Frequency Therapeutics — Hearing Loss Regeneration

[Keith Handy]

Will they give any notice as to when they're going to be released or is it just a spur of the moment deal?

The release will coincide with us reaching page 500 of this thread.

 

[Diesel]

It only makes sense to release it on 3/22

Used to look forward to 420 in my younger days, now I look forward to 322.

While I think this would be meme gold for this drug... it would be great if they didn't wait until the end of March just to hit that coincidental date.

 

[Damien0000]

While I think this would be meme gold for this drug... it would be great if they didn't wait until the end of March just to hit that coincidental date.

Is FX-322 for only one type of tinnitus? There are multiple causes for tinnitus.

Will Frequency Therapeutics know what type of tinnitus FX-322 will work for? Such as noise-induced tinnitus, stress-induced tinnitus, physical trauma-induced tinnitus, etc.

 

[ColinUK]

While I think this would be meme gold for this drug... it would be great if they didn't wait until the end of March just to hit that coincidental date.

This thread is the only reason I check in on these forums consistently and is the only thing that seems to offer any hope of a viable treatment option anytime soon. It's the only thing I bother to read, especially as the other potential treatments seem to drop off or keep extending their timelines.

I am slowly coming to terms with this bloody awful condition which now sees me interacting with my 2-year-old constantly wearing ear muffs fearing her giggles and screams, being scared to be outside every time there is a car with a loud exhaust or someone's mowing their lawn or even as the other day being in line outside getting a coffee when someone's dog starts barking and me wanting to turn round and punch them in the face (oh how intolerant this has made me), what a life

But ok this is my life now my personal battle some people have it worse some people don't get a choice to fight on, I am not going to quit I got to much to live for and if every day is a battle then so be it.

To a layperson (me) when they say using hearing aids or having cochlear implants can improve tinnitus then surely actually fixing damage in the cochlea has got to do something, right.

It would be absolutely fantastic to know if FX-322 has some promise for treating tinnitus, or not. I truly hope it does and that on these boards, everyone suffering can get some relief. Even if it's a 20% improvement that could make all the difference to a lot of people. But now I really just want to know if there is hope or if it's a case of ok, maybe, check back in another 10 - 20 years.

Come on Frequency Therapeutics, put us out of our misery

 

[Philip83]

Is FX-322 for only one type of tinnitus? There are multiple causes for tinnitus.

Will Frequency Therapeutics know what type of tinnitus FX-322 will work for? Such as noise-induced tinnitus, stress-induced tinnitus, physical trauma-induced tinnitus, etc.

It's been discussed over and over in this thread, but I understand it's too big to look through at this point.

In short: FX-322 is not made to treat tinnitus, it's made to treat hearing loss caused by hair cell loss/death, whatever the cause of that death may be. If it will have any effect on tinnitus is "only" anecdotal from Phase 1 and a hope at this point. By the end of March there will be data on this though, following the release of the Phase 2 results, where they have tinnitus as a data point.

 

[Keith Handy]

Is FX-322 for only one type of tinnitus? There are multiple causes for tinnitus.

Will Frequency Therapeutics know what type of tinnitus FX-322 will work for? Such as noise-induced tinnitus, stress-induced tinnitus, physical trauma-induced tinnitus, etc.

They don't and won't know, but many of us are gravitating towards a view that tinnitus is the result of a combination of factors, and that regardless of the trigger that brought it about, it likely rings at the frequencies where hair cells have been lost.

 

[Bailes]

Nice to see the share price rebounded to where it was on Monday after a market driven fall yesterday. J & J was probably the reason for the rebound but still good to see that the markets aren't spooked, though I would would like to see more trade volume... the more eyes on this, the better.

If the medical evidence is further supported by the wolves on Wall Street, the better chance there is for commercialisation.

Yes I'm getting ahead of myself.

Hope is a waking dream... I like dreams, oh and I like dogs

 

[FGG]

It would be absolutely fantastic to know if FX-322 has some promise for treating tinnitus, or not. I truly hope it does and that on these boards, everyone suffering can get some relief. Even if it's a 20% improvement that could make all the difference to a lot of people. But now I really just want to know if there is hope or if it's a case of ok, maybe, check back in another 10 - 20 years.

