Frequency Therapeutics — Hearing Loss Regeneration

[Nobody19]

Thank you for this but I can't seem to find the FX-322-111 study on the ClinicalTrials.gov website.

It's the wrong study, I can't find FX-322-111 either.

 

[Diesel]

Yes, I was reading about this a lot today. Embryologically, you grow IHCs first and signals from them seem necessary for OHC growth. I'm so glad you found this, too.

If this is the case, it would be seen here, too (that is if people were honest about word scores for Phase 2a).

The severe group stands the most chance of replicating this. Especially if they were single dose.

Ok, so thinking through what might be happening in the cochlea... there are a few scenarios to consider when looking at how PCA/FX-322 are affecting IHC/OHC regrowth:

1. IHC Damaged + OHC Damage -> FX-322 Dose regrows IHC first, no OHC.
2. IHC Normal + OHC Damage -> FX-322 Dose should regrow OHC.
3. IHC Damaged + OHC Normal -> FX-322 Dose should regrow IHC.
4. Synaptopathy -> FX-322 wont affect these cells.

Just so we're all clear:
IHC: Send the actual sound signal to the brain. Without it, there is no signal. Needs about 50 dB to send signal.
OHC: Amplify / Tune sensitivity of sound... act to increase/decrease gain of sound below 50 dB.

Scenario 1: Would show gains in WR (Quiet) since no gain is needed, but not on audiogram (where gain is req'd).
Scenario 2: Repairing both should show up in WR (Quiet) + Audiogram.
Scenario 3: Repairing both should show up in WR (Quiet) + Audiogram.

Unknown:
State of damage at Moderate -> Moderately Severe hearing loss? What is the distribution of 1, 2, 3, and 4? Assuming it's a lot of condition 1, then this is why we see word score bumps + spotty audiogram improvements.

Doesn't explain EHF, unless the drug is flowing through too quickly and really only triggers the IHC at that level, and not OHC.

 

[Tezcatlipoca]

I hope you're right! Any way we can reconcile this with what Carl said today in a soundbite:

"It's fair to say we have more Phase 2 work to do. Some of these things we uncovered out of the four-injection study, we really want to home in on as we begin to think about what a pivotal trial design will look like in the future"​

I don't know if I should read this as them doing another Phase 2 trial prior to a Phase 3 trial, or them doing a Phase 2 trial as part of a pivotal Phase 2/Phase 3 trial?

If we assume the other day's anecdote is true, then I think they're going to do a Pivotal Phase 2/3 trial.

We could be back in business!

 

[FGG]

I hope you're right! Any way we can reconcile this with what Carl said today in a soundbite:

"It's fair to say we have more Phase 2 work to do. Some of these things we uncovered out of the four-injection study, we really want to home in on as we begin to think about what a pivotal trial design will look like in the future"​

I don't know if I should read this as them doing another Phase 2 trial prior to a Phase 3 trial, or them doing a Phase 2 trial as part of a pivotal Phase 2/Phase 3 trial?

I think it would depend on what the single dose severe group looks like. If that one also doubled word scores (this is a group that doesn't need to "fake" bad hearing), I could see it being enough for a Phase 2/3.

 

[Diesel]

I hope you're right! Any way we can reconcile this with what Carl said today in a soundbite:

"It's fair to say we have more Phase 2 work to do. Some of these things we uncovered out of the four-injection study, we really want to home in on as we begin to think about what a pivotal trial design will look like in the future"​

I don't know if I should read this as them doing another Phase 2 trial prior to a Phase 3 trial, or them doing a Phase 2 trial as part of a pivotal Phase 2/Phase 3 trial?

In considering the entire context of the conversation, I read it as:

1. We're going with a single-dose study through pivotal. So, we're going to make for absolute certain there's no more a-holes fucking up the pivotal trial.

2. We want to get into the details of the Phase 2 and get evidence of the exact cheating/faking/lying so we know how to prevent these cases.

3. We want to salvage the Phase 2 data to help get us to pivotal on-schedule.

 

[Zugzug]

Why not inject back-to-back dosages to push the first injection further into the cochlea?

