Frequency Therapeutics — Hearing Loss Regeneration

[mrbrightside614]

Doubling their word scores would have to mean there is improvement in the ultra high frequencies, right? UHF provides clarity of understanding, as they explain in the presentation.

The problem is just that they didn't do extended audiograms and therefore they can't objectify improvements on the standard audiogram other than at 8kHz, which is most likely caused due to the delivery challenge as they explained.

The second trial will hopefully confirm threshold shifts in the extended audiogram from 3.5kHz all the way up to 16kHz. Then we will know if they're sitting on gold.

Didn't watch the presentation but the fact they're drawing the correlate of UHF = better clarity is a little surprising to me.

But yea I agree, if they verified UHF hearing restoration, it's a wrap. It's gold.

 

[FGG]

I find this strange. There have been enough scientific studies that researched the frequency distribution of speech and there's very little information over 8kHz. Even over 4kHz. What does clarity mean exactly? In this context it's a vague term... Of course, the word scores don't lie. But what's causing it? It'll be really interesting once they know for sure...

There was a study I posted somewhere months ago--who knows if I can find it again--where they found a rare subpopulation of profoundly deaf people on standard audiogram with good hearing over 8000 Hz. They had unusually good speech compared to those whose deafness covered the extended frequencies, too. I will see if I can find it again.

 

[FGG]

Found it. It's an old study. A follow up would be nice but may partially explain Frequency Therapeutics' results for sure:

https://www.ncbi.nlm.nih.gov/pubmed/114908/

 

[d'Wooluf]

I find this strange. There have been enough scientific studies that researched the frequency distribution of speech and there's very little information over 8kHz. Even over 4kHz. What does clarity mean exactly? In this context it's a vague term... Of course, the word scores don't lie. But what's causing it? It'll be really interesting once they know for sure...

I agree. The first thing I thought when I saw the results was 'synapse repair?'. Put it another way. Take a person with good hearing. Filter out 8kHz and above. My guess is their word recognition would change hardly at all. A word that David Lucchino seems to have grown very fond of is 'clarity'. If you were going to name an anatomical correlate to clarity in hearing what would it be?

Edit: I didn't read the posts above mine clearly enough.

 

[Chinmoku]

I just personally can't understand how it would be possible for a hair to be flopped over without damage to its site of attachment at the cell body.

One of the many doctors I saw claims that excess cochlear hydrops can do that.

 

[brokensoul]

Didn't watch the presentation but the fact they're drawing the correlate of UHF = better clarity is a little surprising to me.

But yea I agree, if they verified UHF hearing restoration, it's a wrap. It's gold.

It's best if more people watch it and see how it needs to be interpreted.

As @FGG says above I remember this was discussed months ago on the forum (after results of the first trial). Perhaps it played part in how I interpreted the presentation. Please do have a look at it, they referred to the improvements as "intelligibility".

So, what else is possible that they had participants with doubled word scores?

Were the list words every time the same? Did the participants memorise the words over time and hence improved? Do we know if the words were randomised? I can't imagine they were not different during every test? That would obviously highly influence the results and we would not be able to draw any scientific conclusions from them. They didn't state randomisation, but I just can't imagine that would not be the case.

Has anyone done several word tests? Can you confirm they are randomised every time?

Other than that I cannot see how the participants suddenly had a doubled word score. There is just no way to attain such an improvement without actually having improved the hearing system on some level.

The blind spot is currently >8kHz. We will have to wait until September to confirm our interpretation on why we saw doubled word scores.

The reason why I feel that there were improvements in the UHF reason is that they did see a 10dB threshold shift at 8kHz for 4 out of 6 people (in the positive sense) and it may not sound like much, but it is significant! In my opinion that 10dB is not related to poor testing. I've done multiple audiograms and I never scored a 10dB variation on them. Perhaps you can have a 5dB variation, but 10 is quite a lot. So if there was real improvement at 8kHz and we know that their delivery compound has limitations to get very far in the cochlea, then what else could we conclude than that there should have been some improvement >8kHz. It's not like the small molecules are going to jump over the UHF and only work at 8kHz.

