Frequency Therapeutics — Hearing Loss Regeneration

[HootOwl]

byproduct of improved hearing

Byproduct of improved cochlear input at the proper frequency.

If you don't parse out all the permutations of what "improved hearing" actually is, you will likely misread the data.

What's important is to determine what structure is damaged, and how low it is in the cochlea. Unfortunately, none of us (outside of people with notable audiogram changes, and even then you still have structures undiagnosable through audiograms like IHC) know with utmost certainty what is actually dead in our cochleas. That's why regenerative medicine will always be a series of test treatments for tinnitus sufferers until diagnostics vastly improve. Many of us will likely have to try everything.

And that's even if we take inflammation off the table, which honestly, is vastly overlooked.

That's why eyes are on Sound Pharmaceuticals as well. Because it could be a significant factor for those who think they have hair cell or synaptic loss, but really their tinnitus could be due to a moderate to severe degree of inflammation that has persisted indefinitely.

 

[100Hz]

Agree 100 percent.

Among those of us suffering with hyperacusis, a typical hyperacusis patient profile is someone who experienced some kind of damage to the auditory system from either too much noise exposure over time or an acoustic shock, and has a "perfect" audiogram but debilitating hyperacusis and tinnitus. We can hear the tones just fine but something is clearly damaged in the hearing system and causes auditory symptoms not related to hearing tones at various frequencies.

This is why I'd love to see a spin off trial on people who are so debilitated they can't even leave the house or function around anything that involves noise, yet have good audiograms. Something else is going on. Yes, it would be trial treating but the results could potentially be more explosive than any audiogram gains. Imagine people who were suicidal and bed ridden for months / years who could all of a sudden, restart their careers, social lives, hobbies, even family life etc. because whatever it is that FX-322 is fixing first is what is massively broken in us. Our audiograms are fine, but we aren't. Something is screwed that isn't measurable and if FX-322 is fixing something un-measurable, then why not try it?

 

[Zugzug]

This is why I'd love to see a spin off trial on people who are so debilitated they can't even leave the house or function around anything that involves noise, yet have good audiograms. Something else is going on. Yes, it would be trial treating but the results could potentially be more explosive than any audiogram gains. Imagine people who could all of a sudden, restart their careers, social lives, hobbies, even family life etc. because whatever it is that FX-322 is fixing first is what is massively broken in us. Our audiograms are fine, but we aren't. Something is screwed that isn't measurable and if FX-322 is fixing something un-measurable, then why not try it?

I would love to sign a shitload of liability waivers and give anything a try. However, this is beyond a pipedream for the FDA. Many otologists roll their eyes at the notion that hyperacusis patients have auditory damage. No chance. The path forward is to draft behind people with hearing loss.

 

[FGG]

This is why I'd love to see a spin off trial on people who are so debilitated they can't even leave the house or function around anything that involves noise, yet have good audiograms. Something else is going on. Yes, it would be trial treating but the results could potentially be more explosive than any audiogram gains. Imagine people who could all of a sudden, restart their careers, social lives, hobbies, even family life etc. because whatever it is that FX-322 is fixing first is what is massively broken in us. Our audiograms are fine, but we aren't. Something is screwed that isn't measurable and if FX-322 is fixing something un-measurable, then why not try it?

In this sense, I think they were right to emphasize word scores. EHF was only an experimental endpoint after all so they weren't planning in relying on it for approval.

The trick is how do you ensure accuracy at baseline?

I wish we could hear their theories on the discrepancy but maybe after the trial is unblinded, we will.

 

[100Hz]

I would love to sign a shitload of liability waivers and give anything a try. However, this is beyond a pipedream for the FDA. Many otologists roll their eyes at the notion that hyperacusis patients have auditory damage. No chance. The path forward is to draft behind people with hearing loss.

I completely agree with you, but I dream.

 

[Greg Sacramento]

@Zugzug, @FGG:

Some articles I had in my library. They may be outdated - I have not completely re-read in a while.

• Niche-Independent High-Purity Cultures of LGR5+ Intestinal Stem Cells and Their Progeny
• Influence of Tinnitus on Auditory Spectral and Temporal Resolution and Speech Perception in Tinnitus Patients - PubMed
• Mechanisms of tinnitus | British Medical Bulletin | Oxford Academic (oup.com)
• Pathophysiology of Subjective Tinnitus: Triggers and Maintenance

 

[GlennS]

The audiogram measures a small part of hearing

I've been here, I dunno, about 2 years I've never, ever heard anyone quantify their hearing health with word score tests, only with audiograms. Audiograms were also a pre-screen for Lenire and I would assume would also be a key factor in any tinnitus treatment.

