Frequency Therapeutics — Hearing Loss Regeneration

[Jrblovsky]

The odds of losing at the casino and on this stock are not in favor of the house. Hang it up dude. The stuff doesn't work.

It does though.

How do you figure?

Just to show another discredit to your theory, I had a hearing test on December 30th. I was at a 70 dB loss at 8 kHz. I had another hearing test last week, I was at a 50 dB loss at 8 kHz. My hearing loss has floated 20 dB in under 90 days. Can I hear better now; nope. I had other frequencies go up as well. Same testing equipment both times.

The minimal improvements are moot. Until they show lateral improvements across the board, it's a failure. Hopefully I can be reformed and it will work but presently it doesn't.

 

[Keith Handy]

restoring one row of OHCs does not produce large audiogram changes (e.g., as in the study @Diesel posted), "delivery" is not the main issue, it's the need for multi dosing (at bigger intervals).

I'm using "delivery" as a broader term which includes dosing schedules and such. Not sure if we are all using this word the same way.

 

[FGG]

I'm using "delivery" as a broader term which includes dosing schedules and such. Not sure if we are all using this word the same way.

I'm sure that's true. I was using it there as synonymous with "penetrance" because that's the context it's most often brought up but there is a broader meaning that includes other aspects.

 

[Zugzug]

How do you figure?

Just to show another discredit to your theory, I had a hearing test on December 30th. I was at a 70 dB loss at 8 kHz. I had another hearing test last week, I was at a 50 dB loss at 8 kHz. My hearing loss has floated 20 dB in under 90 days. Can I hear better now; nope. I had other frequencies go up as well. Same testing equipment both times.

The minimal improvements are moot. Until they show lateral improvements across the board, it's a failure. Hopefully I can be reformed and it will work but presently it doesn't.

I agree that it failed. However, trust me, if they did demonstrate a >=20 dB improvement on PTA compared to placebo, it is way too unrealistic to describe that as a failure. With what we currently have, that kind of improvement would be considered a miracle. Breakthrough Therapy status, no sweat.

I'm not trying to be calloused to your QoL, as there's no way FX-322 would ever make or break my situation either, but the standard for this drug can't be 30 dB improvements on audiograms. In my opinion, we should be very, very critical of the drug not even achieving incremental change, which it has failed to demonstrate thus far.

 

[FGG]

Delivery could still be a big problem beyond just pushing deeper, couldn't it? For example, maybe it needs to maintain itself in the cochlea for a certain amount of time in order for IHC to grow in large amounts or for OHC to grow in any amount. I realize the rebuttal is that if the IHC are all regrown after >=1 passes, then the drug could immediately start working on OHC at future passes. I'm not sold on this. Maybe it helps some IHC and due to quick decay (bad delivery), it's impossible for it to fully revitalize a full layer of hair cells. Is that possible?

The pharmacokinetic should show the "decay" so it doesn't appear that it's a main issue.

Agree on terminology though. Maybe we should just use "penetrance" when discussing that aspect.

 

[Zugzug]

The pharmacokinetic should show the "decay" so it doesn't appear that it's a main issue.

Agree on terminology though. Maybe we should just use "penetrance" when discussing that aspect.

Oh, I just mean like the decay is too quick for what the situation calls for in vivo compared to in vitro. Maybe this could be addressed with the same delivery, but a different formulation. It looks like, by the true definition of delivery, the drug will not penetrate past 6-8 kHz. So it looks like there are multiple issues going on. The lack of EHF PTA is extremely concerning, as that has nothing to do with penetrance.

 

[FGG]

Oh, I just mean like the decay is too quick for what the situation calls for in vivo compared to in vitro. Maybe this could be addressed with the same delivery, but a different formulation. It looks like, by the true definition of delivery, the drug will not penetrate past 6-8 kHz. So it looks like there are multiple issues going on. The lack of EHF PTA is extremely concerning, as that has nothing to do with penetrance.

You mean like the drug has to "sit" longer for OHCs than IHCs separate from just a preference issue? I suppose that's possible but definitely not my first thought.

