Frequency Therapeutics — Hearing Loss Regeneration

[GregCA]

My thoughts initially were that they call it "hidden" because rarely any clinicians measure beyond 8kHz.

"Hidden hearing loss" isn't about the frequency. It's about the fact that it doesn't show up on PTA testing. It can affect frequencies < 8 kHz.

 

[FGG]

Is there any correlation between hidden hearing loss (due to synapses damage) and loss that appears on an extended high frequency audiogram up to at least 16kHz? My thoughts initially were that they call it "hidden" because rarely any clinicians measure beyond 8kHz. It always irritated me when the professionals that I saw for tinnitus and hearing exams called my case "idiopathic" when they weren't even measuring half of the goddamn frequency range! (Newer research has shown decent reliability and not much more clinic down-time in testing higher frequencies these days so that's not a valid excuse for clinicians anymore)

Hidden hearing loss was coined by Liberman to mean just synapse loss (which doesn't show up on any audiogram).

As far as correlation, I'm sure having one makes you more likely to have the other as damage has occurred. Having a high frequency audiogram made it so ENTs could "see" my damage even though it's clear mine is pretty widespread.

 

[Mistertdog15]

If FX-322 is released, how long will it be before people in Europe can get the treatment? And also does FX-322 regenerate inner hair cells as well as outer hair cells?

 

[FGG]

If FX-322 is released, how long will it be before people in Europe can get the treatment? And also does FX-322 regenerate inner hair cells as well as outer hair cells?

To the first question, no one knows but Europeans could come to the US for treatment.

Second question, depends on who you ask but hopefully Frequency could be asked that.

 

[Lucifer]

If FX-322 is released, how long will it be before people in Europe can get the treatment? And also does FX-322 regenerate inner hair cells as well as outer hair cells?

No idea but I think Frequency Therapeutics stated that it restores both inner and outer hair cells.

 

[FGG]

No idea but I think Frequency Therapeutics stated that it restores both inner and outer hair cells.

They haven't directly but one of their graphics implied it and one of their answers in a Q and A also implied it.

 

[Danad]

If FX-322 is released, how long will it be before people in Europe can get the treatment? And also does FX-322 regenerate inner hair cells as well as outer hair cells?

From Frequency's paper below.
Cell Rep. 2017 February 21; 18(8): 1917–1929. doi:10.1016/j.celrep.2017.01.066.
Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells

They grew both types in the adult mouse cochlea:

 

[Lucifer]

They haven't directly but one of their graphics implied it and one of their answers in a Q and A also implied it.

Hopefully we know more about the clinical trials when they release Phase 2a results by October this year.

 

[Jorge1984]

FYI "hidden hearing loss" does not mean hearing loss you don't notice. It was a term coined by Charles Liberman to describe a type of hearing loss (Synaptopathy) that was "hidden" from audiologists and researchers because an audiogram does not detect it.

People with cochlear synaptopathy (aka "hidden hearing loss") often notice their hearing is very abnormal in noisy environments. I.e. they have trouble hearing the person across from them in restaurants.

Noise can damage synapses, hair cells or both. Synapses are more likely to be the most sensitive per Liberman but that was based in rodent models so no one really knows if that's universally true for people.

If you don't notice hearing loss but you have cochlear damage (e.g. from noise) it just means the damage is not widespread enough or at a high enough frequency that you don't notice. It's not diagnostic for "hidden hearing loss."

Thank you for correcting me but since I'm a noob when it comes to this stuff, does that mean I have synapse damage? Because I used to listen to loud music.

 

[Killer]

And also does FX-322 regenerate inner hair cells as well as outer hair cells?

I have been in contact with Dr. McLean two weeks ago. He is the co-founder and vice president of Frequency Therapeutics. He seemed pretty confident about the work they're doing. I won't quote him here word for word, I will just give you the gist of it.

• Regenerating hair cells may be helpful in patients suffering from tinnitus accompanied by hearing loss.

• Tinnitus accompanied by hearing loss may be the result of the brain filling in input for a signal that is lost (eg. missing hair cells and/or neurons in a certain cochlear region).

• Research has found that providing more input can dampen tinnitus.

• They are still on track for the clinical trial start date mentioned in the articles.

