinal column injury. What matters is somewhere along the pathway the signal is lost and the brain feels the same numbness (or pain). I think it's the same with the brain and the "phantom sound".

If you have HF tinnitus and associated hearing loss, the OHCs are likely involved IMO and I think Frequency will help you (assuming you aren't continually on meds that hinder neuroplasticity back to the normal set point when it happens -- I am wondering if this will be a factor or not).

That's why we need all these regeneration drugs because not all of us with cochlear damage have the same injuries. There are even a few structures Chen at Harvard is working on (e.g.. stria) that aren't being addressed by other drugs.

 

[JohnAdams]

My opinion is assuming you don't have TMJ, a brainstem injury, blood flow issues or are/were on meds that cause nerve dysfunction, structural damage anywhere in the cochlea can cause the "phantom sounds" of tinnitus. Whether hair cells or synaptopathy, the signal at some point is not getting through.

An analogy: you can lose feeling in your feet from diabetic neuropathy or from a spinal column injury. What matters is somewhere along the pathway the signal is lost and the brain feels the same numbness (or pain). I think it's the same with the brain and the "phantom sound".

If you have HF tinnitus and associated hearing loss, the OHCs are likely involved IMO and I think Frequency will help you (assuming you aren't continually on meds that hinder neuroplasticity back to the normal set point when it happens -- I am wondering if this will be a factor or not).

That's why we need all these regeneration drugs because not all of us with cochlear damage have the same injuries. There are even a few structures Chen at Harvard is working on (e.g.. stria) that aren't being addressed by other drugs.

I honestly got so used to getting IT injections that I sorta miss the thrill of it. I'm sure that if I ever get FX-322 the ENT will be disturbed when I'm like "awwwww yeah " when he gives me the injection.

 

[mrbrightside614]

For some reason no one in my care system knows where to get a high frequency audiogram. I would travel for this if necessary, as to comply with FX-322's inclusion criteria. Could you please refer me to where you went for yours? @FGG @HootOwl

 

[HootOwl]

This condition gets more sinister by the day. I don't have much problem hearing in noisy environments (or so I think?) so I'm hoping my damage is limited to the hair cells. But this foundation is shaky at best.

If there is registered damage at high frequencies, surely then OHC loss could be the culprit for high frequency tinnitus?

I actually don't believe that most people with normal audiograms and tinnitus have widespread OHC death or synaptopathy so you might not even have speech in noise issues despite having synaptic/nerve fiber degradation. For some reason the brain took minor cochlear damage (in the form of hair cell death/synaptic death) and responded with central gain for us tinnitus people.

It all comes down to 2 things imo:

1. What is the damage? IHC, OHC, synapse, and/or nerve fiber

2. At what frequency is the damage located? Apex or base?

Each component of these 2 questions is being addressed by different regenerative drugs coming to market. It will just be important for people to recognize they don't all do the same thing, and some have much better penetrance than others (at the moment).

 

[mrbrightside614]

I actually don't believe that most people with normal audiograms and tinnitus have widespread OHC death or synaptopathy so you might not even have speech in noise issues despite having synaptic/nerve fiber degradation. For some reason the brain took minor cochlear damage (in the form of hair cell death/synaptic death) and responded with central gain for us tinnitus people.

It all comes down to 2 things imo:

1. What is the damage? IHC, OHC, synapse, and/or nerve fiber

2. At what frequency is the damage located? Apex or base?

Each component of these 2 questions is being addressed by different regenerative drugs coming to market. It will just be important for people to recognize they don't all do the same thing, and some have much better penetrance than others (at the moment).

Nerve fibers can regrow though, albeit at an incredibly sluggish pace. I remember hearing a 1mm/day estimate. Hoping that a combination of time and FX-322 would fix most of us here.

 

[HootOwl]

For some reason no one in my care system knows where to get a high frequency audiogram. I would travel for this if necessary, as to comply with FX-322's inclusion criteria. Could you please refer me to where you went for yours? @FGG @HootOwl

Mine was done in Southern California, in Torrance which just happened to be near one of the test sites. It's called South Bay Hearing. I use Ian, he's a great audiologist - very kind.

I think the test location is also located in an audiologists office who does extended audiograms but I know SBH does up to 20 kHz with no issue.