 

[Zugzug]

I'm not so sure "the bad news" is so bad. In the Phase 1/2, they observed a mixed batch of hearing loss levels based on audiogram. Mild -> Moderately Severe. Word score also varied dramatically at baseline as a result. And, as you pointed out numerous times, the randomization of different hearing classes just happening to end up in placebo vs drug raised some concerns.

With the severe trial, its a very specific population that must will fit a narrower window on both audiogram and word score. I would argue that at these levels, the audiogram and word score tests are actually more useful. So, we should expect there to be 30 "like" candidates; which minimizes the variability that caused a lot of debate from the Phase 1/2.

As far as the next two trials go - Que sera, sera.

Here's the thing though. Consider this graph from Phase 1/2, in particular the four data points furthest to the left (3 responders, 1 non-responder).

Let's say we go with the theory that IHC growth starts first and OHC is neglected. Notice that of those 4 people with low starting WR, two of the responders (top) started with disproportionately worse PTA than WR. Then we have the two data points furthest to the left, which are practically the same. One responded, one didn't. This is not good. The placebo data is harder to make sense of because everything was shifted in the direction of better hearing at baseline.

I think, more than just explainable theories like IHC vs OHC preference (which could be valid to some degree), there's a huge part of this that's just random. Like we literally don't know why some respond and some don't. This is what worries me.

 

[Diesel]

How do you figure?

Just to show another discredit to your theory, I had a hearing test on December 30th. I was at a 70 dB loss at 8 kHz. I had another hearing test last week, I was at a 50 dB loss at 8 kHz. My hearing loss has floated 20 dB in under 90 days. Can I hear better now; nope. I had other frequencies go up as well. Same testing equipment both times.

The minimal improvements are moot. Until they show lateral improvements across the board, it's a failure. Hopefully I can be reformed and it will work but presently it doesn't.

You're kind of validating the discussion on this thread as to why the audiogram is a poor standard for hearing.

 

[Lucifer]

Has anyone here been accepted into the severe hearing loss trial, or have signed up?

 

[Tezcatlipoca]

Here's the thing though. Consider this graph from Phase 1/2, in particular the four data points furthest to the left (3 responders, 1 non-responder).

Let's say we go with the theory that IHC growth starts first and OHC is neglected. Notice that of those 4 people with low starting WR, two of the responders (top) started with disproportionately worse PTA than WR. Then we have the two data points furthest to the left, which are practically the same. One responded, one didn't. This is not good. The placebo data is harder to make sense of because everything was shifted in the direction of better hearing at baseline.

I think, more than just explainable theories like IHC vs OHC preference (which could be valid to some degree), there's a huge part of this that's just random. Like we literally don't know why some respond and some don't. This is what worries me.

View attachment 44410

The fact that there are responders at all is a breakthrough in itself.

 

[FGG]

Here's the thing though. Consider this graph from Phase 1/2, in particular the four data points furthest to the left (3 responders, 1 non-responder).

Let's say we go with the theory that IHC growth starts first and OHC is neglected. Notice that of those 4 people with low starting WR, two of the responders (top) started with disproportionately worse PTA than WR. Then we have the two data points furthest to the left, which are practically the same. One responded, one didn't. This is not good. The placebo data is harder to make sense of because everything was shifted in the direction of better hearing at baseline.

I think, more than just explainable theories like IHC vs OHC preference (which could be valid to some degree), there's a huge part of this that's just random. Like we literally don't know why some respond and some don't. This is what worries me.

View attachment 44410

It's not "just random" though. There is a reason some respond and some don't and the responders all respond with Word Score responses. Which suggests IHC preference.

It just makes sense that the worse your word score is, the more wide spread your IHC loss is going to be so the drug will address these losses (in the especially higher frequencies).

It would be nice obviously if there was the equivalent of an audiogram for IHCs to tell you where you have IHC losses but there isn't such a diagnostic test unfortunately.

 

[Diesel]

Here's the thing though. Consider this graph from Phase 1/2, in particular the four data points furthest to the left (3 responders, 1 non-responder).