• The progenitor cells are a subset of supporting cells that express a gene called Lgr5.

• The hair cells they make in a dish show that they have all the characteristics to function properly. They have long bundles, function electrically, and make the synapse components to connect to hair cells.

• They can make and restore both inner and outer hair cells.

• In development it is the hair cells and supporting cells that release the proteins to attract neurons (NT3, BDNF). Their research shows that regenerated hair cells make the synapse components to communicate with neurons, even if neurons are not present.

• They suspect that there will be several approaches that may be tailored to the cause of a person's hearing loss.

• Their work suggests that starting the regeneration process allows supporting cells and hair cells to restart the synapse formation process. If a person has all of their hair cells, this may not be the best option.

• Their analysis of donated cochleas from patients suggest that hair cells are the primary drivers of hearing loss.

• They are actively exploring the direct role of drugs on neurons.

• They acknowledge that there isn't yet a good system to diagnose "synapse only" conditions in the clinic.

 

[Diesel]

Thanks for sharing this. I see Dr. McLean's correspondence with Samir was from 2017. Seems to me like the science going on at the time was well established before FX-322 was brought to clinical trials.

It would be great of there was a way to keep a Wiki pinned to the top of this discussion to keep track/record of data/information that has been collected on/from Frequency like this conversation.

 

[FGG]

Thank you for correcting me but since I'm a noob when it comes to this stuff, does that mean I have synapse damage? Because I used to listen to loud music.

You might. No one can tell you. You could have synapse or hair cell damage or both. Did you get an extended audiogram by any chance?

 

[FGG]

Thank you! @Killer I hadn't realized anyone from Frequency made a statement about that.

They definitely made them in vitro and their answer at JP Morgan implied it as well ("it is a synaptopathy drug only where new hair cells are regenerated and connect" which had to refer to IHCs).

But Will McLean's statement has this as a "definite" imo. Fantastic find. I didn't realize anyone from Tinnitus Talk had been in contact with them. This personally makes me happy since Macrolides are so destructive to IHCs.

 

[FGG]

From Frequency's paper below.
Cell Rep. 2017 February 21; 18(8): 1917–1929. doi:10.1016/j.celrep.2017.01.066.
Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells

They grew both types in the adult mouse cochlea:
View attachment 38439

This data was part of the IHC discussion a few pages ago on this thread and I firmly believe after their JP Morgan answer they believe it works for humans as well. The quote @Killer brought up pretty much confirms this imo.

It is something they will directly be asked about on the podcast i believe though.

 

[Joly]

When you say "Regenerating hair cells may be helpful in patients suffering from tinnitus accompanied by hearing loss" mean that even with this treatment if we take it and it restores our hearing, tinnitus can stay at the same level without any improvement?

 

[FGG]

When you say "Regenerating hair cells may be helpful in patients suffering from tinnitus accompanied by hearing loss" mean that even with this treatment if we take it and it restores our hearing, tinnitus can stay at the same level without any improvement?

It's just vague scientist language. You have to say "may" until trials are over.

 

[FrontRoomFanatic]

@Killer

If the synapses get regenerated then would it be right to think that someone with tinnitus who also has some form of hyperacusis/sound sensitivity would see benefit? It's the synapses that are likely to be the main driver of hyperacusis/sensitivity aren't they?

 

[HootOwl]

@Killer

If the synapses get regenerated then would it be right to think that someone with tinnitus who also has some form of hyperacusis/sound sensitivity would see benefit? It's the synapses that are likely to be the main driver of hyperacusis/sensitivity aren't they?

Liberman seems to think so. He hypothesizes that loudness hyperacusis (not pain) is due to the destruction of the high threshold afferent nerve fibers - this is a specific type of synaptic connection that you find on the IHC along with low threshold.

He's written extensively on the subject and having dug through his research I personally believe we will be seeing beneficial results clinically once FX-322 and other synaptopathy drugs are released.

The only downside is Liberman has also shown that you can destroy a substantial amount of synaptic connections via noise exposure without OHC or IHC damage, so those of us with minimal (or even no) audiogram changes following an acoustic truama might not benefit from FX-322 alone.