If you have hair cell loss, it's likely contributing to your tinnitus but if you only have TMJ, middle ear disease, hydrops, fistula or synaptopathy without hair cell loss, FX-322 will not address that.

It addresses one (though common) cause of tinnitus.

 

[Diesel]

Not gonna lie, still hung up on this chart showing the calculated concentration of both FX-322 molecules in the perilymph. Maybe someone here with a better understanding of Pharmacokinetics / Pharmacodynamics can shed some light on this one?

We know that the two-molecule concentration was high enough to have a therapeutic effect at 8 kHz on the audiogram, AND that the effective window occurs between 1-3 hours after injection.

So, looking at the 8 kHz reference, I am inferring that CHIR needs to be at a minimum of about 500 ng/ml and VPA 10,000 ng/ml for a sustained period of at least 2 hours at any location in the cochlea to start the progenitor cell activation process.

Considering how the concentration curve looks for CHIR, I would suspect that by a second injection a week later, there would be a baseline of concentration in the perilymph, so additional CHIR concentration need to activate those progenitor cells would reach slightly more deeply into the cochlea.

VPA is where I have a problem. It appears to be absorbed quickly at the base; and even as deep as 2 kHz in the cochlea it is absorbed without (presumably) causing the therapeutic effect. Since both drugs are not at a high enough concentration level long enough. This creates a problem based on the chart. There is no wave of VPA flowing into the cochlea creating that baseline concentration that would be needed to increase concentration after multiple injections. Furthermore, it seems to be absorbed really quickly. So, I don't see how there would be enough VPA left in the cochlea after a 7 day window.

Any thoughts by anyone here?

 

[Jrblovsky]

If you have hair cell loss, it's likely contributing to your tinnitus but if you only have TMJ, middle ear disease, hydrops, fistula or synaptopathy without hair cell loss, FX-322 will not address that.

It addresses one (though common) cause of tinnitus.

Is it even possible to have hydrops without hearing loss? I thought that was a symptom?

 

[FGG]

Is it even possible to have hydrops without hearing loss? I thought that was a symptom?

It's a symptom but the hearing loss caused by hydrops is not due to hair cell loss. This is why often in early stages hearing recovers between Meniere's episodes. Later on, with cumulative damage from attacks, you do get permanent hearing loss though.

They used to do a test called the Glycerol test, where they would give you IV Glycerol and dehydrate your whole body including the cochlea. If you gained at least 15 dB across 3 frequencies, they diagnosed Meniere's because hair cell loss hearing loss does not improve with dehydration.

Evaluation of glycerol test in Meniere's disease with pure tone audiometry and distortion product otoacoustic emission

You can have hydrops with just vestibular symptoms by the way. They are often present before hearing loss.

 

[FGG]

View attachment 43481

Not gonna lie, still hung up on this chart showing the calculated concentration of both FX-322 molecules in the perilymph. Maybe someone here with a better understanding of Pharmacokinetics / Pharmacodynamics can shed some light on this one?

We know that the two-molecule concentration was high enough to have a therapeutic effect at 8 kHz on the audiogram, AND that the effective window occurs between 1-3 hours after injection.

So, looking at the 8 kHz reference, I am inferring that CHIR needs to be at a minimum of about 500 ng/ml and VPA 10,000 ng/ml for a sustained period of at least 2 hours at any location in the cochlea to start the progenitor cell activation process.

Considering how the concentration curve looks for CHIR, I would suspect that by a second injection a week later, there would be a baseline of concentration in the perilymph, so additional CHIR concentration need to activate those progenitor cells would reach slightly more deeply into the cochlea.

VPA is where I have a problem. It appears to be absorbed quickly at the base; and even as deep as 2 kHz in the cochlea it is absorbed without (presumably) causing the therapeutic effect. Since both drugs are not at a high enough concentration level long enough. This creates a problem based on the chart. There is no wave of VPA flowing into the cochlea creating that baseline concentration that would be needed to increase concentration after multiple injections. Furthermore, it seems to be absorbed really quickly. So, I don't see how there would be enough VPA left in the cochlea after a 7 day window.