 

[john paul]

I know they started testing for tinnitus for Phase 2a but surely they must of have participants in Phase 1b that had tinnitus and said it was reduced or gone. Do we really need to wait till end of September to tell us if tinnitus was reduced or not?

Absolutely, where big money is concerned, there is always going to be a wall of silence.

 

[Caveman]

I actually don't believe that most people with normal audiograms and tinnitus have widespread OHC death or synaptopathy so you might not even have speech in noise issues despite having synaptic/nerve fiber degradation. For some reason the brain took minor cochlear damage (in the form of hair cell death/synaptic death) and responded with central gain for us tinnitus people.

It all comes down to 2 things imo:

1. What is the damage? IHC, OHC, synapse, and/or nerve fiber

2. At what frequency is the damage located? Apex or base?

Each component of these 2 questions is being addressed by different regenerative drugs coming to market. It will just be important for people to recognize they don't all do the same thing, and some have much better penetrance than others (at the moment).

What regenerative drug is addressing nerve fiber degradation?

 

[FGG]

For some reason no one in my care system knows where to get a high frequency audiogram. I would travel for this if necessary, as to comply with FX-322's inclusion criteria. Could you please refer me to where you went for yours? @FGG @HootOwl

They can do it up to 12000 Hz at Hough (where i had my last one) but you need loss at multiple data points to qualify for Frequency with just extended loss I believe (so I didn't qualify) but I know I would have had losses at every point over 12000 Hz if measured but possibly in the profound range so i might still not qualify.

I am not sure where to get one to 16000 Hz but there are a few users on reddit who got extended audiograms that high by request. I imagine any big metro area would have it. E.g. I would call around if you live near NY, Chicago, LA, Dallas, etc.

 

[mrbrightside614]

They can do it up to 12000 Hz at Hough (where i had my last one) but you need loss at multiple data points to qualify for Frequency with just extended loss I believe (so I didn't qualify) but I know I would have had losses at every point over 12000 Hz if measured but possibly in the profound range so i might still not qualify.

I am not sure where to get one to 16000 Hz but there are a few users on reddit who got extended audiograms that high by request. I imagine any big metro area would have it. E.g. I would call around if you live near NY, Chicago, LA, Dallas, etc.

Not to digress, but it seems odd that they require extended range hearing loss for inclusion, while they themselves only measure up to 8 kHz.

 

[FGG]

Not to digress, but it seems odd that they require extended range hearing loss for inclusion, while they themselves only measure up to 8 kHz.

They don't require it in that range at all. But you *must* have some documented hair cell loss for this trial for obvious reasons so if you don't have it in the normal range you can still qualify if other conditions are met.

 

[HootOwl]

What regenerative drug is addressing nerve fiber degradation?

PIPE-505 and OTO-413.

PIPE-505 uses a more potent analog of NT3 and OTO-413 uses BDNF. Both are growth factors.

The Hough Ear Institute pill also regenerated nerve fibers but I'm a bit more skeptical of this for chronic cases due to its nature as an antioxidant and not a growth factor. It looks like you can get benefit in a chronic hearing loss model but I couldn't access that paper to learn more about it.

If you want to talk about future drugs Decibel Therapeutics has one in their pipeline but they are still in preclinicals. However it should be noted that Decibel is co-founded by Liberman who specializes in synaptopathy, so I'm anticipating their drug will be extremely effective. If I trust anyone to regrow nerve fibers it would be Liberman.

 

[HootOwl]

My bad everyone! I made a mistake regarding PIPE-505. It is actually a gamma secretase inhibitor/modulator. Not a growth factor. But their data does show it is as effective and in some cases more so than NT3.

 

[Caveman]

My bad everyone! I made a mistake regarding PIPE-505. It is actually a gamma secretase inhibitor/modulator. Not a growth factor. But their data does show it is as effective and in some cases more so than NT3.

Do you think PIPE-505 and OTO-413 will receive fast-track designation by the FDA?

 

[JohnAdams]

but some may be left "unplugged"?

I think a downstream cascade of process cause the nerve to regrow and reconnect.

 

[HootOwl]

Do you think PIPE-505 and OTO-413 will receive fast-track designation by the FDA?

I really have no idea. I know nothing about the fast track process. Sorry.