It also depends on whether the slight notches one might find after noise exposure is due to synaptic death, and not OHC as is usually assumed. I think often about this now after Justin in the Hough thread revealed their pill could improve audiograms by 10-15 dB - theirs is a pure synaptic drug. No OHC or IHC growth there. And yet their synaptic repair translates into full-on audiogram changes.

I actually have these small notches basically at every reactive tinnitus frequency I have, as well as at my normal tinnitus frequencies.

Again though, Liberman's hyperacusis research is concerned primarily with noise. It changes a bit with regards to ototoxicty. Some ototoxins actually preferentially target the IHC, meaning it's likely those people with ototoxic induced hyperacusis mightactually see benefit from FX-322 more so than someone like myself who has pure noise induced damage.

BUT, either way OTO-413 should end up releasing around the same time as FX-322, so I'm not too worried.

We'll be able to pump plenty of regen juice into our ears within the next few years.

Edit: Im not sure if I should add this because it might needlessly complicate things...but that Liberman also mentioned that you can induce substantial syanptopathy without hair cell loss under specific sound conditions.

So the nature/frequency/duration of noise exposure can actually affect which structures are damaged or not. Two people with noise induced hyperacusis might have very different damage etiologies based on how they were exposed, and therefore it's difficult to gage who has damaged what without proper diagnostics.

 

[FGG]

@Killer

If the synapses get regenerated then would it be right to think that someone with tinnitus who also has some form of hyperacusis/sound sensitivity would see benefit? It's the synapses that are likely to be the main driver of hyperacusis/sensitivity aren't they?

They have specifically said in their JP Morgan Q and A that synapses get regenerated on the hair cells that get regenerated but it will not regenerate synapses in places without hair cell damage.

 

[FGG]

Liberman seems to think so. He hypothesizes that loudness hyperacusis (not pain) is due to the destruction of the high threshold afferent nerve fibers - this is a specific type of synaptic connection that you find on the IHC along with low threshold.

He's written extensively on the subject and having dug through his research I personally believe we will be seeing beneficial results clinically once FX-322 and other synaptopathy drugs are released.

The only downside is Liberman has also shown that you can destroy a substantial amount of synaptic connections via noise exposure without OHC or IHC damage, so those of us with minimal audiogram changes following an acoustic truama might not benefit from FX-322 alone.

It also depends on whether the slight notches one might find after noise exposure is due to synaptic death. I think often about this now after Justin in the Hough thread revealed their pill could improve audiograms by 10-15 dB - theirs is a pure synaptic drug. No OHC or IHC growth there. And yet their synaptic repair translates into full-on audiogram changes.

I actually have these small notches basically at every reactive tinnitus frequency I have, as well as at my normal tinnitus frequencies.

Again though, Liberman's hyperacusis research is concerned primarily with noise. It changes a bit with regards to ototoxicty. Some ototoxins actually preferentially target the IHC, meaning it's likely those people with ototoxic induced hyperacusis should actually see benefit from FX-322 more so than someone like myself who has pure noise induced damage.

BUT, either way OTO-413 should end up releasing around the same time as FX-322, so I'm not too worried.

For noise induced tinnitus (not sure about hyperacusis) there is evidence OHCs are one possible important component.

Frequency obviously believes their drug will benefit noise induced tinnitus because they have added that to their experimental arm in the noise induced test population.

I think a lot of people will benefit from a hair cell drug and a synaptopathy drug together. Otonomy thinks so, too, and they pointed out an added synergy between OTO-413 and their pre-clinical drug OTO-6xx.

 

[Koz]

Personally I already believe FX-322 cures tinnitus for noise-induced people who have it in the higher frequencies. There's tons of little indicators of this (such as Frequency agreeing to do the Tinnitus Talk Podcast, as you mentioned).

I also remember there being a soundbyte from a Q&A where someone from Frequency Therapeutics more or less said they have seen evidence that it helps tinnitus, but they said it in a very subtle way that wouldn't potentially get them sued.

My concern is really the FDA not seeing higher frequency regeneration as important/relevant enough where it relates to speech to give FX-322 breakthrough status.

The fact that most of the hearing professional community only uses 0-8kHz audiograms, along with what that implies, is what discourages me a bit.