I think this attempt to disregard audiograms is bargaining.

 

[FGG]

@Zugzug, @FGG:

Some articles I had in my library. They may be outdated - I have not completely re-read in a while.

• Niche-Independent High-Purity Cultures of LGR5+ Intestinal Stem Cells and Their Progeny
• Influence of Tinnitus on Auditory Spectral and Temporal Resolution and Speech Perception in Tinnitus Patients - PubMed
• Mechanisms of tinnitus | British Medical Bulletin | Oxford Academic (oup.com)
• Pathophysiology of Subjective Tinnitus: Triggers and Maintenance

Thank you! I will read through these.

Even though it's Jastreboff (and he has weird, outdated and even victim blaming ideas about hyperacusis), this part was interesting and I remember seeing it elsewhere:

"Jastreboff noted that intense noise and ototoxic agents initially damage the basal turn of the cochlea, and outer hair cells (OHCs), and only later affect inner hair cells (IHCs) if continued or repeated, IHCs being more resistant to such damage"​

Which means the worse hearing, the more IHC damage (which fits the profile of those with worse word scores).

This theory below I haven't encountered before which suggests that tinnitus is either generated by damaged or destroyed OHCs being adjacent to a normal OHCs and causing erroneous transmission to a normal IHC or from an abnormal IHC being stimulated by a normal OHC. A mismatch, basically. If this theory is correct, it would explain why in my case, my worst tinnitus is at the edge of where my hearing drops off.

"Discordant damage of IHC and OHC
Jastreboff noted that intense noise and ototoxic agents initially damage the basal turn of the cochlea, and outer hair cells (OHCs), and only later affect inner hair cells (IHCs) if continued or repeated, IHCs being more resistant to such damage. The inference was made that, within a partially affected organ of Corti, there will be an area with both OHCs and IHCs affected, an area with OHCs are affected but IHCs are intact, and an area with both intact. In the second of these three categories, the coupling between the tectorial membrane and the basilar membrane would be affected, to the extent that the tectorial membrane might directly impinge upon the cilia of the IHCs, thus causing them to depolarise. Clinical support for such modification of auditory afferent activity leading to tinnitus perception has been cited, in that some patients with tinnitus and high-frequency hearing loss match their tinnitus frequency to the point at which the loss begins. The role that increased neural activity in the auditory periphery may have in tinnitus generation is considered in detail below. Jastreboff went on to consider not only the afferent activity generated by the IHCs, but also the possibility that afferent activity of the IHCs might be interpreted in the light of attempted (but failed) reduction of cochlear gain via OHCs, giving rise to increased perceived intensity. It was further suggested that this model might apply to both permanent and temporary discordant damage, the example of temporary damage being temporary tinnitus associated with temporary threshold shift following noise exposure. Chery-Croze et al noted that, in an area where IHC damage was present, any efferent inhibition of the OHCs in that area will be reduced due to the reduced afferent input. That efferent innervation may be shared with neighbouring OHCs partnering undamaged IHCs, due to the diffuse nature of efferent innervation (one fibre for 20–30 OHCs), and so the undamaged area neighbouring the damaged IHCs may also have reduced efferent inhibition, giving rise to a highly active area of the basilar membrane, resulting in tonal tinnitus."​

They also go into why the spontaneous otoacoustic peripheral generation of tinnitus theory is not supported by evidence either (it was discussed many pages back).

 

[FGG]

I've been here, I dunno, about 2 years I've never, ever heard anyone quantify their hearing health with word score tests, only with audiograms. Audiograms were also a pre-screen for Lenire and I would assume would also be a key factor in any tinnitus treatment.

I think this attempt to disregard audiograms is bargaining.

Audiograms are not useless. I think you are completely missing my point. But they are very specific for OHC damage.

 

[Zugzug]

@Zugzug, @FGG:

Some articles I had in my library. They may be outdated - I have not completely re-read in a while.

• Niche-Independent High-Purity Cultures of LGR5+ Intestinal Stem Cells and Their Progeny
• Influence of Tinnitus on Auditory Spectral and Temporal Resolution and Speech Perception in Tinnitus Patients - PubMed
• Mechanisms of tinnitus | British Medical Bulletin | Oxford Academic (oup.com)
• Pathophysiology of Subjective Tinnitus: Triggers and Maintenance

@Greg Sacramento if I ever cheat on my wife, it will be with you. Just playing, friend.

