Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Again, I'm not saying there was anything unorthodox or wrong about the test or that they changed the loudness. All I'm saying that in daily life for a person with hearing loss, "47/50" doesn't say everything. Nor to an audiologist. In a standard hearing test, they register multiple word scores at different volumes. That's why the words you have to repeat keep getting less loud as the test progresses. If you have to set your hearing aid to 70 dB or whatever to get to your best word score, it has all kinds of other drawbacks. Trust me, living with a loud ass hearing aid is no fun. That's one of the reasons why you want to have a situation where both your word scores and your PTA improve. It's better to get the loudness from the cochlea itself than from an aid.

I think as a single test, yes it matters greatly the decibels the word score test is given but when you are repeating a word score test before and after the drug is given and the score doubles, it is extraordinary regardless of what decibels they used.

Whether at 20 dB or 90 dB, if I can only hear 20-something words out of 50 and then suddenly I can hear twice as much at the same volume, the improvement is the more important point not my initial score as a function of loudness.

 

[Diesel]

Again, I'm not saying there was anything unorthodox or wrong about the test or that they changed the loudness. All I'm saying that in daily life for a person with hearing loss, "47/50" doesn't say everything. Nor to an audiologist. In a standard hearing test, they register multiple word scores at different volumes. That's why the words you have to repeat keep getting less loud as the test progresses. If you have to set your hearing aid to 70 dB or whatever to get to your best word score, it has all kinds of other drawbacks. Trust me, living with a loud ass hearing aid is no fun. That's one of the reasons why you want to have a situation where both your word scores and your PTA improve. It's better to get the loudness from the cochlea itself than from an aid.

You're confusing the word score test with the Speech Awareness Threshold.

Word score in a quiet background is done at a FIXED decibel level; at conversational level - typically 50-55 dB.

The Speech Awareness Threshold asks you to repeat words as they get progressively and quieter.

 

[WillBeNimble]

I'm sad that Carl misinterpreted the question concerning the native cell population numbers, but I can see where he was coming from.

With the other questions though, it seems like he thinks even if it doesn't, most should be okay for the support cells? It's a weird issue. I can imagine his answer would have been something along the line of "We can't be certain right now. We're only signaling the living proginator cells to divide though, so maybe in the areas they are, they can be a bit more effective and bridge some gaps, but at this point we're not certain if FX-322 would be able to build up other frequencies as well. We'll see the results from the phase 2a, and that should let us know."

 

[FGG]

I'm sad that Carl misinterpreted the question concerning the native cell population numbers, but I can see where he was coming from.

With the other questions though, it seems like he thinks even if it doesn't, most should be okay for the support cells? It's a weird issue. I can imagine his answer would have been something along the line of "We can't be certain right now. We're only signaling the living proginator cells to divide though, so maybe in the areas they are, they can be a bit more effective and bridge some gaps, but at this point we're not certain if FX-322 would be able to build up other frequencies as well. We'll see the results from the phase 2a, and that should let us know."

In answer to your specific concern, he basically did say he thought anyone who wasn't reduced to flat epithelial should at least have enough support cells to get some effect from this drug.

I think he indirectly answered @mrbrightside614's question too by saying they don't get excessive growth (which would be a cancer risk), and this should work in ears with a variety of damage as long as you are not reduced to flat epithelia. Almost no one's ear is entirely flat epithelia so I took this to mean, you can't in fact use the drug to produce extra support cells and walk them down to the areas of profound damage.

Individual support cells are associated with individual hair cells. I think he didn't realize he was being asked about sending support cells to new locations in the cochlea but I don't see that as feasible (for one thing, what signaling mechanisms would they use to find their "new home") and maybe that lack of mechanism didn't make the intention of the question even click for him.

 

[WillBeNimble]

In answer to your specific concern, he basically did say he thought anyone who wasn't reduced to flat epithelial should at least have enough support cells to get some effect from this drug.

