Frequency Therapeutics — Hearing Loss Regeneration

[Juan]

I'm not following you. All tinnitus is ultimately heard in the auditory cortex, no? It is not the result of external stimulus unless you have something like pulsatile tinnitus.

Sometimes it reacts to external stimulus and it is not pulsatile tinnitus. It increases with sound = reactive tinnitus. Or you heard it like a filter "before" the other sounds, in the same way you can set the black and white mode as a filter on a camera, and there is another kind that does not exactly increase with sound but changes and is perceived not like a filter either. It is hard to describe, you have to experience it. Well, or better not.

 

[FGG]

Sometimes it reacts to external stimulus and it is not pulsatile tinnitus. It increases with sound = reactive tinnitus. Or you heard it like a filter "before" the other sounds, in the same way you can set the black and white mode as a filter on a camera, and there is another kind that does not exactly increase with sound but changes and is perceived not like a filter either. It is hard to describe, you have to experience it. Well, or better not.

I have had reactive tinnitus. I think it's a form of hyperacusis where you hear certain sounds very loud that would normally be a small component of complex sounds. The reason I think is that one of these sounds was familiar to me.

I could hear the sound of a CD being read as louder than music. Something you could normally only hear before music starts. After experiencing this, I think it's a central interpretation of peripheral inflammation personally but most of the reactive tones aren't as recognizable.

 

[jeff W]

I have had reactive tinnitus. I think it's a form of hyperacusis where you hear certain sounds very loud that would normally be a small component of complex sounds. The reason I think is that one of these sounds was familiar to me.

I could hear the sound of a CD being read as louder than music. Something you could normally only hear before music starts. After experiencing this, I think it's a central interpretation of peripheral inflammation personally but most of the reactive tones aren't as recognizable.

Reactive tinnitus is ridiculed by many clinicians.........all of whom have never experienced the phenomenon.

 

[Juan]

I have had reactive tinnitus. I think it's a form of hyperacusis where you hear certain sounds very loud that would normally be a small component of complex sounds. The reason I think is that one of these sounds was familiar to me.

That makes sense. Sounds amplified by hyperacusis could be sounds that cannot hit the right hair cells at the organ of corti and travel through the right connections and pathways to the brain. So that could be the reason why before hyperacusis one can hear sounds lower (they hit the right hair cells and connections, a wide array of them) and after hyperacusis one hears sometimes "duller" sounds but louder.

 

[Zugzug]

Does anyone have a feeling about how restrictive FX-322 will be? I read that it's for people with "stable" hearing loss. Does this mean if it's driven by systemic diseases (like autoimmune), they won't allow people to try it? My instinct says no, but safety seems to be emphasized so I wonder if it would be viable. I should have added this to the questions to ask for the Tinnitus Talk Podcast interview with Frequency Therapeutics, but I'm a doofus.

 

[Tweedleman]

The paper seemed to imply at the end that they thought the cell would die if they couldn't save it by regenerating the bundle. At least that's how I read it. There seemed to be a reason they stopped at 14 days and I think it was to show that in mammals the bundle didn't regenerate and the other thought reversing that (as in frogs, chicks) might prevent that.

I'm just worried that many of us may have lighter stereocilia damage than the amount purposefully inflicted ("ablated") in this study. Perhaps not enough hair bundle damage to kill the hair cell, but enough that it is partially dysfunctional. I suppose it doesn't matter if FX-322 can still replace or address such hair cells. It's reassuring that Frequency said, "damaged or destroyed." You would think that if they could only address totally dead hair cells then they would have just said, "destroyed." We definitely need to follow up with them on this, though. I hope it's not a case where they mean "damaged, as in destroyed."

 

[GlennS]

I was under the impression that there are two types of hair cells, one that picks up the signal and one that controls the "gain" and that in hyperacusis, the latter is damaged and permanently boosts perceived volume in high frequencies. I certainly get the sense that hearing has a gain component to it like how the iris controls visual exposure.