The running theory is the opposite. That is, that more dosages too soon is negatively affecting the impact of the already existing doses and new, developing hair cells.

 

[Diesel]

Can we get some sources please, guys? For my own sanity/self-preservation I need to go down this rabbithole myself.

I am looking at this right now:

https://embryology.med.unsw.edu.au/embryology/index.php/Hearing_-_Inner_Ear_Development

 

[Aaron91]

Ok, so thinking through what might be happening in the cochlea... there are a few scenarios to consider when looking at how PCA/FX-322 are affecting IHC/OHC regrowth:

1. IHC Damaged + OHC Damage -> FX-322 Dose regrows IHC first, no OHC.
2. IHC Normal + OHC Damage -> FX-322 Dose should regrow OHC.
3. IHC Damaged + OHC Normal -> FX-322 Dose should regrow IHC.
4. Synaptopathy -> FX-322 wont affect these cells.

Just so we're all clear:
IHC: Send the actual sound signal to the brain. Without it, there is no signal. Needs about 50 dB to send signal.
OHC: Amplify / Tune sensitivity of sound... act to increase/decrease gain of sound below 50 dB.

Scenario 1: Would show gains in WR (Quiet) since no gain is needed, but not on audiogram (where gain is req'd).
Scenario 2: Repairing both should show up in WR (Quiet) + Audiogram.
Scenario 3: Repairing both should show up in WR (Quiet) + Audiogram.

Unknown:
State of damage at Moderate -> Moderately Severe hearing loss? What is the distribution of 1, 2, 3, and 4? Assuming it's a lot of condition 1, then this is why we see word score bumps + spotty audiogram improvements.

Doesn't explain EHF, unless the drug is flowing through too quickly and really only triggers the IHC at that level, and not OHC.

Very interesting. I wonder whether, in answer to your final question regarding EHF, that because the small molecules would be absorbed by IHCs first, one would then need another pass in order for the respective OHCs to kick in because there is an obvious lag period where we need the IHC to develop first in order to get that signal? This would suggest then that we still need multiple doses if we're going to see audiogram improvements with at least several weeks spaced apart.

In any case, why were things different in the animal studies? Do the animal studies suggest that that there is no equivalent order of operations and that this is unique to humans?

 

[Tezcatlipoca]

In considering the entire context of the conversation, I read it as:

1. We're going with a single-dose study through pivotal. So, we're going to make for absolute certain there's no more a-holes fucking up the pivotal trial.

2. We want to get into the details of the Phase 2 and get evidence of the exact cheating/faking/lying so we know how to prevent these cases.

3. We want to salvage the Phase 2 data to help get us to pivotal on-schedule.

Also make sure no audiologist is involved in any part of the trial whatsoever, for all we know they're fucking up on purpose so they can continue to be hearing aid salesmen.

 

[mrbrightside614]

The running theory is the opposite. That is, that more dosages too soon is negatively affecting the impact of the already existing doses and new, developing hair cells.

I don't think increased concentration in one dose would affect therapeutic efficacy, positively or negatively, in one sitting.

I think they ran into issues because they weren't allowing the prior dose to effectively settle and proliferate. I think their dosing schedule was way too fast, but I didn't think it would absolutely obliterate the entire point of Phase 2 like it might have.

 

[Ali.sy]

What treatment possibilities do we have left? Which treatment will be able to help us after the failure of FX-322?

 

[chinup]

It takes a little bit more time with the inspiration.

I would like to have hope, but you just have to look at the chart.

View attachment 44172

The chart shows the comparison of the highly speculative Otonomy share BEFORE the bad news was released (in mid-February, the market value halved in one day) and Frequency Therapeutics' just before the news now.

Well who notices something?

Are these completely different courses, quite similar or even almost identical?
You tell me, otherwise I look like a know-it-all.

They all doubted and mocked this guy. Not only did the results bomb but the stock crashed and everyone who invested is holding bags down 80%, which will take years to recover if it ever does. Incredible.

The chart never lies.

 

[mrbrightside614]

What treatment possibilities do we have left? Which treatment will be able to help us after the failure of FX-322?

It's not a failure yet. It really isn't. It's just a major setback to people who are holding on for dear life on a day-to-day basis.

