Frequency Therapeutics — Hearing Loss Regeneration

[ThomasRobert]

The Vestibular System:

Detailed Link:
https://neupsykey.com/the-vestibular-system-4/

 

[FGG]

Thank you very much. I always think your knowledge is wonderful.

If the effect really depends on the number of injections, FX-322 is a promising drug.

The invention of being able to regenerate hair cells and connecting synapses is a huge step.

That is, 0 → 1.

Next, improvement of delivery, etc., 1 → 2, 3, ... 10...

I think the really difficult thing is 0 → 1.

I want to believe that the evolution of technology, for development from 1, be surprisingly straightforward.

I am grateful for everyone's courage writing in this thread.

I absolutely think drug delivery will be the "straight forward" part of this.

In fact, if this new surgical technique works as well in people, it could be done without any either new drug formation or new pumping device (etc), i.e. it could be done now:

https://www.jove.com/t/57351/canalostomy-as-surgical-approach-to-local-drug-delivery-into-inner

Unlike cochleostomy, canalostomy doesn't inflame and damage the cochlea and techniques like this will be necessary for gene therapies for genetic deafness as viral vectored therapies need to be directly injected into the cochlea.

 

[Christiaan]

I absolutely think drug delivery will be the "straight forward" part of this.

In fact, if this new surgical technique works as well in people, it could be done without any either new drug formation or new pumping device (etc), i.e. it could be done now:

https://www.jove.com/t/57351/canalostomy-as-surgical-approach-to-local-drug-delivery-into-inner

Unlike cochleostomy, canalostomy doesn't inflame and damage the cochlea and techniques like this will be necessary for gene therapies for genetic deafness as viral vectored therapies need to be directly injected into the cochlea.

Seems like a good idea. Are there ENTs in the US who are working with this method? And do you think this can be done multiple times?

 

[GBB]

Can the synapses or any part of the auditory nerve scar, limit the extent of potential repair?

 

[tommyd87]

Concerning the systemic drug delivery that was utilized in Phase 2a, are you inferring that the first dose of FX-322 administered will cover the frequencies that are expected (say, from 20 kHz to 8 kHz) and a second dose will bypass these frequencies (if PCA has occurred) and commence activating cellular frequencies advancing toward 6 kHz to 2 kHz and so forth- eventually reaching 250 Hz with each additional dose?

Also, aside from an FDA-approved trial in the United States, it is unlikely ENT physicians will break protocol and inject more doses than the four that have been outlined beforehand - perhaps that is for another day. Frequency Therapeutics desires to expedite this wonder drug to market as soon as possible but they are also conducting their research in a rather keen and conservative manner. Nonetheless, the testing you hypothesize will come about in due time in my opinion.

The theory I have seen suggests PCA will only target busted hair cells. Consequently Frequency Therapeutics' theory is that you inject FX-322, allow it to activate the busted hair cells and then you inject it once again after the busted hair cells have been activated. That is why Frequency Therapeutics is trying the repeated dosing method because it is theoretically going to allow much more hair cells to be targeted.

I wouldn't be shocked if Frequency Therapeutics did try to do additional dosings once the clinical trials were finished to discover whether there would be further benefit in people who participated in the clinical trial and got multi doses. This is because there may be scope to see whether further improvement could be obtained by more doses or whether there is indeed a limit to FX-322's reach using this method.

 

[tommyd87]

I absolutely think drug delivery will be the "straight forward" part of this.

In fact, if this new surgical technique works as well in people, it could be done without any either new drug formation or new pumping device (etc), i.e. it could be done now:

https://www.jove.com/t/57351/canalostomy-as-surgical-approach-to-local-drug-delivery-into-inner

Unlike cochleostomy, canalostomy doesn't inflame and damage the cochlea and techniques like this will be necessary for gene therapies for genetic deafness as viral vectored therapies need to be directly injected into the cochlea.

This would be excellent if it was researched and trialled. It seems a really logical and fairly straightforward option.

 

[FGG]

Seems like a good idea. Are there ENTs in the US who are working with this method? And do you think this can be done multiple times?

This is otologic surgeon subspecialist territory, not regular ENTs. But anyone who could put in a cochlear implant, could do this surgery. It isn't being done on humans yet but since AAV therapies have to be delivered intracochlear and as the old method of cochleostomy can be destructive, I imagine approaches like this will be used soon for therapies. There are a few recent publications in it.

But yes, the trick would be convincing someone to do it off label to reach the apex with regenerative medicine.

