Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

Study FX-322-113 is also likely to be a failure if we follow the logic of FX-322-112, an ear that is too damaged to be repaired.

I'm not sure this is logical.

FX-322-112 was focused on Age-Related Hearing Loss. They specifically EXCLUDED patients where NIHL/SSNHL was a known factor. So, nobody had known noise exposure OR sudden hearing loss in that group. Therefore, it is likely other underlying causes that lead to age-related hearing loss where FX-322 / PCA won't work. Some have pointed to the degradation of the stria vascularis being unable to support newly created tissue in the high frequencies. This is of course, theoretical.

FX-322-113 is focused on Severe SNHL. This is an extension of the original Phase 1/2 group, where patients that have a history of NIHL / SSNHL are preferred.

The results from one cannot predict the other.

Also, of note from the Frequency Therapeutics investor deck. This is what I have been trying to say all along, and they announced back in July, 2020. They're probing different patient populations to determine who are the ideal responders for a future trial, and who will not be. (Now we know that's the "New Phase 2"). This is the "game" they have to play with the FDA. Identify the patient group that responds at 1 or more primary endpoints in the trial.

"[Detail from subjects across all single-dose studies will provide key insights into potential responders]"

Page 14: https://investors.frequencytx.com/static-files/6acbafde-4349-4d0c-95ee-11447bd368f6

 

[ThomasRobert]

I'm talking about the Phase 1b study that everyone has been quoting as "successful" because it replicated the same results as Phase 1/2, which apparently is the 111 study. Still, nobody has provided audiograms, despite constantly saying people's audiograms improved. They keep referring to the Phase 1/2 data.

I have a bad feeling that people are applying Phase 1/2 information onto Phase 1b-111 and there's a bunch of people parroting completely wrong information with so much confidence. I would love to be proven wrong.

Below are the positive results till date (Phase 1/2 & Phase 1b-111).

We are waiting for study 113 results soon...

 

[Pete88]

Below are the positive results till date (Phase 1/2 & Phase 1b-111).

We are waiting for study 113 results soon...

View attachment 45136

OK. This isn't providing any details that I'm trying to get at. Maybe those details don't exist yet? Fine. I'm just saying be cautious if there are no details.

Also, where are the audiogram improvements that so many people have been parroting? Why has nobody addressed this?

 

[Zugzug]

OK. This isn't providing any details that I'm trying to get at. Maybe those details don't exist yet? Fine. I'm just saying be cautious if there are no details.

Also, where are the audiogram improvements that so many people have been parroting? Why has nobody addressed this?

I'm a little confused. Who has been saying that FX-322 is a proven audiogram godsend? It's been correctly pointed out that there were some individual improvements from Phase 1/2, but I don't see anyone falsely suggesting that there are groupwide, placebo-controlled, statistically significant audiogram results.

The real debate is whether there are individual IHC super responders or not. I think people are looking for proof of concept -- any evidence at all that IHC or OHC can regrow in vivo. No one is imagining audiogram results that aren't there, as far as I can tell.

 

[Tezcatlipoca]

I wonder if Frequency Therapeutics is going to show individual data at their investor conference.

Also wow, I'm having March flashbacks.

 

[Pete88]

I'm a little confused. Who has been saying that FX-322 is a proven audiogram godsend? It's been correctly pointed out that there were some individual improvements from Phase 1/2, but I don't see anyone falsely suggesting that there are groupwide, placebo-controlled, statistically significant audiogram results.

The real debate is whether there are individual IHC super responders or not. I think people are looking for proof of concept -- any evidence at all that IHC or OHC can regrow in vivo. No one is imagining audiogram results that aren't there, as far as I can tell.

People were saying that the audiogram of the Phase 1b-111 also had 10 dB improvement at 8,000 Hz. All I want is for people to know that is false, so that expectations are tempered. Apparently this information was stuff everyone knew for 2 months. That sounds like a lot of misinformation for a long time.

Maybe people did have audiogram improvements. But it certainly is not published anywhere. Yet numerous people were saying the Phase 1b-111 trial had audiogram improvements and tried to back this up by posting Phase 1/2 data.

All I'm saying is that it was obvious people were confusing different studies and parroting incorrect statements.

 

[Diesel]

People were saying that the audiogram of the Phase 1b-111 also had 10 dB improvement at 8,000 Hz. All I want is for people to know that is false, so that expectations are tempered. Apparently this information was stuff everyone knew for 2 months. That sounds like a lot of misinformation for a long time.