 

[Lucifer]

It's the wrong study, I can't find FX-322-111 either.

That's why I was confused at which results were the FX-322-111 as it was stated in their press release that they got positive results from a new trial which I originally thought they were talking about 2019 results. The ClinicalTrials.gov website only lists age-related FX-322-112 and severe hearing loss for FX-322-113.

 

[FGG]

Can we get some sources please, guys? For my own sanity/self-preservation I need to go down this rabbithole myself.

I wish I thought to bookmark. This is not the best one, but this is the last one I was looking at and at least and it seems to suggest that IHC is the "default" hair cell but eventually inhibits itself:

"These studies suggest that OHC development may be an extended process that begins with inhibition of an IHC fate, followed by a gradual specification of an OHC phenotype."​

Development of the cochlea

 

[Diesel]

Very interesting. I wonder whether, in answer to your final question regarding EHF, that because the small molecules would be absorbed by IHCs first, one would then need another pass in order for the respective OHCs to kick in because there is an obvious lag period where we need the IHC to develop first in order to get that signal? This would suggest then that we still need multiple doses if we're going to see audiogram improvements with at least several weeks spaced apart.

In any case, why were things different in the animal studies? Do the animal studies suggest that that there is no equivalent order of operations and that this is unique to humans?

Based on what I'm reading from here:

http://www.cochlea.eu/en/development-and-plasticity/cochlea

It looks like human hair cells in utero take about 6-10 weeks to grow into a fully-functioning cell. But, in the first 3-4 weeks, sound is detectable. If I am understanding it right.

Lower mammals only have IHC, I believe like mice. I know they mentioned testing the stuff on higher vertebrates, which I assume may have been a dog, cat, chimp... something with IHC/OHC present? But, could be trained to respond to sound signals / commands, etc.

 

[Lucifer]

I wish I thought to bookmark. This is not the best one, but this is the last one I was looking at and at least and it seems to suggest that IHC is the "default" hair cell but eventually inhibits itself:

"These studies suggest that OHC development may be an extended process that begins with inhibition of an IHC fate, followed by a gradual specification of an OHC phenotype."​

Development of the cochlea

Maybe this is the reason why we had a positive anecdote that after 5 months of her last FX-322 dose her tinnitus went away.

In theory it could be that it takes a long time for the effects to permanently settle i.e. it may be quick to regrow the IHCs but the OHCs may take awhile to regrow.

We still do not know whether the delivery method was the problem with additional dosages or whether additional dosages weekly in quick succession kills the process. If it's the latter, it may be that if you inject the ear with additional doses of FX-322 too soon, it has to restart the process all over again as it was interrupted by the additional doses of FX-322.

 

[Tezcatlipoca]

I wish I thought to bookmark. This is not the best one, but this is the last one I was looking at and at least and it seems to suggest that IHC is the "default" hair cell but eventually inhibits itself:

"These studies suggest that OHC development may be an extended process that begins with inhibition of an IHC fate, followed by a gradual specification of an OHC phenotype."​

Development of the cochlea

Doesn't this explain the anecdotes of tinnitus improving/going away several weeks after the injection?

 

[scotty03874]

If the Phase 1b results are positive at the end of the year and the severe patients show substantial improvements in their hearing then they may be able to go through with the pivotal phase early next year.

I doubt it. This company has let us all down. I don't care about the $15,000 I lost. I really want my quality of life back.

 

[FGG]

Very interesting. I wonder whether, in answer to your final question regarding EHF, that because the small molecules would be absorbed by IHCs first, one would then need another pass in order for the respective OHCs to kick in because there is an obvious lag period where we need the IHC to develop first in order to get that signal? This would suggest then that we still need multiple doses if we're going to see audiogram improvements with at least several weeks spaced apart.

In any case, why were things different in the animal studies? Do the animal studies suggest that that there is no equivalent order of operations and that this is unique to humans?

A difference could be accounted for by the fact that rodents do not have a patent cochlear aqueduct (so is less affected by CSF pressure and blood flow) and humans do and this could change the diffusion speed. Maybe an IHC just needs to start developing first?