This is jumping the gun a bit because we don't yet know if repetitive dosing would solve most of this anyway but for the anxiety ridden who think reaching the apex is impossible, it already is technically possible.

No idea about repeat procedures because you can damage a small percent of vestibular cells with this (which, unlike in the cochlea the body can easily compensate for).

 

[tommyd87]

This is otologic surgeon subspecialist territory, not regular ENTs. But anyone who could put in a cochlear implant, could do this surgery. It isn't being done on humans yet but since AAV therapies have to be delivered intracochlear and as the old method of cochleostomy can be destructive, I imagine approaches like this will be used soon for therapies. There are a few recent publications in it.

But yes, the trick would be convincing someone to do it off label to reach the apex with regenerative medicine.

This is jumping the gun a bit because we don't yet know if repetitive dosing would solve most of this anyway but for the anxiety ridden who think reaching the apex is impossible, it already is technically possible.

No idea about repeat procedures because you can damage a small percent of vestibular cells with this (which, unlike in the cochlea the body can easily compensate for).

When you say convincing someone to do this off-label, what do you mean? Do you mean that they would need to do this procedure with the ear medicine off-label because this is not yet an approved procedure?

 

[FGG]

When you say convincing someone to do this off-label, what do you mean? Do you mean that they would need to do this procedure with the ear medicine off-label because this is not yet an approved procedure?

I mean it's being labelled for IT injection and this isn't an IT injection.

 

[tommyd87]

I mean it's being labelled for IT injection and this isn't an IT injection.

Ahh right, so the procedure exists but then the doctor could choose to do the alternative procedure to make the drug delivery better.

 

[Diesel]

@tommyd87

If I am understanding your description of how multiple doses of FX-322 might work, it might look like as follows:

Note: this is a simple representation. The real biological response is probably more complex.

Let's assume, the cochlea to be treated shows significant losses through OHCs/IHCs damage/loss from 4 kHz up to 20 kHz.

Injection 1:
- Flows into the cochlea, most of the drug is absorbed through the damaged/missing cells at the base down to roughly 8 kHz. New IHCs/OHCs are formed int their place above 8 kHz.

Injection 2:
- Flows into the cochlea from the base. This time, since most of the high kHz cells have regrown, not as much is absorbed, and if flows a little deeper. Most is absorbed by the remaining damage/missing cells at 8 kHz to 7 kHz.

Injection 3-4:
- Similar to injection 2. Drug generally flows past areas that are of new IHCs/OHCs. It is absorbed in areas with damage/missing cells deeper in the cochlea that have yet to be "touched" by the drug. Eventually hitting a deeper range of damage: i.e. 4 kHz in this example.

 

[FGG]

@tommyd87

If I am understanding your description of how multiple doses of FX-322 might work, it might look like as follows:

Note: this is a simple representation. The real biological response is probably more complex.

Let's assume, the cochlea to be treated shows significant losses through OHCs/IHCs damage/loss from 4 kHz up to 20 kHz.

Injection 1:
- Flows into the cochlea, most of the drug is absorbed through the damaged/missing cells at the base down to roughly 8 kHz. New IHCs/OHCs are formed int their place above 8 kHz.

Injection 2:
- Flows into the cochlea from the base. This time, since most of the high kHz cells have regrown, not as much is absorbed, and if flows a little deeper. Most is absorbed by the remaining damage/missing cells at 8 kHz to 7 kHz.

Injection 3-4:
- Similar to injection 2. Drug generally flows past areas that are of new IHCs/OHCs. It is absorbed in areas with damage/missing cells deeper in the cochlea that have yet to be "touched" by the drug. Eventually hitting a deeper range of damage: i.e. 4 kHz in this example.

I agree with this. The drug is going to bind to the first target it sees. Once there are less targets in the base, it should be free to bind further down. There is no reason for it to "skip over" missing hair cells to get to the ones further in the apex.

This also makes sense with how the drug is given. It's slowly diffusing across the round window. It's not squirted directly in the cochlea pushing drug evenly to all cells at the same time.

The PCA is going to "activate" what it encounters first.

 

[Diesel]

I agree with this. The drug is going to bind to the first target it sees. Once there are less targets in the base, it should be free to bind further down. There is no reason for it to "skip over" missing hair cells to get to the ones further in the apex.

This also makes sense with how the drug is given. It's slowly diffusing across the round window. It's not squirted directly in the cochlea pushing drug evenly to all cells at the same time.

The PCA is going to "activate" what it encounters first.