Maybe people did have audiogram improvements. But it certainly is not published anywhere. Yet numerous people were saying the Phase 1b-111 trial had audiogram improvements and tried to back this up by posting Phase 1/2 data.

All I'm saying is that it was obvious people were confusing different studies and parroting incorrect statements.

I'm confused... can you cite the post number or page on Tinnitus Talk where Phase 1b-111 and Audiogram improvements were mentioned?

It often comes up for Phase 1/2 (FX-322-201), where it has been disclosed from Frequency Therapeutics below:

Note at the bottom, the Phase 1/2 study is cited.

I'd also like some clarity on who is confused here... if any of the readers are confused... please see my image above. Which states that 4/15 patients who participated in Phase 1/2 and got FX-322 saw a 10 dB improvement at 8 kHz on the audiogram.

 

[Pete88]

I'm confused... can you cite the post number or page on Tinnitus Talk where Phase 1b-111 and Audiogram improvements were mentioned?

It often comes up for Phase 1/2 (FX-322-201), where it has been disclosed from Frequency Therapeutics below:

View attachment 45137

Note at the bottom, the Phase 1/2 study is cited.

I'd also like some clarity on who is confused here... if any of the readers are confused... please see my image above. Which states that 4/15 patients who participated in Phase 1/2 and got FX-322 saw a 10 dB improvement at 8 kHz on the audiogram.

Sure, here are some screenshots from the previous page.

Maybe this is also a case of everyone misunderstanding everyone. But these are some of the posts that indicate people thought there were audiogram improvements from Phase 1b-111.

As long as everyone is aware that there is no audiogram from Phase 1b-111, I'm happy.

But this brings me to another concern; I thought they were testing higher frequencies for all the studies after Phase 1/2 implied improvements in extended frequencies. I would assume this would have been a great supplement to add to the results to solidify confidence. The lack of any mention of extended audiograms for Phase 1b-111 concerns me.

 

[Diesel]

Maybe this is also a case of everyone misunderstanding everyone. But these are some of the posts that indicate people thought there were audiogram improvements from Phase 1b-111.

As long as everyone is aware that there is no audiogram from Phase 1b-111, I'm happy.

But this brings me to another concern; I thought they were testing higher frequencies for all the studies after Phase 1/2 implied improvements in extended frequencies. I would assume this would have been a great supplement to add to the results to solidify confidence. The lack of any mention of extended audiograms for Phase 1b-111 concerns me.

Quite possibly. Any reference I have shown re: Audiogram improvements point to Frequency Therapeutics' disclosures from the Phase 1/2 trial. It's possible by referring to them both may have caused 1 poster to be confused. But, I would argue that this isn't a systemic echoing problem.

They have never disclosed a whole lot about the Open-Label trial, in particular any primary/secondary criteria.

 

[Pete88]

Quite possibly. Any reference I have shown re: Audiogram improvements point to Frequency Therapeutics' disclosures from the Phase 1/2 trial. It's possible by referring to them both may have caused 1 poster to be confused. But, I would argue that this isn't a systemic echoing problem.

They have never disclosed a whole lot about the Open-Label trial, in particular any primary/secondary criteria.

Alright, cool. Glad we are on the same page haha.

 

[Jrblovsky]

There are no successful trials if you're expecting improved audiograms.

View attachment 45125

You're wasting your time arguing with some of the people on this thread. I agree with you that the results and improvements are minimal and honestly not worth the mention.

My audiograms change all the time and have changed thresholds higher than the results of the FX-322 study.

Until there are solid audiogram improvements at ALL frequencies, FX-322 can kick rocks.

Hopefully Frequency Therapeutics will figure out why FX-322 doesn't work and make something happen. Presently it's as useless as a fart in a spacesuit.

 

[kiki]

But this brings me to another concern; I thought they were testing higher frequencies for all the studies after Phase 1/2 implied improvements in extended frequencies. I would assume this would have been a great supplement to add to the results to solidify confidence. The lack of any mention of extended audiograms for Phase 1b-111 concerns me.

I am also worried.

Take a look at page 10 of the May slide.

"High Frequencies are Critical for Intelligibility" on the March slide has been changed to "Intelligibility of Speech and Sound - A Major Unmet Clinical Need".

Also, on page 11, "high frequency consonants" has been changed to "fricative consonants".

Did they change the notation after confirming that there was no audiogram improvement at high frequencies? Or was it simply changed to a more correct wording?

Slide May 2021
https://investors.frequencytx.com/static-files/6acbafde-4349-4d0c-95ee-11447bd368f6

Slide March 2021
https://investors.frequencytx.com/static-files/4a540e6b-b160-4e35-b487-5c82d264103b

 

[Pete88]

You're wasting your time arguing with some of the people on this thread. I agree with you that the results and improvements are minimal and honestly not worth the mention.