This is all theoretical of course. I'm just trying to figure out how to account for the Phase 1 word score results being unprecedented in historical controls without having to explain it with a) people lying who didn't need to for trial entry or b) Frequency Therapeutics is just a total fraud, which I don't believe.

 

[FGG]

Doesn't this explain the anecdotes of tinnitus improving/going away several weeks after the injection?

I think tinnitus trial data could be as unreliable as word scores were, unfortunately, since it's all patient reported.

But if you are talking about the anecdote posted here, assuming it's real, I think it's more likely the brain just takes time to reverse maladaptive plasticity.

 

[scotty03874]

Hearing loss and eye floaters; will there ever be a cure? God I hope so. I'm too young to have to deal with all of this s!!t.

Dr. Randall Wong can fix your floaters in Fairfax VA. He did both of my eyes in 2015.

With hearing loss I think we are all fu*ked. I want to cry... right now. I thought FREQ really had something going here...

 

[Zugzug]

Does anyone know if there's a transcript to the video discussion?

 

[FGG]

Maybe this is the reason why we had a positive anecdote that after 5 months of her last FX-322 dose her tinnitus went away.

In theory it could be that it takes a long time for the effects to permanently settle i.e. it may be quick to regrow the IHCs but the OHCs may take awhile to regrow.

We still do not know whether the delivery method was the problem with additional dosages or whether additional dosages weekly in quick succession kills the process. If it's the latter, it may be that if you inject the ear with additional doses of FX-322 too soon, it has to restart the process all over again as it was interrupted by the additional doses of FX-322.

That's not really what i was saying. Even if the IHC theory is correct, the drug probably doesn't hang around for months to grow OHCs later. You would have to re-dose (a month or few later). Unless all your IHCs were already normal (which you can't test for).

If that anecdote is correct, it's more likely reversing maladaptive plasticity, which takes time.

 

[scotty03874]

Nope. They say so in the press release. They're going to continue with a single-dose regimen. So they can go to Phase 2b/3 with a single dose drug that treat EHF + Word Score.

I think they're finished!

 

[Tezcatlipoca]

That's not really what i was saying. Even if the IHC theory is correct, the drug probably doesn't hang around for months to grow OHCs later. You would have to re-dose (a month or few later). Unless all your IHCs were already normal (which you can't test for).

If that anecdote is correct, it's more likely reversing maladaptive plasticity, which takes time.

The how doesn't matter, if it helps with tinnitus, we are set.

 

[Lucifer]

I doubt it. This company has let us all down. I don't care about the $15,000 I lost. I really want my quality of life back.

The likelihood of severe patients showing substantial improvements is quite low as it would need to reach deeper in the round window.

I wish they specified in both Phase 1b trials whether those who had significant improvements were in the severe category.

 

[Jcmc]

I think it would depend on what the single dose severe group looks like.

I'm sorry, but I really don't see how this could have good results if they continue with the same delivery method to the cochlea.

Can you explain that to me please?

 

[Lucifer]

I don't think increased concentration in one dose would affect therapeutic efficacy, positively or negatively, in one sitting.

I think they ran into issues because they weren't allowing the prior dose to effectively settle and proliferate. I think their dosing schedule was way too fast, but I didn't think it would absolutely obliterate the entire point of Phase 2 like it might have.

I'm guessing they should have done monthly FX-322 injections instead of weekly. We have no idea if the drug delivery method was the problem or the additional doses in quick succession. At least we know now that with the current method weekly doses kill the process so if it does come out, monthly doses will be a better option.

 

[Lucifer]

A difference could be accounted for by the fact that rodents do not have a patent cochlear aqueduct (so is less affected by CSF pressure and blood flow) and humans do and this could change the diffusion speed. Maybe an IHC just needs to start developing first?

This is all theoretical of course. I'm just trying to figure out how to account for the Phase 1 word score results being unprecedented in historical controls without having to explain it with a) people lying who didn't need to for trial entry or b) Frequency Therapeutics is just a total fraud, which I don't believe.

The likelihood of people lying in the Phase 1b is quite low compared to Phase 2a as they only got one dose of FX-322 or one dose of placebo compared to the Phase 2a trials.