I'm curious if they'll be able to "map" the growth of the hair cells as each "wave" of FX-322 flows through the perilymph; starting with the high frequency audiogram.

For example:

The 1x dose over 15, 30, 60, 90 days should show similar improvements at 8 kHz + the HF audiogram. My assumption is that the hearing gradually improved starting at 20 kHz and moved towards 8 kHz as the drug flowed into the cochlea.

Would a 4x dose group show Improvements in comparable frequencies at 15 days what the 1x did at 90 days?

Or, would the 4x dose group still show a similar rate of growth over 90 days, but more spread out into the cochlea?

I hope they're willing to provide this depth of detail at the end of the Phase 2A. This is the level of data that they will have available.

 

[dan]

@tommyd87

If I am understanding your description of how multiple doses of FX-322 might work, it might look like as follows:

Note: this is a simple representation. The real biological response is probably more complex.

Let's assume, the cochlea to be treated shows significant losses through OHCs/IHCs damage/loss from 4 kHz up to 20 kHz.

Injection 1:
- Flows into the cochlea, most of the drug is absorbed through the damaged/missing cells at the base down to roughly 8 kHz. New IHCs/OHCs are formed int their place above 8 kHz.

Injection 2:
- Flows into the cochlea from the base. This time, since most of the high kHz cells have regrown, not as much is absorbed, and if flows a little deeper. Most is absorbed by the remaining damage/missing cells at 8 kHz to 7 kHz.

Injection 3-4:
- Similar to injection 2. Drug generally flows past areas that are of new IHCs/OHCs. It is absorbed in areas with damage/missing cells deeper in the cochlea that have yet to be "touched" by the drug. Eventually hitting a deeper range of damage: i.e. 4 kHz in this example.

That's quite an assumption. Do you know the biological reason of why the gel won't reach the apex in the first place? Is it because all of it gets absorbed on the way there??? Or is it because of the physical distance... like if ya can't dunk a basketball because you can't reach the hoop, you'll never dunk no matter how many times you try...

 

[tommyd87]

I agree with this. The drug is going to bind to the first target it sees. Once there are less targets in the base, it should be free to bind further down. There is no reason for it to "skip over" missing hair cells to get to the ones further in the apex.

This also makes sense with how the drug is given. It's slowly diffusing across the round window. It's not squirted directly in the cochlea pushing drug evenly to all cells at the same time.

The PCA is going to "activate" what it encounters first.

@tommyd87

If I am understanding your description of how multiple doses of FX-322 might work, it might look like as follows:

Note: this is a simple representation. The real biological response is probably more complex.

Let's assume, the cochlea to be treated shows significant losses through OHCs/IHCs damage/loss from 4 kHz up to 20 kHz.

Injection 1:
- Flows into the cochlea, most of the drug is absorbed through the damaged/missing cells at the base down to roughly 8 kHz. New IHCs/OHCs are formed int their place above 8 kHz.

Injection 2:
- Flows into the cochlea from the base. This time, since most of the high kHz cells have regrown, not as much is absorbed, and if flows a little deeper. Most is absorbed by the remaining damage/missing cells at 8 kHz to 7 kHz.

Injection 3-4:
- Similar to injection 2. Drug generally flows past areas that are of new IHCs/OHCs. It is absorbed in areas with damage/missing cells deeper in the cochlea that have yet to be "touched" by the drug. Eventually hitting a deeper range of damage: i.e. 4 kHz in this example.

An absolutely accurate account of how I believe FX-322 will work. The trouble that we have seen in the results thus far is that there needs to be a much larger growth at the very high frequency end for many people. Thus FX-322 may not have worked as effectively in some, hence the small improvements. I am thinking that some people might need much more than four doses. Although it is possible that four doses could be sufficient since we still do not have evidence of what happens with the multiple doses. Especially when we know that there's the theory that the first dose might be less effective in instigating regrowth because it is suggested that this simply kickstarts the process and actually doesn't start the regrowth immediately.

 

[dan]

Especially when we know that there's the theory that the first dose might be less effective in instigating regrowth because it is suggested that this simply kickstarts the process and actually doesn't start the regrowth immediately.

In that case I'll take 100.

 

[FGG]

Especially when we know that there's the theory that the first dose might be less effective in instigating regrowth because it is suggested that this simply kickstarts the process and actually doesn't start the regrowth immediately.

Is this your personal theory or was it suggested by the company?

Why would the first dose only be a priming dose? Mechanistically I mean.