I feel positive about it.

 

[FGG]

One of the many doctors I saw claims that excess cochlear hydrops can do that.

That actually makes sense since the fluid would be holding the hair in an abnormal position. People with hydrops often tend to have fluctuating hearing, too. This would obviously be true only during the episodes of hydrops, though, right?

 

[mrbrightside614]

I agree. The first thing I thought when I saw the results was 'synapse repair?'. Put it another way. Take a person with good hearing. Filter out 8kHz and above. My guess is their word recognition would change hardly at all. A word that David Lucchino seems to have grown very fond of is 'clarity'. If you were going to name an anatomical correlate to clarity in hearing what would it be?

Edit: I didn't read the posts above mine clearly enough.

My first thought was the same.

@brokensoul when I did word recognition tests, the words were more or less the same. Maybe 2 different ones but not really sure.

 

[FGG]

It's best if more people watch it and see how it needs to be interpreted.

As @FGG says above I remember this was discussed months ago on the forum (after results of the first trial). Perhaps it played part in how I interpreted the presentation. Please do have a look at it, they referred to the improvements as "intelligibility".

So, what else is possible that they had participants with doubled word scores?

Were the list words every time the same? Did the participants memorise the words over time and hence improved? Do we know if the words were randomised? I can't imagine they were not different during every test? That would obviously highly influence the results and we would not be able to draw any scientific conclusions from them. They didn't state randomisation, but I just can't imagine that would not be the case.

Has anyone done several word tests? Can you confirm they are randomised every time?

Other than that I cannot see how the participants suddenly had a doubled word score. There is just no way to attain such an improvement without actually having improved the hearing system on some level.

The blind spot is currently >8kHz. We will have to wait until September to confirm our interpretation on why we saw doubled word scores.

The reason why I feel that there were improvements in the UHF reason is that they did see a 10dB threshold shift at 8kHz for 4 out of 6 people (in the positive sense) and it may not sound like much, but it is significant! In my opinion that 10dB is not related to poor testing. I've done multiple audiograms and I never scored a 10dB variation on them. Perhaps you can have a 5dB variation, but 10 is quite a lot. So if there was real improvement at 8kHz and we know that their delivery compound has limitations to get very far in the cochlea, then what else could we conclude than that there should have been some improvement >8kHz. It's not like the small molecules are going to jump over the UHF and only work at 8kHz.

I feel positive about it.

They discussed this in another presentation, only one ear was given FX-322 and the audiologist was blinded as to which one was treated. Only the treated ears in the same patient improved in word scores.

Having done the word score test myself, I can tell you they don't correct the word so if something isn't clear, you are never sure which word it was meant to be. For instance, they don't say "oh sorry, that was supposed to be 'car'" if you say "are" instead.

There are apparently four different standard 50 word lists, so if there is a memorization effect here the *participants* would have had to memorize all of the different lists for the sole purpose of making the drug look better. Which means there is a massive conspiracy involving patients, testing centers and their associated ENTs.

I think it's way more likely the drug actually works.

 

[someone]

I find this strange. There have been enough scientific studies that researched the frequency distribution of speech and there's very little information over 8kHz. Even over 4kHz. What does clarity mean exactly? In this context it's a vague term... Of course, the word scores don't lie. But what's causing it? It'll be really interesting once they know for sure...

I agree the frequency of a phone line is between 300 Hz and 3400 Hz (or at least used to be) and that appears to be sufficient to understand all words. So, I think it would be surprising if a hearing improvement above 8 kHz would make a significant difference in understanding words.

Besides, if this drug restored hearing, shouldn't there have been at least one person in the whole program that had some sort of audiogram improvement at least at the 6 kHz or the 8 kHz tone?

Edit: I just noticed that it was mentioned that there was an improvement at 8 kHz in some patients: https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1 (slide 31)

 

[mrbrightside614]

I agree the frequency of a phone line is between 300 Hz and 3400 Hz (or at least used to be) and that appears to be sufficient to understand all words. So, I think it would be surprising if a hearing improvement above 8 kHz would make a significant difference in understanding words.

Besides, if this drug restored hearing, shouldn't there have been at least one person in the whole program that had some sort of audiogram improvement at least at the 6 kHz or the 8 kHz tone?

Edit: I just noticed that it was mentioned that there was an improvement at 8 kHz in some patients: https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1 (slide 31)

@FGG reported that with higher doses they improved frequencies of 3.5 kHz+ as well.

 

[FGG]

@FGG reported that with higher doses they improved frequencies of 3.5 kHz+ as well.

No. They haven't tested those higher doses in humans until now. But they said they expect their drug will reach >3500 Hz at full dosing in one of their presentations.

 

[FGG]

Guys, please watch the presentation and Q and A. They explain why effects over 8000 Hz have an effect on word score. While the bulk of speech information happens below 8000 Hz there is still information above it.

I also posted an older study showing that profoundly deaf people in the standard audiogram range who had better audiograms above 8000 Hz had "unusually good speech."

 

[Serouj]

@FGG Hello, I'm a 23-year-old hearing loss and tinnitus sufferer and I'm new to Tinnitus Talk.

Is there a link where we can watch the presentation and Q&A of Frequency Therapeutics?

 

[FGG]

@FGG Hello, I'm a 23-year-old hearing loss and tinnitus sufferer and I'm new to Tinnitus Talk.

Is there a link where we can watch the presentation and Q&A of Frequency Therapeutics?

Hi, welcome to the forum. This is a link from their presentations page on their website;

https://investors.frequencytx.com/events-and-presentations/

 

[Bartoli]

Thanks for digging around, FGG.

So it seems the gross of information happens under 8kHz, but in the people having better hearing over 8kHz, it tends to help a little with speech understanding. I guess it's similar to your brain filling in for visual input in your peripheral vision, here making up the fundamentals out of overtones maybe?

What confuses me is the doubling of word scores. Nothing to scoff at. Do we know what doubling means in this situation? Is it from 10 to 20% on average? Or far higher? I believe it has been said that there's a learning process in the word recognition tests also, but never enough to account for doubling of scores. Sorry if this has been said before...

 

[thinlay]

Thanks for digging around, FGG.

So it seems the gross of information happens under 8kHz, but in the people having better hearing over 8kHz, it tends to help a little with speech understanding. I guess it's similar to your brain filling in for visual input in your peripheral vision, here making up the fundamentals out of overtones maybe?

What confuses me is the doubling of word scores. Nothing to scoff at. Do we know what doubling means in this situation? Is it from 10 to 20% on average? Or far higher? I believe it has been said that there's a learning process in the word recognition tests also, but never enough to account for doubling of scores. Sorry if this has been said before...

Doubling the word score means that the overall average is a 100% increase.

So that means that each person has heard 100% more words which is huge.

This figure should be put into perspective because if a person has before heard 10% of the words, they now hear 20% versus a person who has before heard 40% of the words, they now hear 80%.

 

[Don Tinny]

How do I know if I have a healthy eardrum to be eligible for this drug? It would be terrible if in 5 years I'm going to have it injected and they tell me that I have a damaged eardrum or something like that.

I guess I only have dead hair cells, but...

 

[Bartoli]

Doubling the word score means that the overall average is a 100% increase.

So that means that each person has heard 100% more words which is huge.

This figure should be put into perspective because if a person has before heard 10% of the words, they now hear 20% versus a person who has before heard 40% of the words, they now hear 80%.

That was what I was aiming at with my example of 10% to 20%. But we don't know what the average scores were, do we?

 

[FGG]

That was what I was aiming at with my example of 10% to 20%. But we don't know what the average scores were, do we?

They put a chart up with these individuals and their word scores in the presentation.

 

[Bartoli]

They put a chart up with these individuals and their word scores in the presentation.

Found it. Thanks.

 

[RB2014]

I find this strange. There have been enough scientific studies that researched the frequency distribution of speech and there's very little information over 8kHz. Even over 4kHz. What does clarity mean exactly? In this context it's a vague term... Of course, the word scores don't lie. But what's causing it? It'll be really interesting once they know for sure...

Many of the words sound the same... and you end up guessing. It could be that the high frequency gains are just enough to figure out these subtle differences. Many times I would come really close to getting the word right, but never did during a word test. My brain would give me a choice between 2 or 3 words and I would say one.

Words are not the same as phone conversations. You can piece together a sentence based on what sounds right even if you didn't hear everything clearly . You can't piece together a random word based on hearing the word once. That could be the difference in this case and why people got better word scores with improved hearing at 8 kHz and above.

 

[IAmCalifornia]

How do I know if I have a healthy eardrum to be eligible for this drug? It would be terrible if in 5 years I'm going to have it injected and they tell me that I have a damaged eardrum or something like that.

I guess I only have dead hair cells, but...

A GP/ENT will easily be able to tell if you have a healthy, or infected/perforated ear drum or not.

 

[Bartoli]

Many of the words sound the same... and you end up guessing. It could be that the high frequency gains are just enough to figure out these subtle differences. Many times I would come really close to getting the word right, but never did during a word test. My brain would give me a choice between 2 or 3 words and I would say one.

Words are not the same as phone conversations. You can piece together a sentence based on what sounds right even if you didn't hear everything clearly . You can't piece together a random word based on hearing the word once. That could be the difference in this case and why people got better word scores with improved hearing at 8 kHz and above.

With me it was sentences instead of words. I too thought it was stupid because a person with extended vocabulary and language skills would obviously score much better than someone for whom it's a second or non-native language. The former can better predict what's going to come. I took an online speech in noise test with words and that one was ok too.

Obviously it's far from okay.

Hospitals have no clue and I'm happy Frequency is trying to change it at the root cause. Crossing my fingers. We need this to work!

 

[John Queen]

It's best if more people watch it and see how it needs to be interpreted.

As @FGG says above I remember this was discussed months ago on the forum (after results of the first trial). Perhaps it played part in how I interpreted the presentation. Please do have a look at it, they referred to the improvements as "intelligibility".

So, what else is possible that they had participants with doubled word scores?

Were the list words every time the same? Did the participants memorise the words over time and hence improved? Do we know if the words were randomised? I can't imagine they were not different during every test? That would obviously highly influence the results and we would not be able to draw any scientific conclusions from them. They didn't state randomisation, but I just can't imagine that would not be the case.

Has anyone done several word tests? Can you confirm they are randomised every time?

Other than that I cannot see how the participants suddenly had a doubled word score. There is just no way to attain such an improvement without actually having improved the hearing system on some level.

The blind spot is currently >8kHz. We will have to wait until September to confirm our interpretation on why we saw doubled word scores.

The reason why I feel that there were improvements in the UHF reason is that they did see a 10dB threshold shift at 8kHz for 4 out of 6 people (in the positive sense) and it may not sound like much, but it is significant! In my opinion that 10dB is not related to poor testing. I've done multiple audiograms and I never scored a 10dB variation on them. Perhaps you can have a 5dB variation, but 10 is quite a lot. So if there was real improvement at 8kHz and we know that their delivery compound has limitations to get very far in the cochlea, then what else could we conclude than that there should have been some improvement >8kHz. It's not like the small molecules are going to jump over the UHF and only work at 8kHz.

I feel positive about it.

Please note that also:

• the patients in the placebo group had no clinically meaningful improvement whatsoever; the tests were the same. If there was some variation due to memorization or some other factor, I think the results from the placebo group would reflect it.
• many patients only had mild hearing loss, and there was little room for improvement
• the treatment was a single, small dose
• I think they're not dumb and do the tests correctly so that they don't end up with inexplicable results. The p-value used in studies is also useful to evaluate the improvement and how likely it was due to chance.

 

[Bartoli]

Please note that also:

• the patients in the placebo group had no clinically meaningful improvement whatsoever; the tests were the same. If there was some variation due to memorization or some other factor, I think the results from the placebo group would reflect it.
• many patients only had mild hearing loss, and there was little room for improvement
• the treatment was a single, small dose
• I think they're not dumb and do the tests correctly so that they don't end up with inexplicable results. The p-value used in studies is also useful to evaluate the improvement and how likely it was due to chance.

I wholeheartedly agree. So why didn't they do extended audiometry tests? There are many plausible reasons, but I would like to hear it from them.

 

[BohemianLife]

No. They haven't tested those higher doses in humans until now. But they said they expect their drug will reach >3500 Hz at full dosing in one of their presentations.

What did you mean about >3500 Hz? Did you mean 20-3500 Hz or 3500-8000 Hz? I wonder if they will reach "speech frequencies".

 

[WickedCarnival]

My summary:

You have OHCs in larger numbers which connect to IHCs which finally synapse (ribbon synapses) with the spiral ganglion.

Further up you have the axon of the cochlear nerve which synapses at the brainstem (DCN) and then eventually the auditory cortex in the brain is where this signal is "heard."

The overwhelming majority of people who get tinnitus injured their cochlea in some way. Typically this happens through similar mechanisms: Neuro excitation and oxidative stress regardless of the cause.

The synapses and OHCs are more prone to this damage but some things (certain ototoxins, perhaps viral etc) damage the IHCs more. By the time you have audiogram changes, you have probably damaged multiple cochlear structures at that point.

Audiograms are very good at detecting OHC loss. There is some evidence that extended audiogram changes are a good additional tool to tell if you have synaptopathy in the typical audiogram range because if you have moderate damage above 10000 Hz, it is reasonable that the more sensitive synapses may be damaged further down.

I think everyone should get an extended audiogram personally.

Frequency restores OHC and it seems some IHC too from one of their publications. There is a link between loudness hyperacusis and IHC damage being a trigger for central gain so I wish they would test this on hyperacusis too! It may work for many cases imo.

Pipeline, Hough and Otonomy have synaptopathy drugs in trial.

Frequency will restore synapses if there are damaged or destroyed hair cells at that location.

As far as brainstem damage, that would usually be from things trauma, stroke or the rare ototoxin (I believe I am at least partially affected from Macrolide ototoxicity). A solution here would come from channel opening drugs. Or maybe CNS regeneration.

And, finally, Dr. Chen at Harvard is working on regenerating the entire cochlea, including support cells for the very severe cases. He's still in pre clinical but he told me he hopes to have something within a decade to market.

Why do many doctors say that macrolides including azithromycin are not ototoxic, yet some articles claim they are only temporarily ototoxic? What gives?

 

[someone]

She meant >3500 Hz. So, 3500 Hz up to 20 kHz.

The drug only appears to be reaching the beginning of the cochlea where all the high frequencies are located.

(Most people do have a hearing loss or tinnitus at higher frequencies. Well, all people start to get a hearing loss at high frequencies when they reach adulthood).

 

[FGG]

Why do many doctors say that macrolides including azithromycin are not ototoxic, yet some articles claim they are only temporarily ototoxic? What gives?

All I can say is it is shocking how uninformed doctors are (even specialists) about the inner ear.

I know personally (as in not from this forum) of one other person with horrific hearing symptoms from macrolides (she needs hearing aids in both ears now and even then she can't hear her family well as well as 8/10 tinnitus). It's not common but I think it's vastly underdiagnosed.