Any thoughts by anyone here?

Wait. I think I missed this the first time around. Can you link the study again? They are related (obviously) but the concentrations will be slightly different.

Was that endolymph concentration or perilymph? Because the drug enters in the endolymph and drains through the perilymph (that's usually where they sample from though).

 

[patorjk]

View attachment 43481

Not gonna lie, still hung up on this chart showing the calculated concentration of both FX-322 molecules in the perilymph. Maybe someone here with a better understanding of Pharmacokinetics / Pharmacodynamics can shed some light on this one?

We know that the two-molecule concentration was high enough to have a therapeutic effect at 8 kHz on the audiogram, AND that the effective window occurs between 1-3 hours after injection.

So, looking at the 8 kHz reference, I am inferring that CHIR needs to be at a minimum of about 500 ng/ml and VPA 10,000 ng/ml for a sustained period of at least 2 hours at any location in the cochlea to start the progenitor cell activation process.

Considering how the concentration curve looks for CHIR, I would suspect that by a second injection a week later, there would be a baseline of concentration in the perilymph, so additional CHIR concentration need to activate those progenitor cells would reach slightly more deeply into the cochlea.

VPA is where I have a problem. It appears to be absorbed quickly at the base; and even as deep as 2 kHz in the cochlea it is absorbed without (presumably) causing the therapeutic effect. Since both drugs are not at a high enough concentration level long enough. This creates a problem based on the chart. There is no wave of VPA flowing into the cochlea creating that baseline concentration that would be needed to increase concentration after multiple injections. Furthermore, it seems to be absorbed really quickly. So, I don't see how there would be enough VPA left in the cochlea after a 7 day window.

Any thoughts by anyone here?

If we assume that there's any kind of baseline CHIR left in the cochlea after 7 days, wouldn't that make the VPA in the second shot more effective? It would mean that at each given point in time there is more CHIR available for it to work with.

I'm guessing there isn't a lot of action at 2 kHz because both drugs are in low amounts and the chances of them interacting significantly decrease. However, if there's more CHIR available the second time VPA washes through, then maybe the chances of the two molecules completing the needed interaction with the progenitor cells increases.

However, I'm betting the people at Frequency Therapeutics have thought this through. There has to be a reason they spaced the shots out by a week, rather than have them be close together.

 

[Diesel]

Wait. I think I missed this the first time around. Can you link the study again? They are related (obviously) but the concentrations will be slightly different.

Was that endolymph concentration or perilymph? Because the drug enters in the endolymph and drains through the perilymph (that's usually where they sample from though).

 

[Keith Handy]

However, I'm betting the people at Frequency Therapeutics have thought this through. There has to be a reason they spaced the shots out by a week, rather than have them be close together.

I'm hoping that reason isn't "convenient for participants."

 

[Diesel]

If we assume that there's any kind of baseline CHIR left in the cochlea after 7 days, wouldn't that make the VPA in the second shot more effective? It would mean that at each given point in time there is more CHIR available for it to work with.

I'm guessing there isn't a lot of action at 2 kHz because both drugs are in low amounts and the chances of them interacting significantly decrease. However, if there's more CHIR available the second time VPA washes through, then maybe the chances of the two molecules completing the needed interaction with the progenitor cells increases.

However, I'm betting the people at Frequency Therapeutics have thought this through. There has to be a reason they spaced the shots out by a week, rather than have them be close together.

The baseline of CHIR would not be more effective in areas where regrowth already took place. But it would be more effective as a second pass of CHIR increased concentration deeper into the cochlea where regrowth did not take place after the prior injection.

The problem with VPA is that it doesn't show the characteristic "wave of concentration" like CHIR. Instead it gets to 2 kHz and to to this uneducated observer it is absorbed/digested/metabolized. It is clear based on that curve at 2 kHz that drops off to zero by 6 hours.

