Frequency Therapeutics — Hearing Loss Regeneration

[ThomasRobert]

But does it do anything for tinnitus...

If your tinnitus was caused by inner ear hair cell damage, then yes...

 

[Diesel]

But does it do anything for tinnitus...

The only documentation we have is from the international patent based on the Phase 1/2 participants:

Source:
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020210388&tab=PCTBIBLIO

 

[Zugzug]

I'm glad future trials will include "lead in baselines" to mitigate the artificial baseline word score depression in the future.

What does a lead in baseline mean? Does it really mean using the screening as the baseline?

 

[FGG]

What does a lead in baseline mean? Does it really mean using the screening as the baseline?

I interpreted it to mean using longer term measurements as a baseline.

 

[Keith Handy]

The only documentation we have is from the international patent based on the Phase 1/2 participants:

View attachment 44544

Source:
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020210388&tab=PCTBIBLIO

And even if it only gave you back the hearing in the range of your tinnitus, masking would become considerably easier.

 

[FGG]

The only documentation we have is from the international patent based on the Phase 1/2 participants:

View attachment 44544

Source:
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020210388&tab=PCTBIBLIO

This seems to imply that IHC loss was the source of these patients' tinnitus at least. But obviously longer term studies will help shine a light on that.

 

[kiki]

Okay so I have been keeping up with this thread since the onset of my tinnitus, and I was disappointed by the recent results from their multiple injection trial.

However I don't remember reading anywhere of them specifically mentioning the treatment's effect on tinnitus.

Does anyone know if they released some concrete information on the most recent trial's effect on tinnitus?

I know it's only a secondary measure and that they said they were issues with the delivery method, but I don't remember them specifically mentioning tinnitus in their 90 day readout. So for all we know it might still help with tinnitus?

So far, basically, their reports have only been about WR between groups. They reported that WR was not significantly improved compared to the placebo group due to defects in the clinical trial design.

It's just an interim report, and in the final report, there will be detailed reports on everything (WR, WIN, PTA, TFI, etc).

 

[kiki]

While he didn't clarify exactly what the next FX-322 trials would be, they did present that they are working with the FDA to kick off more studies 2H/2021.

I think there is a possibility of a new Phase 2a focusing on Moderate -> Severe.

 

[FGG]

I think there is a possibility of a new Phase 2a focusing on Moderate -> Severe.

Seems like it. Presumably (hopefully), they find candidates who have a long term medical history of lower word scores. I think if they can do that successfully and stick with single dosing (for now), they can advance the drug.

 

[Lucifer]

Next steps for FX-322:

View attachment 44541

Lucchino was quite confident and said the company is focused on gathering more information from ongoing trials to eventually advance to a Phase 3.

When they refer to ongoing trials, it sounds to me that it might be possible to advance to Phase 3/pivotal phase after the results from the age-related and severe hearing loss trials come out.

 

[OptimusPrimed]

Seems like it. Presumably (hopefully), they find candidates who have a long term medical history of lower word scores. I think if they can do that successfully and stick with single dosing (for now), they can advance the drug.

I watched the update on their website. They seem very optimistic about their drug and not too concerned about the recent failure. I mean, who knows what the drug actually did to the patients' cochleas. Have they conducted post-autopsy studies to see if they have actually re-grown human inner ear hair cells?

Also; if any of these companies; Frequency Therapeutics, Otonomy, Pipeline Therapeutics, etc... are successful in regrowing the inner ear hair cells of the cochlea, who is to say that those hair cells will function or connect to the auditory nerve? And if they do; will the auditory input stop tinnitus?

I am not trying to be negative. I have suffered with this disease, and yes it is a disease, since 2007 after an acoustic trauma and for the last two weeks I have had a horrible flare up to the point where I am finding it difficult to hear out of my right ear. I now have ringing in both ears, right ear is near unbearable and left ear is slowly getting worse. I would welcome anything that works and quietens the ringing.

 

[FGG]

I watched the update on their website. They seem very optimistic about their drug and not too concerned about the recent failure. I mean, who knows what the drug actually did to the patients' cochleas. Have they conducted post-autopsy studies to see if they have actually re-grown human inner ear hair cells?