I think he indirectly answered @mrbrightside614's question too by saying they don't get excessive growth (which would be a cancer risk), and this should work in ears with a variety of damage as long as you are not reduced to flat epithelia. Almost no one's ear is entirely flat epithelia so I took this to mean, you can't in fact use the drug to produce extra support cells and walk them down to the areas of profound damage.

Individual support cells are associated with individual hair cells. I think he didn't realize he was being asked about sending support cells to new locations in the cochlea but I don't see that as feasible (for one thing, what signaling mechanisms would they use to find their "new home") and maybe that lack of mechanism didn't make the intention of the question even click for him.

I see what you mean. True, there's not a mechanism in place. I've sorta been hoping cause I can't for the life of me pinpoint my tinnitus tone. It's masked by like 60 dB sounds, so that seems like bad damage, but it's so high pitched I can kinda just ignore it, but the fact it now shows up when I go for a walk and such irritates me. And I can hear every tone under it just fine without increasing the audio, so it makes me think my damage was on my very highest frequency. Also, getting a extended audiogram scares me as I don't want to make it worse, nor do I think it makes sense with COVID-19 going on.

Sorry I keep mentioning that, I just sort of vainly hope that getting a large number of support cells dividing again kicks the body off to go "Oh, it's this time again? Yeah, we can do this." Also, is it individual support cells to individual hairs, cause I keep seeing stuff like this which makes it seem like it's more than one.

https://dev.biologists.org/content/develop/142/9/1561/F4.large.jpg

 

[lymebite]

This is a bit of a tangent, but on word recognition score (WRS) my understanding is that the audiologist sets the volume at the "MCL" or "Most Comfortable Level" for each patient which of course will vary by patient.

I have severe hyperacusis, and earlier this year my ENT requested that I have an audiometry work-up including WRS. Due to the hyperacusis I requested the audiologist to set the volume far below what would normally be the MCL for a typical patient. I wasn't really expecting to do well since I could barely hear the words at the very quiet volume, but somehow I managed to get 100 percent of them, even though I guessed on a couple. The audiologist noted on the chart that "Excellent WRS at patient MCLs, which are significantly reduced."

 

[Lucifer]

This is a bit of a tangent, but on word recognition score (WRS) my understanding is that the audiologist sets the volume at the "MCL" or "Most Comfortable Level" for each patient which of course will vary by patient.

I have severe hyperacusis, and earlier this year my ENT requested that I have an audiometry work-up including WRS. Due to the hyperacusis I requested the audiologist to set the volume far below what would normally be the MCL for a typical patient. I wasn't really expecting to do well since I could barely hear the words at the very quiet volume, but somehow I managed to get 100 percent of them, even though I guessed on a couple. The audiologist noted on the chart that "Excellent WRS at patient MCLs, which are significantly reduced."

I still believe that restoring the underlying issue in the ear such as OHCs, IHCs and synapses should solve our hyperacusis issue. I feel like those of us who have hyperacusis, instead of losing hearing we actually gain hearing due to our low threshold of sound that causes us pain.

And I don't think we actually gain hearing at all we still lose it but it makes our threshold to pain even lower so it looks like our hearing is normal.

 

[tommyd87]

This is a bit of a tangent, but on word recognition score (WRS) my understanding is that the audiologist sets the volume at the "MCL" or "Most Comfortable Level" for each patient which of course will vary by patient.

I have severe hyperacusis, and earlier this year my ENT requested that I have an audiometry work-up including WRS. Due to the hyperacusis I requested the audiologist to set the volume far below what would normally be the MCL for a typical patient. I wasn't really expecting to do well since I could barely hear the words at the very quiet volume, but somehow I managed to get 100 percent of them, even though I guessed on a couple. The audiologist noted on the chart that "Excellent WRS at patient MCLs, which are significantly reduced."

I do not think though that anything other than a consistent clearly determined threshold would have been used when doing this testing for phase 1/2. We don't know exactly what it was. My guess is that it would have been something like an upper limit of 60 dB which would be totally in line with what normal speech is if they wanted genuine results.

 

[lymebite]

@mrbrightside614 and @FGG - I wondered if you might speculate on my situation and the potential for permeability of FX-322.