My audiograms change all the time and have changed thresholds higher than the results of the FX-322 study.

Until there are solid audiogram improvements at ALL frequencies, FX-322 can kick rocks.

Hopefully Frequency Therapeutics will figure out why FX-322 doesn't work and make something happen. Presently it's as useless as a fart in a spacesuit.

I think it depends on what your issues are.

For me, I have no issues until the end of the audiogram and even then, it's not a crazy dip, just enough to identify as hearing loss.

The dip likely continues in the extended range. This long, continuous moderate loss in the extended frequencies is what is most likely causing my hissing, static tinnitus.

The people whose audiograms improved in the study had to have consistent audigrams for a period of time, which would mean that you wouldn't have been accepted in the trial. They wanted to eliminate the risk of people randomly improving or getting worse in order to prove the drug one way or another.

That is why I care a lot about the extended audiograms. I think that as long as I can get a few decibels up there and 10 dB or so in the last bit of the normal audiogram, it will push the input my brain receives high enough to eliminate the hissing.

Now if you're someone who has major hearing loss in the normal audiogram and a lower pitched tinnitus, maybe this drug isn't going to be as much of a difference maker. Though I think it could make a hearing aid work better as the clarity could be improved.

Anyway, that's my take on it. At this stage, I do think FX-322 would be exactly what I need to see a huge change, because my hearing is not overly damaged. But for some, yes, the benefits so far implied may not be a huge deal.

 

[Diesel]

"High Frequencies are Critical for Intelligibility" on the March slide has been changed to "Intelligibility of Speech and Sound - A Major Unmet Clinical Need".

Also, on page 11, "high frequency consonants" has been changed to "fricative consonants".

Did they change the notation after confirming that there was no audiogram improvement at high frequencies? Or was it simply changed to a more correct wording?

Could be a combination of discovery/lack of discovery leading to subtle word changes, and/or legal/compliance requiring that the presentation be more specific/accurate.

For example, high-frequency consonants is really vague. But, fricative consonants are well defined.

Also note: to my knowledge, there isn't a strong correlation between word recognition score and audiogram performance.

 

[Pete88]

I am also worried.

Take a look at page 10 of the May slide.

"High Frequencies are Critical for Intelligibility" on the March slide has been changed to "Intelligibility of Speech and Sound - A Major Unmet Clinical Need".

Also, on page 11, "high frequency consonants" has been changed to "fricative consonants".

Did they change the notation after confirming that there was no audiogram improvement at high frequencies? Or was it simply changed to a more correct wording?

Slide May 2021
https://investors.frequencytx.com/static-files/6acbafde-4349-4d0c-95ee-11447bd368f6

Slide March 2021
https://investors.frequencytx.com/static-files/4a540e6b-b160-4e35-b487-5c82d264103b

Yeah exactly. It seems like they are quietly walking back on the benefits of FX-322. If the Phase 1/2 results are truly indicative of what it does in its current form, that's great but I'm worried those results were inflated for whatever reason. My fear is fuelled by the omission of details on studies since Phase 1/2.

 

[kiki]

Could be a combination of discovery/lack of discovery leading to subtle word changes, and/or legal/compliance requiring that the presentation be more specific/accurate.

For example, high-frequency consonants is really vague. But, fricative consonants are well defined.

Also note: to my knowledge, there isn't a strong correlation between word recognition score and audiogram performance.

I hope the fricative consonants are related to high frequencies, as described in the following article.

I hope it's just a paraphrase to make the word accurate.

Classification of Fricative Consonants for Speech Enhancement in Hearing Devices

 

[Diesel]

I hope the fricative consonants are related to high frequencies, as described in the following article.

I hope it's just a paraphrase to make the word accurate.

Classification of Fricative Consonants for Speech Enhancement in Hearing Devices

Fricative consonants are high frequency sounds in language.

https://en.wikipedia.org/wiki/Fricative

The term "high frequency" isn't specific enough when considering parts of speech. The range of what "high frequency" means is open to interpretation.

 

[Guywithapug]

I would love to see FX-322 delivered as nanoparticles via Otomagnetics. It would be very interesting to see any contrast of results against passive diffusion through the round window.

 

[RingingBrother]

Your synapses are likely damaged. You have also lost hair cells. Both drugs that regenerate either synapses or hair cells will give you some benefit. It is argued that synapses are even more fragile than hair cells and may play a larger roll in hearing than they are credited for.