So, the question is, after that first shot of VPA concentration is gone, which it almost is after 6 hours. What happens with the next shot of VPA? Does it not get absorbed because regeneration already happened? We need to see it flowing in a concentration wave deeper in the cochlea to assume multiple shots are going to work as anticipated.

 

[FGG]

I'm hoping that reason isn't "convenient for participants."

I would rather it be that, than too much is absorbed systemically at once (and becomes a safety concern) if given more frequently.

If that's the case, a modifed protocol using more frequent VPA by itself but once weekly FX-322, should help.

 

[Diesel]

I'm hoping that reason isn't "convenient for participants."

It may have been:

- Let's start with a week spacing as a manageable benchmark.
- Less than a week and we're concerned about toxicity from VPA/CHIR.
- The cells regeneration process need to work for about a week, and dumping more FX-322 in there mid-reproduction causes a coitus-interruptus type problem.

 

[Aaron91]

View attachment 43481

Not gonna lie, still hung up on this chart showing the calculated concentration of both FX-322 molecules in the perilymph. Maybe someone here with a better understanding of Pharmacokinetics / Pharmacodynamics can shed some light on this one?

We know that the two-molecule concentration was high enough to have a therapeutic effect at 8 kHz on the audiogram, AND that the effective window occurs between 1-3 hours after injection.

So, looking at the 8 kHz reference, I am inferring that CHIR needs to be at a minimum of about 500 ng/ml and VPA 10,000 ng/ml for a sustained period of at least 2 hours at any location in the cochlea to start the progenitor cell activation process.

Considering how the concentration curve looks for CHIR, I would suspect that by a second injection a week later, there would be a baseline of concentration in the perilymph, so additional CHIR concentration need to activate those progenitor cells would reach slightly more deeply into the cochlea.

VPA is where I have a problem. It appears to be absorbed quickly at the base; and even as deep as 2 kHz in the cochlea it is absorbed without (presumably) causing the therapeutic effect. Since both drugs are not at a high enough concentration level long enough. This creates a problem based on the chart. There is no wave of VPA flowing into the cochlea creating that baseline concentration that would be needed to increase concentration after multiple injections. Furthermore, it seems to be absorbed really quickly. So, I don't see how there would be enough VPA left in the cochlea after a 7 day window.

Any thoughts by anyone here?

I'm also wondering the same thing. It appears they had this issue in their guinea pig study as well, although it seems the issue there wasn't as bad because guinea pigs have smaller cochleas, as shown in the difference of ST length:

This is from a supplementary doc I found to the study, which has some other useful info some of you may want to mull over (see attached). It really goes into the nitty gritty of the perilymph sampling, the ear anatomy of each individual patient and the guinea pig models.

But the bottom line is that the VPA concentration just doesn't seem high enough. I don't know much about pharmacokinetics/dynamics either, but it's interesting to me that the dosage of VPA is already so much higher than that of CHIR in the first place. It would appear that this was something Frequency Therapeutics had already identified in their preclinical trials.

I wonder then: did they simply underestimate how much VPA was needed, or is there some anatomical limit to the cochlea that we are unaware of that they must adhere to? If so, to your point @Diesel, this could explain why they waited a week between doses rather than say hours or days - perhaps because the cochlea simply couldn't take more than that. I'm only speculating of course and this isn't my area, but something to mull over nonetheless.

 

[FGG]

I'm also wondering the same thing. It appears they had this issue in their guinea pig study as well, although it seems the issue there wasn't as bad because guinea pigs have smaller cochleas, as shown in the difference of ST length:

View attachment 43489

This is from a supplementary doc I found to the study, which has some other useful info some of you may want to mull over (see attached). It really goes into the nitty gritty of the perilymph sampling, the ear anatomy of each individual patient and the guinea pig models.

But the bottom line is that the VCA concentration just doesn't seem high enough. I don't know much about pharmacokinetics/dynamics either, but it's interesting to me that the dosage of VPA is already so much higher than that of CHIR in the first place. It would appear that this was something Frequency Therapeutics had already identified in their preclinical trials.