I had the hyperacusis surgery done in one ear a several years ago, which involves adding a layer of additional tissue over the round and oval windows. It seems to help a lot of hyperacusis patients somewhat, but it did not help in my case unfortunately.

Anyway, I am wondering if the added tissue may reduce or prevent entirely the permeability of FX-322 into the cochlea. A year or so ago, I actually put this question to one of the Frequency Therapeutics scientists, and they kindly replied to my question, though their answer was that they did not really know if the extra tissue might present an issue.

But it's been a while since I asked them, and I thought with your extensive knowledge of FX-322 you might have some grounds to speculate how much of an issue the extra tissue might or might not be.

Thanks in advance!

 

[serendipity1996]

I still believe that restoring the underlying issue in the ear such as OHCs, IHCs and synapses should solve our hyperacusis issue. I feel like those of us who have hyperacusis, instead of losing hearing we actually gain hearing due to our low threshold of sound that causes us pain.

And I don't think we actually gain hearing at all we still lose it but it makes our threshold to pain even lower so it looks like our hearing is normal.

One thing I am worried about is the other weird symptoms that accompany it, e.g facial pain etc. Pain hyperacusis seems to trigger weird widespread/referred pain etc - I hope that cochlear regeneration would have a positive downstream effect and our systems would adapt to a 'normalised' auditory system. Perhaps then the pain would lessen. I think I'm just a bit despairing tbh and worried this stuff won't go away.

I wonder whether referred pain like this is a common thing that happens in other body parts when they get injured?

 

[Lucifer]

One thing I am worried about is the other weird symptoms that accompany it, e.g facial pain etc. Pain hyperacusis seems to trigger weird widespread/referred pain etc - I hope that cochlear regeneration would have a positive downstream effect and our systems would adapt to a 'normalised' auditory system. Perhaps then the pain would lessen. I think I'm just a bit despairing tbh and worried this stuff won't go away.

I wonder whether referred pain like this is a common thing that happens in other body parts when they get injured?

I'm worried the pain hyperacusis won't go away either. I just hope when you have a normalised auditory system by regenerating the OHCs, IHCs and synapses then this should reduce the hyperacusis symptoms as well.

 

[WillBeNimble]

One thing I am worried about is the other weird symptoms that accompany it, e.g facial pain etc. Pain hyperacusis seems to trigger weird widespread/referred pain etc - I hope that cochlear regeneration would have a positive downstream effect and our systems would adapt to a 'normalised' auditory system. Perhaps then the pain would lessen. I think I'm just a bit despairing tbh and worried this stuff won't go away.

I wonder whether referred pain like this is a common thing that happens in other body parts when they get injured?

I mean, phantom pain happens. If we restored the limbs, I imagine it would normalize. Similar for the auditory system.

 

[Lucifer]

I was reading the transcript of the Tinnitus Talk Podcast interview and it stated that before you get the IT injection they numb the ear drum, then inject your ear your ear, and then you are done.

Is there no lying down for 10 minutes or so before you can stand up? From reading it sounds like once you get the injection in your ear you can stand up straight away after it's done?

 

[GregCA]

I was reading the transcript of the Tinnitus Talk Podcast interview and it stated that before you get the IT injection they numb the ear drum, then inject your ear your ear, and then you are done.

Is there no lying down for 10 minutes or so before you can stand up? From reading it sounds like once you get the injection in your ear you can stand up straight away after it's done?

When I went through my dexamethasone injection, I had to keep the head tilted so the compound can stay adjacent to the round window and diffuse into the cochlea.

If you get up, the compound will drain down your eustachian tube, and very little will have gone to the cochlea, where it's supposed to go.

I'd imagine there's a similar requirement here.

 

[FGG]

I was reading the transcript of the Tinnitus Talk Podcast interview and it stated that before you get the IT injection they numb the ear drum, then inject your ear your ear, and then you are done.

Is there no lying down for 10 minutes or so before you can stand up? From reading it sounds like once you get the injection in your ear you can stand up straight away after it's done?