Point is, you'll need both to have excellent hearing but having one will likely still bring a lot of benefit.

To answer your last question though, yes, FX 322 grows the hair cells but you will benefit from either regeneration.

A few hundred pages ago, didn't they say that new hair cells automatically reconnect to the nerve and it's seen as a miracle in the scientific community?

 

[Pete88]

A few hundred pages ago, didn't they say that new hair cells automatically reconnect to the nerve and it's seen as a miracle in the scientific community?

Yeah but that's basically just saying that the new hair cells regrow completely. A hair cell without a synapse is like having a cell phone without a network connection. Hair cells need that synapse to work properly. Without it, the new regrown hair cells wouldn't be very useful.

What can often happen is synapses being damaged with the hair cells still functioning. FX-322 apparently does not help this issue but something like OTO-413 does.

 

[Tezcatlipoca]

Frequency Therapeutics just posted a pre-March infographic. Looks like they really are going for the clarity/WIN route. Thank God.

 

[GlennS]

Frequency Therapeutics update their marketing and your response is "thank God"? Neuromod is nothing if not some flashy marketing and how does that help us in the end? I fail to see how this is worth getting excited about.

 

[kiki]

Frequency Therapeutics just posted a pre-March infographic. Looks like they really are going for the clarity/WIN route. Thank God.

View attachment 45155

My concern:

They may have realized that high frequencies could not be improved after late March (Phase 2a interim announcement and age-related deafness announcement).

Because they haven't announced any improvements in high frequency (including EHF) audiograms. And the notation of "high frequency" was erased from the slide in May.

 

[Gb3]

Frequency Therapeutics update their marketing and your response is "thank God"? Neuromod is nothing if not some flashy marketing and how does that help us in the end? I fail to see how this is worth getting excited about.

Why are you on here so much then?

 

[Tezcatlipoca]

Sorry, I think I wasn't clear enough. If they go this route, they have better chances for approval because these are endpoints that have been successful.

 

[Pete88]

Honestly, any improvement is great for the not-severely compromised person. It may give lots of people a second chance who maybe went to a few too many concerts unprotected or used a table saw a couple too many times.

Anything that makes having hearing issues go from "sorry, nothing can be done" to "maybe this will help fix you up" is amazing. You make one wrong move and can be screwed for life. This may give people a little bit of a safety net.

 

[Sentinel]

I think it depends on what your issues are.

For me, I have no issues until the end of the audiogram and even then, it's not a crazy dip, just enough to identify as hearing loss.

The dip likely continues in the extended range. This long, continuous moderate loss in the extended frequencies is what is most likely causing my hissing, static tinnitus.

The people whose audiograms improved in the study had to have consistent audigrams for a period of time, which would mean that you wouldn't have been accepted in the trial. They wanted to eliminate the risk of people randomly improving or getting worse in order to prove the drug one way or another.

That is why I care a lot about the extended audiograms. I think that as long as I can get a few decibels up there and 10 dB or so in the last bit of the normal audiogram, it will push the input my brain receives high enough to eliminate the hissing.

Now if you're someone who has major hearing loss in the normal audiogram and a lower pitched tinnitus, maybe this drug isn't going to be as much of a difference maker. Though I think it could make a hearing aid work better as the clarity could be improved.

Anyway, that's my take on it. At this stage, I do think FX-322 would be exactly what I need to see a huge change, because my hearing is not overly damaged. But for some, yes, the benefits so far implied may not be a huge deal.

I think we are in a similar boat, but if the theory regarding cochlear synaptopathy is true and the synapses are less resilient than the OHCs, then I think we will have to hope FX-322 restores enough of whatever is there in order to give the brain enough input to rid us of the tinnitus.

If not, then it seems we have to wait for OTO-413 to work in concert with it.

 

[GlennS]

Why are you on here so much then?

And so it begins...

 

[Tezcatlipoca]

I think we are in a similar boat, but if the theory regarding cochlear synaptopathy is true and the synapses are less resilient than the OHCs, then I think we will have to hope FX-322 restores enough of whatever is there in order to give the brain enough input to rid us of the tinnitus.

If not, then it seems we have to wait for OTO-413 to work in concert with it.

Well depends. The theory you refer to mainly applies to NIHL. I agree with it though.

However, I think that FX-322 could give us a decent amount of relief.

 

[Sentinel]

However, I think that FX-322 could give us a decent amount of relief.

Yeah, I think it probably will too, it's just going to be interesting how it varies from treatment to cure for different people in different circumstances. I don't see more input in any category as being a bad thing.