It's not considered ethical to do post-autopsy studies in humans, though I would volunteer at this point...

They have done necropsies on their animal models as well as tested the drug in human cochlea explants (removed human cochleas, perhaps this is what you meant by autopsy studies).

They have also observed hearing recovery in their animal models as well as saw histological evidence of nerve reconnection.

Also, unless the Phase 1 results were fraud, IHCs were regrown and made nerve connections (otherwise the word scores would not have improved the way they did).

 

[kiki]

Seems like it. Presumably (hopefully), they find candidates who have a long term medical history of lower word scores. I think if they can do that successfully and stick with single dosing (for now), they can advance the drug.

What do you think the indication of the drug would be if they followed this policy and succeeded in all future clinical trials and FX-322 hit the market? "SNHL" or "SNHL (Moderate-> Severe)"?

If there are certain anecdote about FX-322 improving tinnitus, could tinnitus also be an indication for FX-322?

I previously posted the following:

If there is sufficient evidence of WR improvement and there are a certain number of anecdotes of PTA improvement, FX-322 will go on the market.

In that case, the indication might be "SNHL" rather than "WR deterioration".
In that case, there is a possibility that insurance will be applied even for "PTA deterioration".

If FX-322 goes on the market, I don't think reinjection is prohibited after a certain period of time. It may be accepted as a second, third, fourth..."single injection".

 

[OptimusPrimed]

It's not considered ethical to do post-autopsy studies in humans, though I would volunteer at this point...

They have done necropsies on their animal models as well as tested the drug in human cochlea explants (removed human cochleas, perhaps this is what you meant by autopsy studies).

They have also observed hearing recovery in their animal models as well as saw histological evidence of nerve reconnection.

Also, unless the Phase 1 results were fraud, IHCs were regrown and made nerve connections (otherwise the word scores would not have improved the way they did).

This makes their poor results even more troubling and more mystifying... Some people who get cochlear implants still have tinnitus even after they turn on the electrical probe and stimulate the auditory pathway. But then there are others who have tinnitus and when the probe is zapped; bang - tinnitus gone. So will restoring those hair cells end the tinnitus? Nobody knows!

It is possible that the immune system rejected the medication, it is also possible that the hair cells grew but are not lined up correctly and therefore don't work. Also maybe once the brain re-routes neurons in the auditory pathway they might die and not function even when the lost hair cells are regenerated?

This trial has left us with more questions than answers. I have to say though, when I first got my tinnitus in 2007 there were little prospects of hope. I searched the internet for cures, answers, with nothing. AM-101 was the first I had heard of but I am happy to see now that the prospect of restoring hearing is realistic and no longer a complete pipe dream. Both tinnitus and hearing loss are huge markets with unmet demand that have the potential to be major cash cows for these companies; that makes me optimistic and hopeful.

 

[Diesel]

This makes their poor results even more troubling and more mystifying... Some people who get cochlear implants still have tinnitus even after they turn on the electrical probe and stimulate the auditory pathway. But then there are others who have tinnitus and when the probe is zapped; bang - tinnitus gone. So will restoring those hair cells end the tinnitus? Nobody knows!

It is possible that the immune system rejected the medication, it is also possible that the hair cells grew but are not lined up correctly and therefore don't work. Also maybe once the brain re-routes neurons in the auditory pathway they might die and not function even when the lost hair cells are regenerated?

This trial has left us with more questions than answers. I have to say though, when I first got my tinnitus in 2007 there were little prospects of hope. I searched the internet for cures, answers, with nothing. AM-101 was the first I had heard of but I am happy to see now that the prospect of restoring hearing is realistic and no longer a complete pipe dream. Both tinnitus and hearing loss are huge markets with unmet demand that have the potential to be major cash cows for these companies; that makes me optimistic and hopeful.

Ahem... at least 3 people do...

Source:
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020210388&tab=PCTBIBLIO

 

[FGG]

This makes their poor results even more troubling and more mystifying... Some people who get cochlear implants still have tinnitus even after they turn on the electrical probe and stimulate the auditory pathway. But then there are others who have tinnitus and when the probe is zapped; bang - tinnitus gone. So will restoring those hair cells end the tinnitus? Nobody knows!