I don't think it was a detail of the entire process. I would think you'd have to be reclined and stationary for at least some length of time.

 

[FGG]

@mrbrightside614 and @FGG - I wondered if you might speculate on my situation and the potential for permeability of FX-322.

I had the hyperacusis surgery done in one ear a several years ago, which involves adding a layer of additional tissue over the round and oval windows. It seems to help a lot of hyperacusis patients somewhat, but it did not help in my case unfortunately.

Anyway, I am wondering if the added tissue may reduce or prevent entirely the permeability of FX-322 into the cochlea. A year or so ago, I actually put this question to one of the Frequency Therapeutics scientists, and they kindly replied to my question, though their answer was that they did not really know if the extra tissue might present an issue.

But it's been a while since I asked them, and I thought with your extensive knowledge of FX-322 you might have some grounds to speculate how much of an issue the extra tissue might or might not be.

Thanks in advance!

I couldn't even begin to speculate on that. Sorry.

 

[Lucifer]

When I went through my dexamethasone injection, I had to keep the head tilted so the compound can stay adjacent to the round window and diffuse into the cochlea.

If you get up, the compound will drain down your eustachian tube, and very little will have gone to the cochlea, where it's supposed to go.

I'd imagine there's a similar requirement here.

That's what I thought too but the way Carl LeBel explained, it seems like you could get up straight away.

 

[tommyd87]

That's what I thought too but the way Carl LeBel explained, it seems like you could get up straight away.

I think that is possible because this is a gel and it is supposed to go into the cochlea and not diffuse until it is in there. Although I do not know if it is like that for also dexamethasone.

 

[F-u-T]

That's what I thought too but the way Carl LeBel explained, it seems like you could get up straight away.

FX-322 turns into a gel when injected so it should stay in place until it dissolves. Gel formula helps it diffuse into round window over time.

 

[Jurger]

You're confusing the word score test with the Speech Awareness Threshold.

Word score in a quiet background is done at a FIXED decibel level; at conversational level - typically 50-55 dB.

The Speech Awareness Threshold asks you to repeat words as they get progressively and quieter.

That doesn't make any sense for the moderate-severe patients that were tested in Phase 1/2. Moderate-severe is at least 55 dB loss. If you test them on normal conversational level, they won't be able to hear. And certainly not 47 out of 50 words.

 

[Jurger]

@mrbrightside614 and @FGG - I wondered if you might speculate on my situation and the potential for permeability of FX-322.

I had the hyperacusis surgery done in one ear a several years ago, which involves adding a layer of additional tissue over the round and oval windows. It seems to help a lot of hyperacusis patients somewhat, but it did not help in my case unfortunately.

Anyway, I am wondering if the added tissue may reduce or prevent entirely the permeability of FX-322 into the cochlea. A year or so ago, I actually put this question to one of the Frequency Therapeutics scientists, and they kindly replied to my question, though their answer was that they did not really know if the extra tissue might present an issue.

But it's been a while since I asked them, and I thought with your extensive knowledge of FX-322 you might have some grounds to speculate how much of an issue the extra tissue might or might not be.

Thanks in advance!

This question wasn't directed at me, but if I were you, I'd ask the ENT that performed the surgery if he/she thinks there will be any issues if you ever need intratympanic steroid injections for whatever reason (acoustic trauma, Meniere's etc.). That might give some indication if there are any issues if FX-322 hits the market.

 

[Lucifer]

I think that is possible because this is a gel and it is supposed to go into the cochlea and not diffuse until it is in there. Although I do not know if it is like that for also dexamethasone.

FX-322 turns into a gel when injected so it should stay in place until it dissolves. Gel formula helps it diffuse into round window over time.

True, I almost forgot it was a gel like substance.

 

[Diesel]

That doesn't make any sense for the moderate-severe patients that were tested in Phase 1/2. Moderate-severe is at least 55 dB loss. If you test them on normal conversational level, they won't be able to hear. And certainly not 47 out of 50 words.

This is how we know FX-322 had a positive effect on hearing.