 

[FGG]

I'm just worried that many of us may have lighter stereocilia damage than the amount purposefully inflicted ("ablated") in this study. Perhaps not enough hair bundle damage to kill the hair cell, but enough that it is partially dysfunctional. I suppose it doesn't matter if FX-322 can still replace or address such hair cells. It's reassuring that Frequency said, "damaged or destroyed." You would think that if they could only address totally dead hair cells then they would have just said, "destroyed." We definitely need to follow up with them on this, though. I hope it's not a case where they mean "damaged, as in destroyed."

Well stereocilia damage short of loss (based on first link) is cross tip link breakage and actin damage. Both of which apparently can repair themselves per the first study.

Also, did you read the second study? They said the cross linking was so strong they doubted the previous studies on stereocilia damage were able to remove them without manual dissection and suction. I think that means major damage isn't much (if at all) a contributing factor and minor damage seems linked more with TTS than permanent damage.

 

[FGG]

I was under the impression that there are two types of hair cells, one that picks up the signal and one that controls the "gain" and that in hyperacusis, the latter is damaged and permanently boosts perceived volume in high frequencies. I certainly get the sense that hearing has a gain component to it like how the iris controls visual exposure.

There is peripheral gain (normal physiologic) and "central gain". The central gain is from maladaptive plasticity in response to reduced peripheral (cochlear) function.

 

[FGG]

Does anyone have a feeling about how restrictive FX-322 will be? I read that it's for people with "stable" hearing loss. Does this mean if it's driven by systemic diseases (like autoimmune), they won't allow people to try it? My instinct says no, but safety seems to be emphasized so I wonder if it would be viable. I should have added this to the questions to ask for the Tinnitus Talk Podcast interview with Frequency Therapeutics, but I'm a doofus.

They list their inclusion/exclusion criteria for the study on clinicaltrials.gov. Chronic, active disease in an exclusion for the trial but that wouldn't mean you couldn't try the drug when it comes to market.

 

[Juan]

I was under the impression that there are two types of hair cells, one that picks up the signal and one that controls the "gain" and that in hyperacusis, the latter is damaged and permanently boosts perceived volume in high frequencies. I certainly get the sense that hearing has a gain component to it like how the iris controls visual exposure.

Adding Insult to Injury: Cochlear Nerve Degeneration after "Temporary" Noise-Induced Hearing Loss

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812055/

There are pictures of hair cells etc, quite informative...

 

[FGG]

Adding Insult to Injury: Cochlear Nerve Degeneration after "Temporary" Noise-Induced Hearing Loss

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812055/

There are pictures of hair cells etc, quite informative...

Keep in mind that since this study, they have found that rodent SGNs are completely different from humans and very deafened (over decades even) humans often have completely normal SGNs based on human autopsy studies.

 

[serendipity1996]

Keep in mind that since this study, they have found that rodent SGNs are completely different from humans and very deafened (over decades even) humans often have completely normal SGNs based on human autopsy studies.

Wow that's really interesting - do you have a link to the paper containing this?

Good point to add.

 

[FGG]

Wow that's really interesting - do you have a link to the paper containing this?

Good point to add.

I can't locate the exact paper I originally referenced (I believe it is buried somewhere on this thread ages ago, though) but if you look at recent papers in PubMed, you can see many papers highlighting this difference. I have included one below. This is why CIs work even in the long deaf (they wouldn't work in long deafened rodents by comparison).

http://www.nrronline.org/article.as...ue=5;spage=710;epage=712;aulast=Rask-Andersen

 

[Juan]

Keep in mind that since this study, they have found that rodent SGNs are completely different from humans and very deafened (over decades even) humans often have completely normal SGNs based on human autopsy studies.

So there's no hope? :-P

 

[FGG]

So there's no hope? :-P

Quite the opposite, actually.

 

[Tweedleman]

Well stereocilia damage short of loss (based on first link) is cross tip link breakage and actin damage. Both of which apparently can repair themselves per the first study.