Sorry I'm confused, are you assuming this drug won't be effective for the entire range of hair cells and frequencies involved in hearing loss or did they already show that to be the case? Are you basing what you're saying out of your personal fear or are you going by their Phase 1 results?

I thought this drug was ideally meant to regenerate sensorineural hearing loss among all ranges

I haven't kept up with this thread or FX-322 in general much, I try to limit it for the sake of my own mental health. Everyone hypothesizing just adds to the uncertainty which adds to my anxiety, I do hope there are some positive things to come out of the upcoming trial results for FX-322 and other related drugs. Just a shame COVID-19 put a spanner in the works.

 

[serendipity1996]

@Killer

If the synapses get regenerated then would it be right to think that someone with tinnitus who also has some form of hyperacusis/sound sensitivity would see benefit? It's the synapses that are likely to be the main driver of hyperacusis/sensitivity aren't they?

That's a really comprehensive explanation by HootOwl - just delving a little into pain hyperacusis here. Regarding pain hyperacusis (the type I have) one of the most convincing theories is to do with the type 2 nerve fibers in the inner ear. There are two kinds, 95% of which are type 1 fibers which connect to inner hair cells and then the type 2 fibers (5%) connect to the OHCs. So these fibers are only activated by trauma and 'noxious' levels of noise and seem to be pain-sensing fibers - they think that the upregulation of these fibers following tissue damage is what may be contributing to painful hyperacusis (noxacusis), with noise activating them at a far lower threshold than before hence pain from ordinary sounds. (Here's the paper that discusses it: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664349/) There was also a really good Tinnitus Talk podcast interview with Bryan Pollard from Hyperacusis Research who talked a bit more about the latest developments in pain hyperacusis. Liberman has also said that he believes pain and loudness hyperacusis have differing pathologies. I think there's a little more uncertainty as to hair cell regeneration helping pain hyperacusis - one thing that's been mentioned with regards to developing treatments for it is developing a drug that can silence these fibers. And it will be interesting to see whether HC regeneration will have positive effects for pain hyperacusis - upshot is nobody really knows but I'd still be optimistic about it.

And another thing I am really curious about is why some of us only have pain hyperacusis for certain sounds - like it makes me wonder wtf is going on at a physiological level and whether it correlates with damage only at certain frequencies or something.

 

[Lucifer]

What phase is OTO-413 at the moment?. That's great news that it may be released at the same time FX-322 comes out.

Gives us more chances to fix our ear problems whether it's hair cell loss or synapses loss.

 

[Paulmanlike]

I came across a video from a hearing doctor on YouTube uploaded last month (not associated with Frequency Therapeutics):



Apologies if this has been discussed before but I don't have the time these days to read everything. But the results that have implied efficacy is that it has increased word recognition (associated with hidden hearing loss) but has not effected pure tone hearing loss. He explains its likely to affect inner hair cell damage but not outer hair cell damage. So far, this only seems that Frequency Therapeutics may just help hearing aid users understand more word recognition while the hearing aids turn the actual volume up.

Am I missing something here, because so far, it would seem people labelling this as a 'cure' for HL exaggerated.

 

[FrontRoomFanatic]

That's a really comprehensive explanation by HootOwl - just delving a little into pain hyperacusis here. Regarding pain hyperacusis (the type I have) one of the most convincing theories is to do with the type 2 nerve fibers in the inner ear. There are two kinds, 95% of which are type 1 fibers which connect to inner hair cells and then the type 2 fibers (5%) connect to the OHCs. So these fibers are only activated by trauma and 'noxious' levels of noise and seem to be pain-sensing fibers - they think that the upregulation of these fibers following tissue damage is what may be contributing to painful hyperacusis (noxacusis), with noise activating them at a far lower threshold than before hence pain from ordinary sounds. (Here's the paper that discusses it: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664349/) There was also a really good Tinnitus Talk podcast interview with Bryan Pollard from Hyperacusis Research who talked a bit more about the latest developments in pain hyperacusis. Liberman has also said that he believes pain and loudness hyperacusis have differing pathologies. I think there's a little more uncertainty as to hair cell regeneration helping pain hyperacusis - one thing that's been mentioned with regards to developing treatments for it is developing a drug that can silence these fibers. And it will be interesting to see whether HC regeneration will have positive effects for pain hyperacusis - upshot is nobody really knows but I'd still be optimistic about it.