The moderate-to-moderate-severe patient got 26/50 words right BEFORE receiving FX-322. A test given at 55 dB in a quiet background. So you're right, they didn't hear a whole lot.

The exact same random word score test was applied at 55 dB, 90 days after receiving FX-332. Now they got 47/50 words right!

The test didn't change. Their hearing improved.

 

[Jurger]

This is how we know FX-322 had a positive effect on hearing.

The moderate-to-moderate-severe patient got 26/50 words right BEFORE receiving FX-322. A test given at 55 dB in a quiet background. So you're right, they didn't hear a whole lot.

The exact same random word score test was applied at 55 dB, 90 days after receiving FX-332. Now they got 47/50 words right!

The test didn't change. Their hearing improved.

Where does it say the test was administered at 55 dB? The four people who had moderate-severe hearing loss are already at 55 PTA minimum. They can't hear at 55 dB.

 

[Diesel]

Where does it say the test was administered at 55 dB? The four people who had moderate-severe hearing loss are already at 55 PTA minimum. They can't hear at 55 dB.

We already covered a few comments ago that the standard word recognition test is performed at 50-55 dB. Freq has disclosed numerous times that they're testing with standard measures used in the clinic. The standard is 50-55 dB for the WRS test.

The group was moderate to moderately-severe. Which appears to be a PTA between 40 dB and 55db for Mod and to 70 dB for mod-severe. So, the test would have been detectable within the moderate and severe range. This also an average across frequencies.

 

[lymebite]

I'd ask the ENT that performed the surgery if he/she thinks there will be any issues if you ever need intratympanic steroid injections for whatever reason

Thanks, that's a great idea, it never occurred to me that an intratympanic steroid injection that permeates would be a good way to raise this question for ENTs not familiar with FX-322. The precise permeability characteristics of the two substances might vary, but it's an excellent parallel.

 

[FGG]

Thanks, that's a great idea, it never occurred to me that an intratympanic steroid injection that permeates would be a good way to raise this question for ENTs not familiar with FX-322. The precise permeability characteristics of the two substances might vary, but it's an excellent parallel.

Worst case scenario, it appears the surgery is reversible from a brief web search (I'm sure it would not be fun getting a second surgery but it may be an option at least.

 

[Jurger]

We already covered a few comments ago that the standard word recognition test is performed at 50-55 dB. Freq has disclosed numerous times that they're testing with standard measures used in the clinic. The standard is 50-55 dB for the WRS test.

The group was moderate to moderately-severe. Which appears to be a PTA between 40 dB and 55db for Mod and to 70 dB for mod-severe. So, the test would have been detectable within the moderate and severe range. This also an average across frequencies.

You never covered anything, you just stated it. Again, Frequency Therapeutics measured word recognition improvements mostly in the moderate-severe hearing loss category. I believe there were four people in that category that improved word scores. A person with hearing loss that's moderate-severe - 55-70 dB (https://www.asha.org/public/hearing/Degree-of-Hearing-Loss/) - can't hear at 55 dB. That's an audiological fact that's self explanatory. So I don't know what we're talking about here.

 

[Jurger]

Thanks, that's a great idea, it never occurred to me that an intratympanic steroid injection that permeates would be a good way to raise this question for ENTs not familiar with FX-322. The precise permeability characteristics of the two substances might vary, but it's an excellent parallel.

True, dexamethasone and prednisolone are not administered with a gel, although Otonomy is working on that for Meniere's. Should problems arise for you with intratympanic delivered FX-322, an alternative might be injecting the drug intracochlear via a microneedle. That way, the drug is injected through the RWM instead of letting the drug permeate through it.

 

[GregCA]

I don't think it was a detail of the entire process. I would think you'd have to be reclined and stationary for at least some length of time.

Oddly enough, the hardest part isn't to keep the same position for 15 minutes. It's to not swallow.

We stay many minutes without swallowing in our daily lives without batting an eye, but when someone asks you to not swallow and that is brought to the forefront of our consciousness, it becomes a struggle.

As you read this, try to not swallow and tell me how long you can hold without doing it.