It is possible that the immune system rejected the medication, it is also possible that the hair cells grew but are not lined up correctly and therefore don't work. Also maybe once the brain re-routes neurons in the auditory pathway they might die and not function even when the lost hair cells are regenerated?

This trial has left us with more questions than answers. I have to say though, when I first got my tinnitus in 2007 there were little prospects of hope. I searched the internet for cures, answers, with nothing. AM-101 was the first I had heard of but I am happy to see now that the prospect of restoring hearing is realistic and no longer a complete pipe dream. Both tinnitus and hearing loss are huge markets with unmet demand that have the potential to be major cash cows for these companies; that makes me optimistic and hopeful.

I think you are putting all of the weight on audiogram changes. Those reflect OHCs. The word score changes reflect IHC regrowth (and reconnection).

Here is a good video that explains the difference:



So the hair cells are grown and aren't rejected by the immune system.

As to why they grew IHCs preferentially with their protocol, it's not known yet but they did just hire an audiologist who specializes (among other things) in using SFOAEs to detect OHC changes. It's possible single dosing grows only a small amount of OHCs but multi-dosing may help increase this amount (just not weekly as that was found to be problematic).

If you look at their patent, the responders who grew IHCs (we know because they increased their word scores), were the ones whose tinnitus improved.

 

[Diesel]

It is possible that the immune system rejected the medication, it is also possible that the hair cells grew but are not lined up correctly and therefore don't work. Also maybe once the brain re-routes neurons in the auditory pathway they might die and not function even when the lost hair cells are regenerated?

If the hair cells died, didn't line up correctly, and don't function... how do we explain this slide? It appears function was retained to some extent for at a minimum 13 months.

 

[kiki]

NOTE: Zero discussion on reformulation or changing FX-322 itself.

I think they have already started research on the improved version (Ver. 2.0).

However, I don't think they will announce that before Ver. 1.0 is on the market until just before the start of the Ver. 2.0 clinical trial.

 

[OptimusPrimed]

If the hair cells died, didn't line up correctly, and don't function... how do we explain this slide? It appears function was retained to some extent for at a minimum 13 months.

View attachment 44547

Why only 13 months? It's not a long lasting effect? I find this stuff fascinating.

 

[paul mclean]

When they refer to ongoing trials, it sounds to me that it might be possible to advance to Phase 3/pivotal phase after the results from the age-related and severe hearing loss trials come out.

Please let that be true. If they are able to do the pivotal phase without redoing Phase 2, then that's a godsend and saves alot of time.

 

[Diesel]

Why only 13 months? It's not a long lasting effect? I find this stuff fascinating.

The participants highlighted in blue retained their audiogram improvement at 8 kHz. So, i suspect where FX-322 caused regeneration, it was still like new. However, un-replaced/regenerated cells lower in the cochlea continued to wear, causing a reduced word score.

Frequency Therapeutics mentions that they believe regenerating in the high frequency is causing an improvement in understanding fricatives in the English language are benefitting patients. It's possible then that overtime the ability to understand fricatives is retained, but lower consonants like affricates confined to decline; causing a different word recognition loss.

 

[FGG]

I think they have already started research on the improved version (Ver. 2.0).

However, I don't think they will announce that before Ver. 1.0 is on the market until just before the start of the Ver. 2.0 clinical trial.

Is this just speculation? Or is this based on a recent statement?

Why only 13 months? It's not a long lasting effect? I find this stuff fascinating.

That's just how far out they tested them. It doesn't mean it only lasts 13 months.

When they refer to ongoing trials, it sounds to me that it might be possible to advance to Phase 3/pivotal phase after the results from the age-related and severe hearing loss trials come out.

"Eventually" doesn't mean go straight to pivotal. I took that to mean the ongoing trials will provide info will help them design and pass the next Phase 2, therefore moving on to Phase 3 at that point.