And another thing I am really curious about is why some of us only have pain hyperacusis for certain sounds - like it makes me wonder wtf is going on at a physiological level and whether it correlates with damage only at certain frequencies or something.

Thanks. I was going to ask for clarification regarding pain/discomfort hyperacusis.

Being in the same boat as yourself in that regard I am just hoping that the pain/discomfort I experience from those sounds don't then branch out to other sounds as well.

 

[Koz]

I came across a video from a hearing doctor on YouTube uploaded last month (not associated with Frequency Therapeutics):



Apologies if this has been discussed before but I don't have the time these days to read everything. But the results that have implied efficacy is that it has increased word recognition (associated with hidden hearing loss) but has not effected pure tone hearing loss. He explains its likely to affect inner hair cell damage but not outer hair cell damage. So far, this only seems that Frequency Therapeutics may just help hearing aid users understand more word recognition while the hearing aids turn the actual volume up.

Am I missing something here, because so far, it would seem people labelling this as a 'cure' for HL exaggerated.

The results were based on a Phase 1 safety trial dose, there are no results based on efficacy doses yet. That's what we're waiting for. Nobody called it a cure just yet but people's hopes are high because some improvement from a safety dose means there is potential for something exciting when the actual efficacy phase 2 results come out.

 

[HootOwl]

What phase is OTO-413 at the moment?. That's great news that it may be released at the same time FX-322 comes out.

Gives us more chances to fix our ear problems whether it's hair cell loss or synapses loss.

They are currently completing a phase 1/2 (initiated in summer 2019) with results expected within the second half of this year. Not sure if it will drop closer to the end though.

 

[Lucifer]

They are currently completing a phase 1/2 (initiated in summer 2019) with results expected within the second half of this year. Not sure if it will drop closer to the end though.

Has a Research News thread for OTO-413 been created on Tinnitus Talk? I want to know more about it.

 

[Diesel]

I came across a video from a hearing doctor on YouTube uploaded last month (not associated with Frequency Therapeutics):



Apologies if this has been discussed before but I don't have the time these days to read everything. But the results that have implied efficacy is that it has increased word recognition (associated with hidden hearing loss) but has not effected pure tone hearing loss. He explains its likely to affect inner hair cell damage but not outer hair cell damage. So far, this only seems that Frequency Therapeutics may just help hearing aid users understand more word recognition while the hearing aids turn the actual volume up.

Am I missing something here, because so far, it would seem people labelling this as a 'cure' for HL exaggerated.

Just watched this video for the first time... While I acknowledge that he is a doctor and probably knows more than me about the science behind hearing loss, I feel like he didn't do all of his homework. Frequency, in its own presentation and prior Q&As have debunked some of his critiques of FX-322. As I watch this video I consider that we are seeing "old world" metrics being used to measure a "new world" solution. For example, the PTA comment was really a narrow-minded comment.

Much like we see those in favor of gasoline cars use re-fueling and range as a the measurement for Tesla, but disregarding all of the other benefits of electric vehicles... okay, I'll stop with the analogies.

I do like to see that he is increasing awareness of FX-322 with a fairly large audience. The greater awareness, the greater exposure to possible participants. It's also free advertising for Frequency Therapeutics, which is good for business.

I am also a little miffed about FX-322 being presented as a cure by a Doctor! No one should see FX-322 as a cure. It is a treatment. The expectations should be that as a treatment it may reverse damage/loss, and reduce symptoms.

 

[serendipity1996]

Thanks. I was going to ask for clarification regarding pain/discomfort hyperacusis.

Being in the same boat as yourself in that regard I am just hoping that the pain/discomfort I experience from those sounds don't then branch out to other sounds as well.

I hope so too. Basically with mine I was at a point even 2 months ago where I had to go outside with earplugs, pain/discomfort was pretty constant whereas now it's pretty much back to normal apart from on/off weird facial symptoms and the sensitivity to artificial audio... like logically it seems like it should also go away with time since everything else has too. So I think if there's been a general upward trajectory it's definitely encouraging I just feel so impatient.