 

[Zugzug]

Audiograms are not useless. I think you are completely missing my point. But they are very specific for OHC damage.

I don't think you're wrong, but I tend to side with @GlennS on this for a widespread efficacy study. Do I think there are people with normal audiograms and bad speech? Absolutely. Do I think n=96 people saw groupwide no changes in any PTA, including EHF, and it was largely because of design issues? I do not.

Honestly, I think you two might be arguing about different things. I think @FGG is arguing that it's important to make sense of IHC vs OHC for diagnostics and @GlennS is arguing that no matter how we slice it, the drug currently isn't good enough. Both are right, IMO.

 

[ColinUK]

Where is the feedback from tinnitus? Prior to this Carl LeBel said there was anecdotal reports of tinnitus being improved people coming forward to tell their audiologists, people on here have claimed to know people in the trial that said their tinnitus improved... so where is there any measurement or reports of that surely there should be something.

Even if hearing hadn't improved dramatically but some people reported their tinnitus vanished or improved that would be a massive win and another avenue to explore.

But what to believe someone somewhere is lying and again to me none of this adds up or sits right. We have gone from improved WR, improved standard audiograms, anecdotal reports of improvement in tinnitus to nothing... How does that happen?

 

[GlennS]

I think you are completely missing my point.

When I got my audiogram done, it verified my belief that the hearing in my left ear was worse than my right. And that's also (surprise surprise) where my worse tinnitus symptoms are. Funny how the two tend to correspond, isn't it? I'm not trying to disregard the complexities of the auditory system but that should not be cited as an attempt to paper-over FX-322's poor test results.

I mean, let's all be honest. If, hypothetically, test subject audiograms dramatically improved I'm sure you and others would be citing that as a proof that FX-322 is the holy grail, but since audiograms are unchanged then suddenly we're supposed to read through 100s of pages of medical mumbo jumbo to somehow imply that it could still (counter-intuitive as it may be) work for us.

While I'm not saying it's impossible, it seems highly unlikely.

All we really care about is whether this works. Sure, at an academic level it might still be a useful incremental step along the way to determine FX-322 at least successfully regenerates part of the necessary whole, but that's not what all of us were on pins and needles over, was it? I also doubt that's what investors were expecting either.

 

[Tezcatlipoca]

I don't think you're wrong, but I tend to side with @GlennS on this for a widespread efficacy study. Do I think there are people with normal audiograms and bad speech? Absolutely. Do I think n=96 people saw groupwide no changes in any PTA, including EHF, and it was largely because of design issues? I do not.

Honestly, I think you two might be arguing about different things. I think @FGG is arguing that it's important to make sense of IHC vs OHC for diagnostics and @GlennS is arguing that no matter how we slice it, the drug currently isn't good enough. Both are right, IMO.

We always knew it wasn't good enough, we were hopeful because of the tinnitus anecdotes.

 

[Philip83]

I know anecdotes are to some extent useless, but man I would like to hear some from the people who were in Phase 1. By hearing them articulate their improvements I think it would be possible to gauge how legit they were.

For example, the Lenire testimonials (on video!) were utter crap. I would love some sit-down interviews with the FX-322 participants, whether they be crap or not.

 

[Zugzug]

When I got my audiogram done, it verified my belief that the hearing in my left ear was worse than my right. And that's also (surprise surprise) where my worse tinnitus symptoms are. Funny how the two tend to correspond, isn't it? I'm not trying to disregard the complexities of the auditory system but that should not be cited as an attempt to paper-over FX-322's poor test results.

I mean, let's all be honest. If, hypothetically, test subject audiograms dramatically improved I'm sure you and others would be citing that as a proof that FX-322 is the holy grail, but since audiograms are unchanged then suddenly we're supposed to read through 100s of pages of medical mumbo jumbo to somehow imply that it could still (counter-intuitive as it may be) work for us.

While I'm not saying it's impossible, it seems highly unlikely.

All we really care about is whether this works. Sure, at an academic level it might still be a useful incremental step along the way to determine FX-322 at least successfully regenerates part of the necessary whole, but that's not what all of us were on pins and needles over, was it? I also doubt that's what investors were expecting either.

To be fair, I don't think @FGG is arguing that Phase 2a was secretly a success. I think she's trying to damage control the notion that the science is all a hoax. She has even said that she thinks Phase 2 will need to be redone.

The drug failed. Everyone agrees.