Let's say we go with the theory that IHC growth starts first and OHC is neglected. Notice that of those 4 people with low starting WR, two of the responders (top) started with disproportionately worse PTA than WR. Then we have the two data points furthest to the left, which are practically the same. One responded, one didn't. This is not good. The placebo data is harder to make sense of because everything was shifted in the direction of better hearing at baseline.

I think, more than just explainable theories like IHC vs OHC preference (which could be valid to some degree), there's a huge part of this that's just random. Like we literally don't know why some respond and some don't. This is what worries me.

View attachment 44410

I see what you mean. Take a look at the research I shared re: IHC damage a few pages back - that speaks to the effect on audiogram and word comprehension.

Let me run this theory by the readers here:

It seems there is agreement that OHC performance is highly related to specific sound frequencies and the power of those frequencies as they enter the cochlea. This is largely due to the mechanical nature of the OHC, and position in the cochlea. When those OHCs are worn / damaged / depleted, the ability for the brain to receive signals is equally diminished. Therefore it is expected that OHCs damaged in a specific area of the cochlea will no longer provide the brain with the input on those specific frequencies and their level of power. There also appears to be very little overlap in the performance of the OHC - one at the base of the cochlea just simply cannot adapt to start providing signal for a lost high frequency OHC.

IHC lack this clear definition and understanding; atleast from what I can find. First, their function seems to be much more binary: they're hearing sound or they aren't, and that's the "on" / "off" signal that the brain gets. Second, their range of sensitivity to frequency is not as well understood; as opposed to OHC, which is much more specific based on mechanical nature and location in cochlea. There does seem to be some agreement that IHC sensitivity must have considerable overlap in the cochlea; so they're likely to be highly redundant. What I mean by this is that an IHC smack in the middle of the cochlea where we might put "4Khz" on a diagram, might be MOST sensitive to 4Khz in that position, but it can also provide some level of information to the brain that spans from 3Khz - 5Khz. So, as one can expect, there's a ton of redundancy in IHC amongst neighboring cells. Therefore - as IHC are depleted, it would take a fairly significant dead region, or a lot of scattered regions of dead / dysfunctioning IHC to start having noticeable impact on WR and Audiogram.

Ok so what am I getting to by saying all of this:

It may depend on where the IHC losses are concentrated AND where they are restored in the cochlea for FX-322 to show a gain on the tests used today. The make-up of the overall IHC situation may really, really matter.

In these super-responders it's possible that Frequency Therapeutics chased a red herring, thinking that OHC+IHC in the EHF was causing the performance gains. But in reality, perhaps these patients just happened to have enough IHC concentrated restoration in the right place where FX-322 hit to show the gains they did. It's just as possible that other patients have enough IHC in the EHF floating around that gains from FX-322 won't do any good because there is a location deeper in the cochlea with IHC deficiency where FX-322 would be more effective.

What I do think is that the Severe loss group has a higher likelyhood of having concentrations of missing IHC in the cochlea that might bump those odds up slightly. But it still may be a mixed bag.

I am not so sure there is a great way right now to diagnose where IHC are missing like is done with the Audiogram for OHC. The only thing I can think of is to analyze where words are missing in the WR and WIN tests to determine if the consonants and vowel combinations would exercise specific regions of the cochlea.

 

[kiki]

Then we have the two data points furthest to the left, which are practically the same. One responded, one didn't. This is not good.

"PTA4" is "Pure Tone Average".

It is not known whether the high frequency band is particularly deteriorated. Is it my misunderstanding?

 

[Jrblovsky]

You're kind of validating the discussion on this thread as to why the audiogram is a poor standard for hearing.

That's true. I'm also confirming the Phase 1 data everyone is raving about is absolute horseshit.

 

[FGG]

That's true. I'm also confirming the Phase 1 data everyone is raving about is absolute horseshit.

So your point is that you don't think either audiograms or word scores reflect hearing?

How do you suggest people assess hearing drugs?

 

[Tezcatlipoca]

I'm also confirming the Phase 1 data everyone is raving about is absolute horseshit.