I wonder then: did they simply underestimate how much VPA was needed, or is there some anatomical limit to the cochlea that we are unaware of that they must adhere to? If so, to your point @Diesel, this would explain why they waited a week between doses rather than say hours or days - perhaps because the cochlea simply couldn't take more than that. I'm only speculating of course and this isn't my area, but something to mull over nonetheless.

At least systemically, VPA does not seem to have a great toxicity risk:

Valproate overdose: a comparative cohort study of self poisonings

I wonder how much crosses the blood/cochlear layer, i.e. could you supplement FX-322 with oral or IV VPA.

 

[Aaron91]

I would rather it be that, than too much is absorbed systemically at once (and becomes a safety concern) if given more frequently.

If that's the case, a modifed protocol using more frequent VPA by itself but once weekly FX-322, should help.

Interesting you should mention this. The supplementary doc I just posted shows a much more linear reduction in VPA concentrations over time compared to CHIR, which has a much quicker fall-off.

 

[Diesel]

I'm also wondering the same thing. It appears they had this issue in their guinea pig study as well, although it seems the issue there wasn't as bad because guinea pigs have smaller cochleas, as shown in the difference of ST length:

View attachment 43489

This is from a supplementary doc I found to the study, which has some other useful info some of you may want to mull over (see attached). It really goes into the nitty gritty of the perilymph sampling, the ear anatomy of each individual patient and the guinea pig models.

But the bottom line is that the VCA concentration just doesn't seem high enough. I don't know much about pharmacokinetics/dynamics either, but it's interesting to me that the dosage of VPA is already so much higher than that of CHIR in the first place. It would appear that this was something Frequency Therapeutics had already identified in their preclinical trials.

I wonder then: did they simply underestimate how much VPA was needed, or is there some anatomical limit to the cochlea that we are unaware of that they must adhere to? If so, to your point @Diesel, this could explain why they waited a week between doses rather than say hours or days - perhaps because the cochlea simply couldn't take more than that. I'm only speculating of course and this isn't my area, but something to mull over nonetheless.

Thank you for sharing this. I had read this supplemental study and those graphics reinforce why they were able to regenerate guinea pig cochlea at all frequencies. Clearly, the concentration stays high enough for long enough in the cochlea in 1 go.

I frankly don't think we know the toxicity limits of either drug in the cochlea. There are studies that reference toxicity in the body for VPA, but it is insanely high compared to this tiny injection of drug in the cochlea.

Perhaps they can crank the VPA volume up in an FX-322 "2.0" or in the Phase 2b/3, test injections closer together in time.

 

[Aaron91]

Thank you for sharing this. I had read this supplemental study and those graphics reinforce why they were able to regenerate guinea pig cochlea at all frequencies. Clearly, the concentration stays high enough for long enough in the cochlea in 1 go.

I frankly don't think we know the toxicity limits of either drug in the cochlea. There are studies that reference toxicity in the body for VPA, but it is insanely high compared to this tiny injection of drug in the cochlea.

Perhaps they can crank the VPA volume up in an FX-322 "2.0" or in the Phase 2b/3, test injections closer together in time.

It would seem though that they already had this information before they started Phase 2? The fact then that they simply opted to increase doses for Phase 2 and space them out by a week would suggest that this is something they've already taken into consideration. So I can only see one of three possibilities:

a) Frequency Therapeutics have accepted this problem for what it is, presumably because there is indeed some kind of anatomical limitation that we are unaware of. The multiple doses would be designed more to get max benefit from 8 kHz and over rather than anything below.

b) They have increased VPA levels for Phase 2 without needing FDA approval/Phase 1 re-trial but haven't made this public knowledge. I asked earlier in this thread whether this was possible but have yet to see a concrete answer on this. Perhaps this is something they are doing in their age-related Phase 1 trial in anticipation of combining all patient groups for the pivotal trial?

c) We are missing something in our analysis and Frequency Therapeutics believe that multiple doses will indeed fix this problem.

