Frequency Therapeutics — Hearing Loss Regeneration

[all to gain]

Unless we see a large improvement on the 10 dB threshold shift at 8 kHz, those of us who wear hearing aids now will still need hearing aids. If anything it might move people into that zone where hearing aids can actually do some good.

I don't want to derail the thread, but what is your hearing loss now?

Would FX-322 make a significant difference for someone with a 50 dB loss at 8 kHz, i.e. me?

 

[weab00]

Here's a counterpoint/topic of discussion: there seems to be a link between visual snow syndrome and tinnitus/hyperacusis. Probably because the neurons are overexcited and the parts of the brain that process sound/vision are associated with each other in the thalamus.

So I guess what I'm wondering is if developing visual snow syndrome after tinnitus/hyperacusis means that the issue now runs deeper than hair cells/synapses and is shifted in some way in the brain.

I think similar topics have been brought up in this thread, but never in conjunction to visual snow syndrome as well.

 

[FGG]

Here's a counterpoint/topic of discussion: there seems to be a link between visual snow syndrome and tinnitus/hyperacusis. Probably because the neurons are overexcited and the parts of the brain that process sound/vision are associated with each other in the thalamus.

So I guess what I'm wondering is if developing visual snow syndrome after tinnitus/hyperacusis means that the issue now runs deeper than hair cells/synapses and is shifted in some way in the brain.

I think similar topics have been brought up in this thread, but never in conjunction to visual snow syndrome as well.

Neuroplasticity is not stuck in one direction. Just as in phantom limb, if you use mirror therapy, you can affect the maladaptive plasticity. Unfortunately, there is no "mirror therapy" with the cochlea.

If tinnitus caused a permanent brain change no one would recover from it and people would not have fluctuating tinnitus with hydrops treatment or improvements from TMJ treatment. If you fix the underlying cause (when possible), tinnitus responds. That would not be true if maladaptive plasticity was permanent.

As far as visual snow, it's so much more poorly understood.

What is known is that a lot of people with visual snow never have tinnitus (some people are born with visual snow) and a lot of people with tinnitus never get visual snow. It seems genetic or at least congenital in some people (some people recall always having it) but in others it seems to result also from maladaptive neuroplasticity after getting things like tinnitus.

It's hard to say exactly what effect tinnitus treatment would have on visual snow but it seems to have a thalamus connection according to many researchers. The thalamus is a particularly plastic part of the brain and I think restoring normal input would probably help visual snow is well. This question is looking to be answered within the next 5 years it looks like though.

 

[patorjk]

@all to gain All they could do is talk shit on FX-322 and say it doesn't work and people don't get benefits from it.

Once the cat's out of the bag they are done. They will still have a fairly large market as hearing aids are needed for congenital hearing loss but the majority of hearing loss is acquired so FX-322, assuming it works and hits the market, will almost immediately take 70% of the hearing aid market away from the hearing aid companies.

They won't be happy about it but it's guaranteed they all knew one day this would happen and they would have made marketing strategies to maximize profits before their D-Day.

From their own studies they've learned that they can't really deliver the drug much below the 8 kHz range. The range that is important for people with hearing aids is 250 Hz to 8000 Hz. So as it stands now, this drug will ultimately just make people with hearing aids hear better and possibly (hopefully) reduce tinnitus.

However, it's pretty clear that Frequency Therapeutics' ultimate goal is to cure hearing loss. After listening to their last few presentations, I get the feeling that they're not really keen on releasing interim results. That means there is very little news that could come from them between November and April. I can't imagine that they'll want to have half a year with no new news.

I suspect that they're working on something. A better formulation that does a slow release inside the ear could be one thing they're looking into. If you look at the job postings on their website, the one for "Senior Scientist/Engineer, Pharmaceutical Development" seems to focus heavily on drug formulations:

https://www.frequencytx.com/jobs/senior-scientist-engineer-pharmaceutical-development/

However, the fact that that's remained open for over a year is a little concerning - unless they already have people working on this and are just in the market for more if someone comes along?

 

[FGG]

I don't want to derail the thread, but what is your hearing loss now?

Would FX-322 make a significant difference for someone with a 50 dB loss at 8 kHz, i.e. me?

No one knows yet what results can be expected with repetitive dosing.

Repetitive dosing apparently makes intracochlear dexamethasone much more effective (and is more important than concentration or total dose given) and phase 2A has a repetitive dosing schedule so it could make. FX-322 likewise have a much more dramatic difference at 8000 Hz (I think it's almost a given that it has a much bigger effect at UHF considering the word score changes). We will know in about 6 months.

That being said, even a 10 dB difference would be very noticeable to you.

 

[serendipity1996]

Neuroplasticity is not stuck in one direction. Just as in phantom limb, if you use mirror therapy, you can affect the maladaptive plasticity. Unfortunately, there is no "mirror therapy" with the cochlea.

If tinnitus caused a permanent brain change no one would recover from it and people would not have fluctuating tinnitus with hydrops treatment or improvements from TMJ treatment. If you fix the underlying cause (when possible), tinnitus responds. That would not be true if maladaptive plasticity was permanent.

As far as visual snow, it's so much more poorly understood.

What is known is that a lot of people with visual snow never have tinnitus (some people are born with visual snow) and a lot of people with tinnitus never get visual snow. It seems genetic or at least congenital in some people (some people recall always having it) but in others it seems to result also from maladaptive neuroplasticity after getting things like tinnitus.

It's hard to say exactly what effect tinnitus treatment would have on visual snow but it seems to have a thalamus connection according to many researchers. The thalamus is a particularly plastic part of the brain and I think restoring normal input would probably help visual snow is well. This question is looking to be answered within the next 5 years it looks like though.

I feel like we need some kind of sticky to reiterate that neuroplasticity is not stuck in one direction and does not lead to permanent brain damage. I think this misconception is something that seems to spark a bit of panic and alarm on this thread from time to time.

 

[Jack V]

Anyone else thinking about freezing themselves until FX-322 comes out? Might be the smart/easiest option.

I'm already frozen bro, typing through one of Elon Musk's brain-computer interfaces with strict instructions not to be defrosted until there's viable regenerative ear medicine, or Fleabag comes back with a 3rd season.

 

[Jack V]

Neuroplasticity is not stuck in one direction. Just as in phantom limb, if you use mirror therapy, you can affect the maladaptive plasticity. