Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

Yeah, which doesn't seem to convey much if you had anything by the way of hidden hearing loss. I guess that's why it's "hidden", lol.

Is there much value in an audiogram otherwise then? Considering you won't know what happens in between the intervals and the fact it only goes up to so high, I'm not sure what information I can glean from it.

Since you usually lose hearing at the highest frequencies first, do changes or dips on the lower frequencies mean you have above mild hearing loss?

I'm so confused how this all plays together.

It's basically a sales tool for selling hearing aids. Which is why it maxes at 8 kHz.

This is the reason why I don't understand how many skeptics point to the audiogram as a valuable tool for measuring hearing regeneration performance for FX-322.

 

[FGG]

Yeah, which doesn't seem to convey much if you had anything by the way of hidden hearing loss. I guess that's why it's "hidden", lol.

Is there much value in an audiogram otherwise then? Considering you won't know what happens in between the intervals and the fact it only goes up to so high, I'm not sure what information I can glean from it.

Since you usually lose hearing at the highest frequencies first, do changes or dips on the lower frequencies mean you have above mild hearing loss?

I'm so confused how this all plays together.

Audiogram's primary purposes are to help rule in/out a conductive component and fit you for a hearing aid (and monitor progression). It's more useful for diffuse disease.

 

[Drachen]

It's basically a sales tool for selling hearing aids. Which is why it maxes at 8 kHz.

Audiogram's primary purposes are to help rule in/out a conductive component and fit you for a hearing aid (and monitor progression). It's more useful for diffuse disease.

I see. I will keep this in mind during my appointment then. I had high hopes in the first few days that I could receive some tangible answers from a visit to the audiologist, but as I have learned more about them, it seems almost pointless to visit.

I do not have the money for hearing aids, and they are not covered by my insurance. I doubt they would even help, and that money would probably be best put towards something like FX-322/OTO-413 if my condition does not resolve itself soon.

I find myself further disappointed with the state of medicine, especially as it pertains to things such as hearing loss and tinnitus, with each passing day. It is truly amazing how those who have had this before drugs like FX-322/OTO-413 were on the horizon have survived for so long.

This is the reason why I don't understand how many skeptics point to the audiogram as a valuable tool for measuring hearing regeneration performance for FX-322.

I actually saw a lot of this as I was reading earlier pages from this thread, apparently in 2019 around the IPO launch. Some people seem to think that because this is all we have, it must be a surefire way to diagnose problems.

We need to do better. We need to have better diagnostics and methods of evaluation in addition to treatments.

 

[Diesel]

I see. I will keep this in mind during my appointment then. I had high hopes in the first few days that I could receive some tangible answers from a visit to the audiologist, but as I have learned more about them, it seems almost pointless to visit.

I do not have the money for hearing aids, and they are not covered by my insurance. I doubt they would even help, and that money would probably be best put towards something like FX-322/OTO-413 if my condition does not resolve itself soon.

I find myself further disappointed with the state of medicine, especially as it pertains to things such as hearing loss and tinnitus, with each passing day. It is truly amazing how those who have had this before drugs like FX-322/OTO-413 were on the horizon have survived for so long.

I actually saw a lot of this as I was reading earlier pages from this thread, apparently in 2019 around the IPO launch. Some people seem to think that because this is all we have, it must be a surefire way to diagnose problems.

We need to do better. We need to have better diagnostics and methods of evaluation in addition to treatments.

From my own research, the two word score measures that Frequency Therapeutics is using in all of the FX-322 trials are significantly better indicators of hearing performance than pure tone audiometry.

Both utilize the the Consonant-Nucleus-Consonant (CNC) lists; These are made up of a randomly selected sample of 50 English words from a bank of about 1000. The words chosen require enough hearing function to distinguish the slight detailed differences in common words. Like: time and dime, home and foam, etc. The bank typically includes both words (time and dime, for example). Furthermore, there's enough data on the CNC lists that researchers know what words are 'harder' and 'easier' to distinguish, so the lists are updated to ensure an even distribution of hard and easy words for any repeated random selection of a 50-word test. Apparently word pairings that get above a certain % of "correct" guesses over time are removed from the revised lists.

The hearing function needed to distinguish CNC - Words-in-Quiet in English, actually requires a sufficient range/sensitivity of hearing across all frequencies in the cochlea. And, because the word list is random, and resampled about every 30 days, is a good indicator of actual improvement from FX-322.

To make matters more challenging, the CNC - Words-in-Noise uses the same list of already challenging words that really put the entire cochlea to test, and add in background audio that intermixes with the words. This requires enough healthy hearing function to not only distinguish the subtle differences between words, but also to filter out a layer of talking overtop of the words.

I'm starting to wonder if these word tests actually are a better indicator of both IHC and OHC function.

I'd also like to point out that the Words-in-Quiet and Words-in-Noise test is probably a better indicator of restoring hearing for people who are experiencing distortion, and other hearing-damage related anomalies. If the restored cochleas are able to detect fine details in words, that sensitivity/clarity gain should help with people who experience distortion listening to music and from other ambient noises (fans, motors, water running, etc). I think this because the word score tests are an indicator that the brain is receiving finer/more sensitive intricate details about sound that is broken down in the cochlea, so as we see language improvements, that should carry over other sound-related events.

Finally, audiogram isn't good because it doesn't show IHC function or any noise-related function.

 

[Drachen]

From my own research, the two word score measures that Frequency Therapeutics is using in all of the FX-322 trials are significantly better indicators of hearing performance than pure tone audiometry.

Both utilize the the Consonant-Nucleus-Consonant (CNC) lists; These are made up of a randomly selected sample of 50 English words from a bank of about 1000. The words chosen require enough hearing function to distinguish the slight detailed differences in common words. Like: time and dime, home and foam, etc. The bank typically includes both words (time and dime, for example). Furthermore, there's enough data on the CNC lists that researchers know what words are 'harder' and 'easier' to distinguish, so the lists are updated to ensure an even distribution of hard and easy words for any repeated random selection of a 50-word test. Apparently word pairings that get above a certain % of "correct" guesses over time are removed from the revised lists.

The hearing function needed to distinguish CNC - Words-in-Quiet in English, actually requires a sufficient range/sensitivity of hearing across all frequencies in the cochlea. And, because the word list is random, and resampled about every 30 days, is a good indicator of actual improvement from FX-322.

To make matters more challenging, the CNC - Words-in-Noise uses the same list of already challenging words that really put the entire cochlea to test, and add in background audio that intermixes with the words. This requires enough healthy hearing function to not only distinguish the subtle differences between words, but also to filter out a layer of talking overtop of the words.

I'm starting to wonder if these word tests actually are a better indicator of both IHC and OHC function.

I'd also like to point out that the Words-in-Quiet and Words-in-Noise test is probably a better indicator of restoring hearing for people who are experiencing distortion, and other hearing-damage related anomalies. If the restored cochleas are able to detect fine details in words, that sensitivity/clarity gain should help with people who experience distortion listening to music and from other ambient noises (fans, motors, water running, etc). I think this because the word score tests are an indicator that the brain is receiving finer/more sensitive intricate details about sound that is broken down in the cochlea, so as we see language improvements, that should carry over other sound-related events.

Finally, audiogram isn't good because it doesn't show IHC function or any noise-related function.

Very interesting stuff! It's great to learn that these are the tests that Frequency Therapeutics are using instead of simply relying on a stock audiogram. It should be all the more impressive then if good results are provided come March.

I will ask this despite probably knowing the answer already, but I assume audiologists typically do not offer these sorts of tests? I would very much like to see how I would perform with these as it may give me a better indication of my hearing.

If audiologists specifically do not offer them, is there any way for those in the public to have them done?

 

[Diesel]

Very interesting stuff! It's great to learn that these are the tests that Frequency Therapeutics are using instead of simply relying on a stock audiogram. It should be all the more impressive then if good results are provided come March.

I will ask this despite probably knowing the answer already, but I assume audiologists typically do not offer these sorts of tests? I would very much like to see how I would perform with these as it may give me a better indication of my hearing.

If audiologists specifically do not offer them, is there any way for those in the public to have them done?

Audiologists do offer both word score tests. I have had them for every visit.

This is why Frequency Therapeutics is using these particular tests; to prove that FX-322 improvements can be measured in the everyday clinical setting.

 

[FGG]

Very interesting stuff! It's great to learn that these are the tests that Frequency Therapeutics are using instead of simply relying on a stock audiogram. It should be all the more impressive then if good results are provided come March.

I will ask this despite probably knowing the answer already, but I assume audiologists typically do not offer these sorts of tests? I would very much like to see how I would perform with these as it may give me a better indication of my hearing.

If audiologists specifically do not offer them, is there any way for those in the public to have them done?

They do but if you have mild or isolated hearing loss, you will typically score normal on both of those tests.

Unfortunately, diagnostics haven't caught up with the treatments in trial. A lot of people will just have to "trial treat."

If you don't notice hearing loss, but you have hearing loss, the test that's most likely to be abnormal is the extended audiogram imo.

 

[serendipity1996]

They do but if you have mild or isolated hearing loss, you will typically score normal on both of those tests.

Unfortunately, diagnostics haven't caught up with the treatments in trial. A lot of people will just have to "trial treat."

If you don't notice hearing loss, but you have hearing loss, the test that's most likely to be abnormal is the extended audiogram imo.

I was actually wondering this about hidden hearing loss - it's said that speech in noise difficulties are the main indicator of this. However, could you have synaptopathy without struggling with this? I clearly have some level of hearing damage to bring about tinnitus and hyperacusis but I have no difficulties with speech in noise therefore I wonder if it's mostly extended high-frequency loss for me. I feel like many of us would have some sort of mixed pathology.

 

[Gb3]

Don't a lot of people start losing those high frequencies like 16 kHz in their 40s?

 

[FGG]

I was actually wondering this about hidden hearing loss - it's said that speech in noise difficulties are the main indicator of this. However, could you have synaptopathy without struggling with this? I clearly have some level of hearing damage to bring about tinnitus and hyperacusis but I have no difficulties with speech in noise therefore I wonder if it's mostly extended high-frequency loss for me. I feel like many of us would have some sort of mixed pathology.

If you have synaptopathy at higher frequencies, I would expect they'd be less likely to interfere with understanding speech in noise as the synapses in the major speech frequencies.

This is why i think extended audiograms are most useful but still really imperfect. It can at least possibly assess any sort of damage at frequencies higher than 8000 Hz.

These tests are really crude. Let's put it this way, I aced my speech in noise test but need captions to watch TV if there is any background music.

 

[Piet]

I developed tinnitus probably from long-term use of headphones playing games. My hearing is fine. I only struggle to hear above 15 kHz in my right ear, 16 kHz in my left ear.

My question is if FX-322 will maybe help me?

 

[Cernuto]

The word tests are done with a live voice, or prerecorded? If it's live then the pitch of the person's voice performing the test is an influence on the test?

 

[Diesel]

The word tests are done with a live voice, or prerecorded? If it's live then the pitch of the person's voice performing the test is an influence on the test?

Pre recorded. Played at 50 dB through headphones. Mine has always been a man's voice.

 

[FGG]

The word tests are done with a live voice, or prerecorded? If it's live then the pitch of the person's voice performing the test is an influence on the test?

Pre-recorded. And they can do both male or female voices.

 

[Philip83]

https://hearinghealthmatters.org/innovationsinhearing/2020/top-post-2020/

It's a bit discouraging when getting the question if he thinks that a treatment will be out within the next five years, Carl LeBel replies with "within this decade".

To me that implies that he is pretty sure it will take more than five years.

How can that be if FX-322 has been granted a fast track status and are most likely starting a pivotal phase sometime this year? Is he just hedging his bets if everything goes awry? Is there some kind of tactical/economical reason for a statement like that?

 

[FGG]

Don't a lot of people start losing those high frequencies like 16 kHz in their 40s?

It's common because modern society is so noisy and also environmental damage is cumulative.

 

[ThomasC]

I think it's normal if you can't hear anything above 16 kHz when you are 20+ years old.
It might also be a hardware problem.

 

[FGG]

I think it's normal if you can't hear anything above 16 kHz when you are 20+ years old.
It might also be a hardware problem.

Someone posted a study awhile ago that showed isolated tribal people did not lose hearing in those ranges. It seems to be a side effect of modern living.

 

[FGG]

https://hearinghealthmatters.org/innovationsinhearing/2020/top-post-2020/

It's a bit discouraging when getting the question if he thinks that a treatment will be out within the next five years, Carl LeBel replies with "within this decade".

To me that implies that he is pretty sure it will take more than five years.

How can that be if FX-322 has been granted a fast track status and are most likely starting a pivotal phase sometime this year? Is he just hedging his bets if everything goes awry? Is there some kind of tactical/economical reason for a statement like that?

I think that's the most conservative statement he could give because ultimately it depends on the FDA. In another interview, he said Phase 3 typically takes multiple years (he used the example of cardiac drugs) but FX-322 won't need that long because they can get away with a smaller sample size since improved hearing is innately "placebo controlled."

 

[serendipity1996]

https://hearinghealthmatters.org/innovationsinhearing/2020/top-post-2020/

It's a bit discouraging when getting the question if he thinks that a treatment will be out within the next five years, Carl LeBel replies with "within this decade".

To me that implies that he is pretty sure it will take more than five years.

How can that be if FX-322 has been granted a fast track status and are most likely starting a pivotal phase sometime this year? Is he just hedging his bets if everything goes awry? Is there some kind of tactical/economical reason for a statement like that?

I'm pretty sure this article was discussed and dissected already on this thread when it came out last year. The consensus seems to be that he's being quite conservative with his estimate to avoid any legal issues. Frequency Therapeutics have given every indication that they are working to get a viable treatment out as soon as feasible - Chris Loose explicitly said in a webinar a few months ago that they are working "as hard and as fast as they possibly can".

Carl LeBel also hinted that Phase 3 would be a lot quicker than it would for some other medications e.g cardiac medications.

 

[Pete88]

https://hearinghealthmatters.org/innovationsinhearing/2020/top-post-2020/

It's a bit discouraging when getting the question if he thinks that a treatment will be out within the next five years, Carl LeBel replies with "within this decade".

To me that implies that he is pretty sure it will take more than five years.

How can that be if FX-322 has been granted a fast track status and are most likely starting a pivotal phase sometime this year? Is he just hedging his bets if everything goes awry? Is there some kind of tactical/economical reason for a statement like that?

I wouldn't let that concern you much. His statements have to be conservative in order to avoid legal trouble. Assuming everything goes smooth, it looks like 2023 to 2025 for a FX-322 release. "Within 5 years" leaves no wiggle room but "within the decade" is uncontroversial. It generates excitement without setting them up for legal trouble if everything doesn't go perfectly.

Actions speak louder than words. They have recently been making moves that suggest they are preparing to make FX-322 available to the public in the next couple of years.

I would love for him to be cocky and say "it will be out by 2023" but he can't. Every word he says has to be bulletproof. I bet behind closed doors at parties, he says "within a few years".

 

[Diesel]

https://hearinghealthmatters.org/innovationsinhearing/2020/top-post-2020/

It's a bit discouraging when getting the question if he thinks that a treatment will be out within the next five years, Carl LeBel replies with "within this decade".

To me that implies that he is pretty sure it will take more than five years.

How can that be if FX-322 has been granted a fast track status and are most likely starting a pivotal phase sometime this year? Is he just hedging his bets if everything goes awry? Is there some kind of tactical/economical reason for a statement like that?

Director of an SEC-regulated company has to take care about making specific comments about future expectations. If he said, "It's going to be in 2024." and it slips to 2025... lawsuits and investigations would bury Frequency Therapeutics, and maybe none of us would get FX-322 at all...

 

[Philip83]

Cool, thanks for all the replies.

The top of the article dated December 29th, 2020, so I thought it was brand new! I got confused when he said results would be out second half of 2020, but that explains it then.

 

[Lucifer]

I'm pretty sure this article was discussed and dissected already on this thread when it came out last year. The consensus seems to be that he's being quite conservative with his estimate to avoid any legal issues. Frequency Therapeutics have given every indication that they are working to get a viable treatment out as soon as feasible - Chris Loose explicitly said in a webinar a few months ago that they are working "as hard and as fast as they possibly can".

Carl LeBel also hinted that Phase 3 would be a lot quicker than it would for some other medications e.g cardiac medications.

If that's true that Carl LeBel hinted that Phase 3 would be quicker then I hope that they review patients up to 90 days or less instead of the current Phase 2a clinical trial where they are reviewing patients up to Day 210. This is why there was such a long delay but also they only just completed enrolment in October.

 

[Drachen]

My question is if FX-322 will maybe help me?

I think this got buried in the previous discussion, but this graphic provided by Diesel should explain the scenarios in which this drug will be beneficial.

The general opinion formulated by several users here who have extensively researched this topic is that if your tinnitus is a result of sensorineural hearing loss, which includes "hidden" hearing loss, you may receive benefits from FX-322 if said loss is a result of damage or death of IHC/OHCs. Depending on the condition of your synapses, you may also need something along the lines of OTO-413, which aims to restore those connections between viable hair cells and the brain. FX-322 seems to only restore damaged or destroyed hair cells and reconnect those synapses with no apparent or known effect on the intact hairs.

Take note that no clinical results for FX-322 have so far officially shown anything with regards to tinnitus outside of anecdotal reports (and these are favorable). Carl LeBel, the Chief Development Officer of Frequency Therapeutics, also stated in a Tinnitus Talk Podcast episode that there is "biological rationale" in the idea that restoration of hair cells could reduce the effects of tinnitus. Frequency Therapeutics have taken this a step further and added tinnitus measurement as a secondary outcome to the current ongoing trial, and the first set of results are expected in March 2021.

 

[twa]

In the 2020 JPMorgan Fireside Chat, Chris Loose was asked if in the Phase 1/2 about the response of the drug... he quickly said, "All patients that received FX-322 in the Phase 1/2 saw a benefit." They went on to explain that due to a ceiling effect with hearing (human hearing can only get so good), the mild group saw improvement but it wasn't significant enough to show a measurable benefit.

This tells me that even patients with mild hearing loss where they may have worn or damaged hair cells scattered throughout will still see benefits.

I believe the ceiling effect was again discussed in the same chat by Loose, but in relation to multiple doses in the Phase 2A. Loosed discussed recruiting a more homogeneous group for the Phase 2A to show how effective multiple doses may be.

My take-away is that they probably screened for patients with moderate+ hearing loss that look like those 5 strong responders in the Phase 1/2. This gives them the ability to demonstrate improvement with multiple doses.

I think it stands to reason that if this drug can double word score for those with moderate+ hearing loss, those with milder cases will see some kind of favorable result.

I want to understand your rationale. If the mild group saw improvement, but it wasn't significant enough to show measurable benefit how do you see that milder cases will see some kind of favorable benefit?

 

[ThomasC]

Listening to your tinnitus pitch softens your tinnitus for a few seconds, because the altered signal from the cochlea is momentarily restored. It proves that healing hearing loss should be enough to treat tinnitus.

 

[d'Wooluf]

I don't see why Audiologists couldn't do a menu of packages, and charge more per package depending on the complaint and feedback from the patient. This is standard for other types of diagnostics in other industries, where they start with a 30-min broad diagnostic, and determine if a deeper inspection is needed.

The bundled pricing model that most of them use is a disincentive.

 

[Drachen]

Listening to your tinnitus pitch softens your tinnitus for a few seconds, because the altered signal from the cochlea is momentarily restored.

This is residual inhibition, right?

It proves that healing hearing loss should be enough to treat tinnitus.

I will admit I don't know a whole lot about it, but does that definitely prove it's enough?

 

[Diesel]

I want to understand your rationale. If the mild group saw improvement, but it wasn't significant enough to show measurable benefit how do you see that milder cases will see some kind of favorable benefit?

Great question.

So, to answer it, we first have to look at the measurements used in the Phase 1/2: Word Recognition Score in a quiet background (WR), and Word Score in a Noisy background (WIN), and the pure tone audiometry.

For both word scores, a "perfect" score is 50/50. For the audiometry, ideally, you'd want to see improvements at each frequency band until they reach the "normal" hearing range - between 0 dB and 20 dB.

For either word score measure, a significant improvement is one where there is an increase by roughly more 9 words.
For audiometry, an increase of 10 dB or greater is considered significant.

With mild hearing loss, chances are both the word score and audiometry is already fairly good. And, as we know, there is a clear "ceiling effect" with hearing improvement measures. One cannot score above 50/50 words, and can only improve so far into the "normal" hearing range of 0-20 dB.

I would expect that mild hearing loss cases with small deficits in WR word score (40 - 45 words) will improve to near perfect score, and likely see an improvement in WIN score as well, and they may also see minor improvements back to an audiogram that is above 20 dB. This would not be seen as significant in the clinical setting, but certainly would be noticeable to the patient.

I think the limitations of current hearing tests won't show the improvements in mild cases as obvious as moderate+. So, it may come down to simply quality of life improvements for mild folks who have their hearing return closer to normal to the point where they can go on and live their lives normally.