 

[FGG]

I don't think you're wrong, but I tend to side with @GlennS on this for a widespread efficacy study. Do I think there are people with normal audiograms and bad speech? Absolutely. Do I think n=96 people saw groupwide no changes in any PTA, including EHF, and it was largely because of design issues? I do not.

Honestly, I think you two might be arguing about different things. I think @FGG is arguing that it's important to make sense of IHC vs OHC for diagnostics and @GlennS is arguing that no matter how we slice it, the drug currently isn't good enough. Both are right, IMO.

In terms of objective data, yes the FDA would like to see audiogram because it's a great standard metric. Zero disagreement.

But the OHC/IHC distinction is actually important for determining if the drug is "good enough" to help people (regardless of what the FDA would like).

Think of it this way: hearing aids are a surrogate for OHCs. They increase loudness only. Audiograms match this and are an excellent tool for hearing aid fitting.

Hearing aids do not improve clarity once you have lost it. Part of clarity is improving loudness so you hear all the parts of sound but IHCs/synapses are extremely important for clarity because that's where sound is transmitted to the auditory nerve after OHCs first make them louder.

Doubling word scores can mean IHC regeneration, for instance. And that's not "the drug isn't good enough" that's "this can really help a certain patient."

In pre clinical they were able to generate both in the mouse, however mice don't have a patent cochlear aqueduct like people do so it is possible the drug "sat" long enough to do IHCs first and then OHCs. There is clearly a difference but it worked in explants and it doubled word scores in Phase 1. There is a notable hearing effect if it's not fraud.

What will determine this for me is the severe group. They have a much higher chance of both more damaged IHCs and lower natural word scores.

 

[GlennS]

We always knew it wasn't good enough

 

[Philip83]

"Frequency Therapeutics throws a left punch, but misses! Otonomy counters with an upper-cut!"

Otonomy Initiates Phase 2 Clinical Trial of OTO-313 in Tinnitus

 

[Zugzug]

I know anecdotes are to some extent useless, but man I would like to hear some from the people who were in Phase 1. By hearing them articulate their improvements I think it would be possible to gauge how legit they were.

For example, the Lenire testimonials (on video!) were utter crap. I would love some sit-down interviews with the FX-322 participants, whether they be crap or not.

True anecdotes (not faking or whatever) have a very valuable place in science if they really aren't explained by other things.

They are 100% useless for proving something works widespread, but they are super important for intellectual discovery.

The main issue with the tinnitus anecdotes is the challenge in verifying that it was from the drug. I'm at least a little more interested in the WR anecdotes because word scores never improve like that (doubling) just from being more alert, test variation, etc.

I have read the papers, and test-retest stability is something that has been studied plenty. Of the 3 super responders in Phase 1/2, there's no way all 3 just improved that much just by pure chance. Now, to be fair, it doesn't mean it's from the drug either. It could be by study design or testing inconsistencies, but it's just not possible that all 3 improved like that my chance. These are anecdotes to better understand.

 

[Philip83]

The main issue with the tinnitus anecdotes is the challenge in verifying that it was from the drug. I'm at least a little more interested in the WR anecdotes because word scores never improve like that (doubling) just from being more alert, test variation, etc.

I agree, I meant mainly anecdotes or results in general - hearing, tinnitus, etc. Hearing affects a lot of things in one's perception of "life" so to say, as we all know.

 

[Street Novelist]

So, we just wait and hope for the best? Will Lucchino or anyone else be making any more statements?

 

[FGG]

I have read the papers, and test-retest stability is something that has been studied plenty. Of the 3 super responders in Phase 1/2, there's no way all 3 just improved that much just by pure chance. Now, to be fair, it doesn't mean it's from the drug either. It could be by study design or testing inconsistencies, but it's just not possible that all 3 improved like that my chance. These are anecdotes to better understand.

That's why the binary is this for me: the drug does something very significant for hearing (even if it's not OHCs with one dose and rapid redosing is problematic) or Phase 1 is fraudulent in some way. To me, that's the thing to zero in on.

 

[Zugzug]

In terms of objective data, yes the FDA would like to see audiogram because it's a great standard metric. Zero disagreement.

But the OHC/IHC distinction is actually important for determining if the drug is "good enough" to help people (regardless of what the FDA would like).

Think of it this way: hearing aids are a surrogate for OHCs. They increase loudness only. Audiograms match this and are an excellent tool for hearing aid fitting.