Also, did you read the second study? They said the cross linking was so strong they doubted the previous studies on stereocilia damage were able to remove them without manual dissection and suction. I think that means major damage isn't much (if at all) a contributing factor and minor damage seems linked more with TTS than permanent damage.

This is what is tripping me up in the first link:
"Many other changes in stereocilia F-actin cores have been observed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM) following traumatic noise exposure, including actin depolymerization, loss of F-actin crosslinkers, rootlet breakage, and stereocilia fusion [33–36]. A reduction in stereocilia number, variability in stereocilia height and width, and gaps in fluorescent phalloidin signal in the F-actin stereocilia core have also been shown following noise exposure [37]. The physiological relevance of these gaps is not known, but they likely represent areas of F-actin depolymerization or disorganization, which would decrease bundle stiffness and sensitivity"

 

[FGG]

This is what is tripping me up in the first link:
"Many other changes in stereocilia F-actin cores have been observed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM) following traumatic noise exposure, including actin depolymerization, loss of F-actin crosslinkers, rootlet breakage, and stereocilia fusion [33–36]. A reduction in stereocilia number, variability in stereocilia height and width, and gaps in fluorescent phalloidin signal in the F-actin stereocilia core have also been shown following noise exposure [37]. The physiological relevance of these gaps is not known, but they likely represent areas of F-actin depolymerization or disorganization, which would decrease bundle stiffness and sensitivity"

What you are quoting was talking about temporary threshold shift injury. The more severe injury (and these were in feline studies apparently, so who knows...) results in holes in the actin core and permanent threshold shifts per the link. Permanent shifts are associated with hair cell loss so presumably these are in cells that would be lost anyway. My take anyway.

But more importantly, if this was a significant issue, would be more obvious in the pre clinical and clinical studies if these regenerative drugs.

Remember that *all* phase 1 subjects had an increase in word score and had different levels of inciting damage.

I think you can always find ways to feed your anxiety that *something* will prevent healing but keep in mind:

The clinical data is what you should focus on because this is real world data in humans (which have key differences). If phase 2 shows uniform hearing and tinnitus improvements than esoteric hypothetical scenarios aren't likely to be clinically significant.

 

[Jorge1984]

If you guys can make a guess how much do you think FX-322 will cost?

 

[Diesel]

If you guys can make a guess how much do you think FX-322 will cost?

In their 10-K, they indicate their most prevalent competitor to FX-322 in the market today is primarily hearing aids. So, it stands to reason the price per "injection" will be comparable for it to be marketable. So, I would not be surprised if initially, FX-322 is as expensive as a set of high-end hearing aids.

I would guess a range of $3000 - $6000 for a set of injections (1 per ear).

 

[Jorge1984]

In their 10-K, they indicate their most prevalent competitor to FX-322 in the market today is primarily hearing aids. So, it stands to reason the price per "injection" will be comparable for it to be marketable. So, I would not be surprised if initially, FX-322 is as expensive as a set of high-end hearing aids.

I would guess a range of $3000 - $6000 for a set of injections (1 per ear).

Are you willing to spend all that money? Also I wonder if they will let people pay in payments.

 

[AtlasFainted]

Are you willing to spend all that money? Also I wonder if they will let people pay in payments.

I would definitely pay 6k for both ears.

Not just to be able to lay in silence again, but also to have my hearing regenerated.

I love music and other forms of media. While I still enjoy it, I know it would be even better if I could hear the full range of frequencies out of both ears.

As of now, higher pitched sounds always sound way louder in my left ear than my right. Across all other frequencies, I hear in more detail with my left ear, and sound is slightly louder in my left ear.

It is a strange sensation... I also can't hear cicadas chirping at all with my right ear which is off putting during walks outside.

While my left ear still hears great, it has tinnitus too.

6k to make all of this go away for life is nothing, and I am not a rich man.

 

[AtlasFainted]

Google the cochlear anatomy online. That should help clear it up. There are no synapses inside hair cells. Synapses connect inner hair cells to the spiral ganglion neurons.