Oh you're confirming data now, interesting...

 

[Diesel]

I needed a little entertainment this evening...

 

[Tezcatlipoca]

So your point is that you don't think either audiograms or word scores reflect hearing?

How do you suggest people assess hearing drugs?

All data must be confirmed by him now.

 

[Zugzug]

I needed a little entertainment this evening...

View attachment 44411

George Costanza would pretend to be Jon Stewart, just like he pretended to be an architect.

 

[Diesel]

George Costanza would pretend to be Jon Stewart, just like he pretended to be an architect.

 

[Jrblovsky]

All data must be confirmed by him now.

I could confirm my foot in your behind if that will help. From my own experience of this hell the gains shown are nothing. Maybe in milder loss but in severe/moderate I haven't noticed a difference. Go on and continue to rave about this drug. Actually you should take a second mortgage on your house and buy all the stock you can.

So your point is that you don't think either audiograms or word scores reflect hearing?

How do you suggest people assess hearing drugs?

I have no idea.

 

[Zugzug]

@Diesel

I read the paper you posted about IHC loss and central gain. The following diagram provides me with a theory about what could happen with my problem over the course of years -- loudness hyperacusis getting worse and worse until it just breaks and I'm mostly deaf. It's not just IHC, but also the auditory nerve fibers.

Several things from your paper that I found interesting:

• Removing the third row of OHC from styrene administration does very little to decrease amplification
• The average 54 year old man has ~10% OHC loss and ~0% IHC loss, while the average 89 year old man has 10-40% OHC loss and ~10% IHC loss. There's also a huge gap in synapses lost, leading to the theory that synapse loss is a precursor to IHC loss.

I'm a little confused about your (and @FGG's) theory regarding FX-322. So the hypothesis is that it may work for IHC and do nothing or very little for OHC. If I am understanding the picture correctly, wouldn't it seem like if IHC are regrown, then the first layer of OHC will be regrown? But I thought the first two layers were the most important and the third layer wasn't.

More doubts about the severe group: Okay, sure, if IHC really are regrown first, then this is the group that should see the most cochlear gains. But will it show up even if it was there? I ask because there seems to be a sudden difference between little IHC loss accompanied by central gain versus so much IHC loss and disastrous WR scores. Is it possible that the drug helps IHC loss a little bit, but not enough to really do anything?

That's not a defense of the drug, as it would still be a failure. I just don't really understand how the results are going to look so beautiful.

I'm also concerned about the one person from Phase 1/2 who had plenty low enough WR to improve, but didn't at all. Their improvement easily fell within the margin of error. What is going on with this person? It's just one person, but we are also using only three people to paint the drug in a positive light.

 

[kiki]

Agree, if there is an IHC preference and/or restoring one row of OHCs does not produce large audiogram changes (e.g., as in the study @Diesel posted), "delivery" is not the main issue, it's the need for multi dosing (at bigger intervals).

Is there a possibility that the effect of improving dB is small with just one OHC?

Is there a possibility that the dB improvement effect will not occur unless there is a lot of OHC regeneration concentrated in a certain area?

Is it possible that each OHC influences each other in terms of amplification effect?

Is it possible that the efficacy of OHC will increase slowly even with the same amount of regeneration as IHC?

Or:
Isn't the length of the synapse connecting to the OHC also relevant?

 

[Diesel]

I'm also concerned about the one person from Phase 1/2 who had plenty low enough WR to improve, but didn't at all. Their improvement easily fell within the margin of error. What is going on with this person? It's just one person, but we are also using only three people to paint the drug in a positive light.

Yeah this is where I was commenting in my last post that IHC regeneration improvements are going to largely depend on the location where there is significant loss, AND if FX-322 can get there. There's no diag to know where IHC loss is located within the cochlea.

 

[FGG]

@Diesel

I read the paper you posted about IHC loss and central gain. The following diagram provides me with a theory about what could happen with my problem over the course of years -- loudness hyperacusis getting worse and worse until it just breaks and I'm mostly deaf. It's not just IHC, but also the auditory nerve fibers.