Hearing aids do not improve clarity once you have lost it. Part of clarity is improving loudness so you hear all the parts of sound but IHCs/synapses are extremely important for clarity because that's where sound is transmitted to the auditory nerve after OHCs first make them louder.

Doubling word scores can mean IHC regeneration, for instance. And that's not "the drug isn't good enough" that's "this can really help a certain patient."

In pre clinical they were able to generate both in the mouse, however mice don't have a patent cochlear aqueduct like people do so it is possible the drug "sat" long enough to do IHCs first and then OHCs. There is clearly a difference but it worked in explants and it doubled word scores in Phase 1. There is a notable hearing effect if it's not fraud.

What will determine this for me is the severe group. They have a much higher chance of both more damaged IHCs and lower natural word scores.

I hear what you're saying. Sorry if it seems like I'm being obtuse to the idea of normal OHC, but poor sound quality. I definitely understand the frustrations of this idea since I have horrific hyperacusis, but with normal audiograms. It's all definitely super complex.

For me, my issue is so much more with the statistics of damage distribution. As you noted above in response to @Greg Sacramento, it appears that OHC die first, on average. So my big issue is that if we have n=96 patients who are selected, we should have enough people with more OHC than IHC damage so that even if the in utero concept of IHC regrowing before OHC occurs, there should still be audiogram changes from this group — at least definitely in the EHF range. Calibration is more of an issue, but I want to see more evidence, and by default, I'm going to assume it's negligible since all of the other PTA were unchanged.

This is how I see the problem. Imagine like a radial, infinitesimally small cut out slice from the cochlea. There's some distribution of OHC vs IHC loss based on patient selection filters. For the trials to be impacted by this idea, the patients would (largely across the board) have to have greater IHC than OHC across all cut outs, in order for the drug to fill up the IHC growth before starting OHC growth.

Now, if they tried really hard to select patients to fit this theory, maybe something interesting could be seen. I just really struggle with the lack of EHF PTA. And @GlennS does make some degree of a point, which is that if the EHF PTA results were good, we would celebrate them.

The IHC vs OHC theory is useful for diagnostics though. You probably agree with most of what I said, but I'm just making my position clear.

 

[FGG]

I hear what you're saying. Sorry if it seems like I'm being obtuse to the idea of normal OHC, but poor sound quality. I definitely understand the frustrations of this idea since I have horrific hyperacusis, but with normal audiograms. It's all definitely super complex.

For me, my issue is so much more with the statistics of damage distribution. As you noted above in response to @Greg Sacramento, it appears that OHC die first, on average. So my big issue is that if we have n=96 patients who are selected, we should have enough people with more OHC than IHC damage so that even if the in utero concept of IHC regrowing before OHC occurs, there should still be audiogram changes from this group — at least definitely in the EHF range. Calibration is more of an issue, but I want to see more evidence, and by default, I'm going to assume it's negligible since all of the other PTA were unchanged.

This is how I see the problem. Imagine like a radial, infinitesimally small cut out slice from the cochlea. There's some distribution of OHC vs IHC loss based on patient selection filters. For the trials to be impacted by this idea, the patients would (largely across the board) have to have greater IHC than OHC across all cut outs, in order for the drug to fill up the IHC growth before starting OHC growth.

Now, if they tried really hard to select patients to fit this theory, maybe something interesting could be seen. I just really struggle with the lack of EHF PTA. And @GlennS does make some degree of a point, which is that if the EHF PTA results were good, we would celebrate them.

The IHC vs OHC theory is useful for diagnostics though. You probably agree with most of what I said, but I'm just making my position clear.

The exception though is the severe population. They should have more people with IHC damage.

 

[Zugzug]

The exception though is the severe population. They should have more people with IHC damage.

I have a question about this actually. So I do agree with you that more total loss greatly raises the chances of IHC loss.

But isn't there at least some component of OHC to WR? Like don't they play the words at a fixed volume?

In the Wilson and McArdle paper, they looked at WIN stability. Something really caught my eye that I found surprising. Essentially, in the second part of the paper, they had two groups: Group 1 was mild-to-severe and Group 2 was moderate-to-severe. They looked at retest reliability of the WIN test (FYI, this paper is where they calculate the 50% correct SNR per the Spearman-Karber formula and basically show that retesting is reliable with large sample sizes. Hence why Frequency Therapeutics used the same technique.)

Anyways, the following caught my idea. So to do the WIN test, they calibrated it as follows.