I'll do that! I saw an image from the Liberman interview I read that looked like synapses ran inside the hair cell, but I likely misinterpeted said image.

 

[all to gain]

Are you willing to spend all that money? Also I wonder if they will let people pay in payments.

I know this was a question for someone else, but I would definitely spend all that money. And I am far from rich.
Even to get a 25% reduction in my tinnitus would be something, but I'm hoping for more and also hoping for a good improvement in my hearing.

Good question about installments. My guess is yes if you are a citizen of and resident in the USA, and no if you are coming from abroad. Hopefully though we will be able to shop around for providers offering different deals. Of course, if we need multiple courses of the drug then the cost is going to stack up.

But first things first: Let's just hope it makes it to the market and is shown to be low on side effects.

 

[Jorge1984]

I would definitely pay 6k for both ears.

Not just to be able to lay in silence again, but also to have my hearing regenerated.

I love music and other forms of media. While I still enjoy it, I know it would be even better if I could hear the full range of frequencies out of both ears.

As of now, higher pitched sounds always sound way louder in my left ear than my right. Across all other frequencies, I hear in more detail with my left ear, and sound is slightly louder in my left ear.

It is a strange sensation... I also can't hear cicadas chirping at all with my right ear which is off putting during walks outside.

While my left ear still hears great, it has tinnitus too.

6k to make all of this go away for life is nothing, and I am not a rich man.

Alright you changed my my mind I'll definitely spend my money on this I wanna lay on my bed too in silence. Whatever it takes imma work my butt off to pay for the injections. Screw tinnitus!

 

[FGG]

I'll do that! I saw an image from the Liberman interview I read that looked like synapses ran inside the hair cell, but I likely misinterpeted said image.

This image maybe?

I can see how it could look like the synapse somehow is inside the cell on that one. Maybe this one would be better:

 

[xyz]

I would guess a range of $3000 - $6000 for a set of injections (1 per ear).

If someday some tinnitus treatment with proven efficacy comes to market it will probably a bit more expensive (I think Lenire is already 2k - 3k). However I hope it is covered by insurance otherwise I would just as well spend my whole savings on it.

 

[Diesel]

Are you willing to spend all that money? Also I wonder if they will let people pay in payments.

Absolutely. Even at the high estimate, in the long run it pays for itself; especially when compared to 1 replacement cycle of hearing aids; roughly 5 years. This doesn't take into consideration quality-of-life benefits and associated monetary returns (education, career, income); which are likely several factors greater than the expense!

 

[Tweedleman]

I would definitely pay 6k for both ears.

Not just to be able to lay in silence again, but also to have my hearing regenerated.

I love music and other forms of media. While I still enjoy it, I know it would be even better if I could hear the full range of frequencies out of both ears.

As of now, higher pitched sounds always sound way louder in my left ear than my right. Across all other frequencies, I hear in more detail with my left ear, and sound is slightly louder in my left ear.

It is a strange sensation... I also can't hear cicadas chirping at all with my right ear which is off putting during walks outside.

While my left ear still hears great, it has tinnitus too.

6k to make all of this go away for life is nothing, and I am not a rich man.

Do you hear your own voice better out of your left? That's been the worst part for me. It's like my left ear just steals letters away from the right, really screwed up my imaging of words

 

[Jorge1984]

I know this was a question for someone else, but I would definitely spend all that money. And I am far from rich.
Even to get a 25% reduction in my tinnitus would be something, but I'm hoping for more and also hoping for a good improvement in my hearing.

Good question about installments. My guess is yes if you are a citizen of and resident in the USA, and no if you are coming from abroad. Hopefully though we will be able to shop around for providers offering different deals. Of course, if we need multiple courses of the drug then the cost is going to stack up.

But first things first: Let's just hope it makes it to the market and is shown to be low on side effects.

Don't worry man. Anyone can answer the question. I personally can't wait to put my money to good use. Hopefully we are able to pay in payments.