Edit: As @Keith Handy has pointed out, point (a) would be consistent with some of their current marketing messages, where they seem to have focused on EHF loss (and recovery).

 

[FGG]

Thank you for sharing this. I had read this supplemental study and those graphics reinforce why they were able to regenerate guinea pig cochlea at all frequencies. Clearly, the concentration stays high enough for long enough in the cochlea in 1 go.

I frankly don't think we know the toxicity limits of either drug in the cochlea. There are studies that reference toxicity in the body for VPA, but it is insanely high compared to this tiny injection of drug in the cochlea.

Perhaps they can crank the VPA volume up in an FX-322 "2.0" or in the Phase 2b/3, test injections closer together in time.

Since the graphs @Aaron91 posted show the concentration of FX-322 dropping quickly, that does point to the drug being safer given more frequently than a week. Off label use?

 

[serendipity1996]

Given that progenitor cells can only divide a limited number of times, would this suggest that there is a limit to how many times you can repeat a FX-322 treatment?

 

[FGG]

Given that progenitor cells can only divide a limited number of times, would this suggest that there is a limit to how many times you can repeat a FX-322 treatment?

Are you talking about the Hayflick limitation? If so, that's 70 times or so and hopefully no one needs that even over their lifetime.

 

[Diesel]

Given that progenitor cells can only divide a limited number of times, would this suggest that there is a limit to how many times you can repeat a FX-322 treatment?

That limit is unknown to my knowledge. If a fresh copy of the progenitor is replaced, one can assume it is many many times. Also, in the case of the cochlea, if a healthy hair cell is above the support progenitor, it won't activate and divide.

 

[Keith Handy]

a) Frequency Therapeutics have accepted this problem for what it is, presumably because there is indeed some kind of anatomical limitation that we are unaware of. The multiple doses would be designed more to get max benefit from 8 kHz and over rather than anything below.

This could unfortunately explain their emphasis on "clarity" in recent online media.

 

[Aaron91]

Are you talking about the Hayflick limitation? If so, that's 70 times or so and hopefully no one needs that even over their lifetime.

I'm not well read on this, but is that assuming the progenitor cell starts at zero divisions? My point being, do we know how many times a progenitor cell in the cochlea has already divided by the time we're born (before they eventually deactivate)?

 

[Diesel]

It would seem though that they already had this information before they started Phase 2? The fact then that they simply opted to increase doses for Phase 2 and space them out by a week would suggest that this is something they've already taken into consideration. So I can only see one of three possibilities:

a) Frequency Therapeutics have accepted this problem for what it is, presumably because there is indeed some kind of anatomical limitation that we are unaware of. The multiple doses would be designed more to get max benefit from 8 kHz and over rather than anything below.

b) They have increased VPA levels for Phase 2 without needing FDA approval/Phase 1 re-trial but haven't made this public knowledge. I asked earlier in this thread whether this was possible but have yet to see a concrete answer on this. Perhaps this is something they are doing in their age-related Phase 1 trial in anticipation of combining all patient groups for the pivotal trial?

c) We are missing something in our analysis and Frequency Therapeutics believe that multiple doses will indeed fix this problem.

Edit: speculation again, but point a) would be consistent with some of their current marketing messages, where they seem to have focused on EHF loss.

Thanks for the reply; I have suspected similarly. Thoughts added:

a) I suspect this as well. I think though in the marketing, since they don't have hard data to back up anything beyond the Phase 1/2, this is why they're hitting on the EHF in the marketing comms. You'll notice they don't talk about age-related loss at all, even though a Phase 1B is currently going on (and it is now believed that age-related hearing loss is basically SNHL).

b) I'm not sure if this is considered a reformulation. Considering FX-322 is two separate molecules, I don't know if if from an FDA standpoint it is considered a reformulation to dial either molecule's concentration/volume up or down per injection. Technically for the two Phase 1B programs, they could test a higher dose of FX-322, since they are new safety trials. At one point I saw them call those studies "FX-322.02" or something along those lines in a presentation; can't find it now.

c) It's likely we are.