• Have Group 1 take WR at 60 and 80 dB HL
• Have Group 2 take WR at 70 and 90 dB HL
• On the SIN test, 0 dB SNR basically meant the "noise" and "signal" were of equal volume (hence, amounts to practically all noise and why most people don't get anything correct). And 24 dB SNR is the maximum. The process consisted of decrements in the form SNR: 24-20-16-12-8-4-0.
• Group 1 had the SIN test taken twice with the "noise" babble fixed at 60 dB for the first trial and then fixed at 80 dB for the second.
• Group 2 had the SIN test taken twice with the "noise" babble fixed at 70 dB for the first trial and then fixed at 90 dB for the second.

Okay, sorry, that was a lot to just say this. They observed that it didn't really matter where they shifted the starting point. All that mattered (mostly) for this test was separation. So if someone had horrible PTA and needed the noise babble fixed at a high volume, it didn't matter. All that mattered was that they could surely hear it. The SIN test was then almost entirely independent of this volume choice and was entirely based on those 4 dB separations between signal and noise.

So roughly speaking, if Group 1 had the noise babble at 60 dB, when the SNR was 12 dB (so total speech signal was 72 dB), their performance would be similar to if the noise babble started at 80 dB (so the total speech signal was 92 dB).

This fact also agreed with previous literature (Wilson, 2003). I found this completely surprising.

So, my question is, for the WR test, how much does this shifting idea matter? I am asking because for the severe group, they might need to have the words blasted at them. But how do we calibrate this? It seems surprising to me that volume wouldn't have some impact on speech perception. What do you think of this?

 

[FGG]

I have a question about this actually. So I do agree with you that more total loss greatly raises the chances of IHC loss.

But isn't there at least some component of OHC to WR? Like don't they play the words at a fixed volume?

In the Wilson and McArdle paper, they looked at WIN stability. Something really caught my eye that I found surprising. Essentially, in the second part of the paper, they had two groups: Group 1 was mild-to-severe and Group 2 was moderate-to-severe. They looked at retest reliability of the WIN test (FYI, this paper is where they calculate the 50% correct SNR per the Spearman-Karber formula and basically show that retesting is reliable with large sample sizes. Hence why Frequency Therapeutics used the same technique.)

Anyways, the following caught my idea. So to do the WIN test, they calibrated it as follows.

• Have Group 1 take WR at 60 and 80 dB HL
• Have Group 2 take WR at 70 and 90 dB HL
• On the SIN test, 0 dB SNR basically meant the "noise" and "signal" were of equal volume (hence, amounts to practically all noise and why most people don't get anything correct). And 24 dB SNR is the maximum. The process consisted of decrements in the form SNR: 24-20-16-12-8-4-0.
• Group 1 had the SIN test taken twice with the "noise" babble fixed at 60 dB for the first trial and then fixed at 80 dB for the second.
• Group 2 had the SIN test taken twice with the "noise" babble fixed at 70 dB for the first trial and then fixed at 90 dB for the second.

Okay, sorry, that was a lot to just say this. They observed that it didn't really matter where they shifted the starting point. All that mattered (mostly) for this test was separation. So if someone had horrible PTA and needed the noise babble fixed at a high volume, it didn't matter. All that mattered was that they could surely hear it. The SIN test was then almost entirely independent of this volume choice and was entirely based on those 4 dB separations between signal and noise.

So roughly speaking, if Group 1 had the noise babble at 60 dB, when the SNR was 12 dB (so total speech signal was 72 dB), their performance would be similar to if the noise babble started at 80 dB (so the total speech signal was 92 dB).

This fact also agreed with previous literature (Wilson, 2003). I found this completely surprising.

So, my question is, for the WR test, how much does this shifting idea matter? I am asking because for the severe group, they might need to have the words blasted at them. But how do we calibrate this? It seems surprising to me that volume wouldn't have some impact on speech perception. What do you think of this?

Speech in noise is more specific to synaptopathy. But yes you need it at a volume you can hear.

 

[kiki]

Do you think that FX-322 has no chance of improving audiograms in the future, no matter what improvements they make?

 

[FGG]

Do you think that FX-322 has no chance of improving audiograms in the future, no matter what improvements they make?

Imo that depends on whether Phase 1 participants were legit and what is causing the hearing signal (ie there is a scenario where esp multiple properly spaced doses could have more notable audiogram changes).

 

[Zugzug]

Do you think that FX-322 has no chance of improving audiograms in the future, no matter what improvements they make?

Depends on your definition of the future. There's almost a 100% chance that something will help in the next 10-20 years. How soon they improve delivery will be a major factor in determining this.