Several things from your paper that I found interesting:

• Removing the third row of OHC from styrene administration does very little to decrease amplification
• The average 54 year old man has ~10% OHC loss and ~0% IHC loss, while the average 89 year old man has 10-40% OHC loss and ~10% IHC loss. There's also a huge gap in synapses lost, leading to the theory that synapse loss is a precursor to IHC loss.

I'm a little confused about your (and @FGG's) theory regarding FX-322. So the hypothesis is that it may work for IHC and do nothing or very little for OHC. If I am understanding the picture correctly, wouldn't it seem like if IHC are regrown, then the first layer of OHC will be regrown? But I thought the first two layers were the most important and the third layer wasn't.

More doubts about the severe group: Okay, sure, if IHC really are regrown first, then this is the group that should see the most cochlear gains. But will it show up even if it was there? I ask because there seems to be a sudden difference between little IHC loss accompanied by central gain versus so much IHC loss and disastrous WR scores. Is it possible that the drug helps IHC loss a little bit, but not enough to really do anything?

That's not a defense of the drug, as it would still be a failure. I just don't really understand how the results are going to look so beautiful.

I'm also concerned about the one person from Phase 1/2 who had plenty low enough WR to improve, but didn't at all. Their improvement easily fell within the margin of error. What is going on with this person? It's just one person, but we are also using only three people to paint the drug in a positive light.

View attachment 44413

I think this is way more multi factorial than that (as medicine tends to be).

For instance, you could have low word scores and a lot of IHC loss and for whatever reason, it be concentrated below 6 kHz. I would actually like to see that individuals' audiogram because it would make sense for them to be weighted towards more losses towards the apex than the responders.

To make this even more complicated, synapse loss only tends to come before IHC loss with gradual hearing loss. There was one researcher who showed that there are certain types of acute noise-induced losses that only damage IHCs (a loud 4000 Hz noise specifically if i remember correctly), some that only damage OHCs and some that are mixed and it depends on frequency and duration.

@HootOwl has that study and maybe she can repost it. So, there isn't even a uniform way that people lose hair cells.

I noted before that @Diesel's paper showed that losing one row of OHCs only results in a 5-10 dB change. If the rat study holds true for people that's another potential reason we didn't see significant audiogram changes (i still think we would see a lot more 5-10 dB changes unless there was also an IHC preference unless they did see that in individuals but it doesn't exceed the allowed test/retest variation?). The individual audiograms matched to word scores would help so much.

I don't understand what you mean by only helping IHCs a little bit. Unless you mean not across the whole cochlea and I agree with that.

As far as your own hyperacusis, when they say "auditory nerve fibers" in those studies, they mean the neurites regress because they are no longer synapsed (aka synaptopathy), it doesn't mean you will go deaf.

 

[Tezcatlipoca]

There's no diag to know where IHC loss is located within the cochlea.

Just like @FGG said, treatments are coming before diagnostics, which is bad because it makes getting a drug approved more complicated.

 

[FGG]

Is there a possibility that the effect of improving dB is small with just one OHC?

Is there a possibility that the dB improvement effect will not occur unless there is a lot of OHC regeneration concentrated in a certain area?

Is it possible that each OHC influences each other in terms of amplification effect?

Is it possible that the efficacy of OHC will increase slowly even with the same amount of regeneration as IHC?

Or:
Isn't the length of the synapse connecting to the OHC also relevant?

I sort of answered this in my reply to Zug. As far as your last question, I'm not sure what you are implying exactly.

 

[RingingBrother]

So when can we expect a new Phase 2 trial with the single dosing? I would be in it if I could.

 

[kiki]

As far as your last question, I'm not sure what you are implying exactly.

Dear @FGG,

Thank you. And I'm sorry. I will withdraw the last question.

I just felt that the OHC-related synapses were longer than the IHC, and that it might not be fully regenerated. It was a strange question.

By the way, about OHC:

I have a feeling that each OHC influences each other vertically, horizontally, and diagonally.

It is an intuition from the shape that is neatly arranged in 3 rows and the function called "amplification".