 

[Billy_Shears]

It is my understanding that FX-322 is made of two molecular agents, one to activate and one to instigate growth - it has been proven this is the case. Given the shape of the cochlea, I am still pondering the thought of how FX-322 will travel to the apex (250 Hz) through multiple dosing and if the higher frequencies have to withstand this barrage of drug activity with each dose without implications.

 

[tommyd87]

Is this your personal theory or was it suggested by the company?

Why would the first dose only be a priming dose? Mechanistically I mean.

I had heard how some think that the first dose might need to instigate the growth because they reckoned that there was something about the hair cell regeneration needed to be kickstarted first before better subsequent regrowth happened. I have not heard this from Frequency Therapeutics, only from other sources so it might be basically rubbish.

Nevertheless I think more doses and also deeper dosing are the two things that need to occur in order to provide better and more complete regrowth.

 

[tommyd87]

In that case I'll take 100.

That's what I think too. I totally have no issues taking 100 doses if needed in order to get the desired outcome.

 

[Billy_Shears]

Keep in mind, a deaf mouse was cured with total hearing restored all with FX-322!

 

[Michael01]

I just wish they'd hurry up and release FX-322 or at the very least, run a clinical trial with a substantially larger sample size so I could participate, but I guess some things can't be rushed.

 

[tommyd87]

I just wish they'd hurry up and release FX-322 or at the very least, run a clinical trial with a substantially larger sample size so I could participate, but I guess some things can't be rushed.

There will be another clinical trial. However, the question remains that if it is run with participants from outside of America, what countries would they select.

I think that they could do Europe because there is a big population within a small space. I also wouldn't be surprised if they selected Japan because this is where FX-322 will get manufactured.

 

[NewLionel]

That's what I think too. I totally have no issues taking 100 doses if needed in order to get the desired outcome.

That will be $100,000, please.

 

[Mathieulh]

The fact that FX-322 is still not available while people are suffering with no alternative treatment is a travesty.

 

[Danad]

There may be many more "small molecules" in FX-322 than there are receiving sites in the cochlea; it's just they are not getting deep enough diffusion.

Let's use Sodium Valproate as an example since it's one of the small molecules in the cocktail.

Molecular Weight 166.19g/mol
A typical drug concentration is 50ug/ml
Assume 1ml gel injection
Unless my math is off that's 1.811 x10 (17th power) molecules of Sodium Valproate
181100000000000000.0

Maybe someone with recent chemistry experience can check that number.

How many of those penetrate the round window and diffuse through the perilymph fluid is unknown to us.

 

[ManyLeavesLeft]

Are there any updates in terms of compassionate use/general timeline for when FX-322 will be commercially available? I am thinking it will be more than a year, but how much more?

 

[Diesel]

I agree with this. The drug is going to bind to the first target it sees. Once there are less targets in the base, it should be free to bind further down. There is no reason for it to "skip over" missing hair cells to get to the ones further in the apex.

This also makes sense with how the drug is given. It's slowly diffusing across the round window. It's not squirted directly in the cochlea pushing drug evenly to all cells at the same time.

The PCA is going to "activate" what it encounters first.

If you don't mind educating me on this a little... how does the drug target/bind to the targeted damaged/destroyed cells; and yet move on and not bind to healthy hair cells? Since it's floating through the perilymph, how does it not just bind to everything?

Does this explain why Loose once said (I believe in the JP call from earlier in 2020) that FX-322 will affect damaged/destroyed cells, but not cells that are healthy, even though they may have broken synapses?

Is Loose basically saying they know the drug will pass over those healthy cells and "bind" to the next available damaged/destroyed cell to flow across?

 

[tommyd87]

The fact that FX-322 is still not available while people are suffering with no alternative treatment is a travesty.

It is not desirable, however at least if FX-322 goes through the clinical trials and meets its requirements then we know everything is fine with it. If we just wait I think we'll get a good outcome.

 

[Danad]

If you don't mind educating me on this a little... how does the drug target/bind to the targeted damaged/destroyed cells; and yet move on and not bind to healthy hair cells? Since it's floating through the perilymph, how does it not just bind to everything?

Does this explain why Loose once said (I believe in the JP call from earlier in 2020) that FX-322 will affect damaged/destroyed cells, but not cells that are healthy, even though they may have broken synapses?

Is Loose basically saying they know the drug will pass over those healthy cells and "bind" to the next available damaged/destroyed cell to flow across?

I thought the drug only activates the LGR5 cells which are usually dormant and are proximal to damaged and undamaged hair cells. If there is cross signaling between these two types of cells is an interesting question. If not then the action may occur regardless of the health of the local hair cells.