 

[GlennS]

I think you are putting all of the weight on audiogram changes. Those reflect OHCs. The word score changes reflect IHC regrowth (and reconnection).

I think most of us expect improved audiograms to classify a treatment like this as successful. You're the exception who keeps splitting hairs on the OHC vs. IHC front.

 

[Diesel]

I think most of us expect improved audiograms to classify a treatment like this as successful. You're the exception who keeps splitting hairs on the OHC vs. IHC front.

What if it were the other way around? And audiogram improved but WR and WIN showed no improvement? Would the conversation be the same?

 

[Sunshine007]

I interpreted it to mean using longer term measurements as a baseline.

My understanding of this is there will be a couple of tests before a baseline is accepted. I think they will want to see stable word recognition scores (within a tight range) during the lead in period before receiving treatment.

 

[RB2014]

What if it were the other way around? And audiogram improved but WR and WIN showed no improvement? Would the conversation be the same?

I'm pretty sure improvement in the audiogram was what they were initially after. What we are getting is something completely different. I bet they were surprised at the outcome of the Phase 1 trial, and even more surprised at the outcome of this last trial. They and everyone else was hoping for more. This will help some people and it is a great first step, but the initial experiments showed it has much more potential. If the improved word scores hold true, then they will have something to market and they can start generating money to keep the company going, but I seriously doubt this was anywhere near the plan.

Hey... that was funny, Glenn... splitting hairs... on inner and outer hair cells. Good one!!!

 

[Diesel]

I'm pretty sure improvement in the audiogram was what they were initially after. What we are getting is something completely different. I bet they were surprised at the outcome of the Phase 1 trial, and even more surprised at the outcome of this last trial. They and everyone else was hoping for more. This will help some people and it is a great first step, but the initial experiments showed it has much more potential. If the improved word scores hold true, then they will have something to market and they can start generating money to keep the company going, but I seriously doubt this was anywhere near the plan.

Hey... that was funny, Glenn... splitting hairs... on inner and outer hair cells. Good one!!!

Without a doubt, whatever the living biology is doing to regenerate cells in the cochlea doesn't seem to align with what was observed in vivo. Which appears to be unexpected on the surface; but also somewhat likely considering that they are performing science on people for the first time in human history.

What I was trying to get is how it's not just oversimplification is to disregard all of the evidence and point to the audiogram; it's also lazy.

The honest attempt to understand what changes in the underlying biology may have led to word score increases alone that led @FGG to point to IHC regrowth appears to have some merit.

Now that Frequency Therapeutics has hired Jeffery Lichtenhan to specifically lead their hearing diagnostics effort; who appears to have some significant credentials in researching and developing novel hearing metrics. If the firm starts using various OAE methods to better understand IHC/OHC/synapse restoration, but still cannot validate any audiogram improvements, are we going to disregard those results as well?

 

[kiki]

Is this just speculation? Or is this based on a recent statement?

I'm sorry, it's speculation, not based on actual statement.

This year, Frequency Therapeutics posted a pharmacokinetic observation job listing (web page has already been removed). And after the announcement of Phase 1/2 results (only 10 dB improvement at 8 kHz), it's hard to imagine that they haven't researched anything for more than a year and a half on the improvements they were aiming for up to 4 kHz.

 

[FGG]

I think most of us expect improved audiograms to classify a treatment like this as successful. You're the exception who keeps splitting hairs on the OHC vs. IHC front.

That wasn't my point. I was responding to the idea that there is no nerve connection and the idea that the drug doesn't regrow hair cells.

@OptimusPrimed was likely basing those theories on the audiogram (because why else would you conclude that?).

And this is not a matter of "splitting hairs," it's about being accurate.

 

[Lucifer]

I think most of us expect improved audiograms to classify a treatment like this as successful. You're the exception who keeps splitting hairs on the OHC vs. IHC front.

There were improvements in audiogram (OHCs) in Phase 1b trials. They only tested up to 8 kHz, but I would assume if there was an improvement in 8 kHz then 8-20 kHz should have improvements in audiogram as well.

It's a shame they did not do an extended hearing test in the Phase 1b trials. The audiogram results would have looked much better if they did an extended hearing test.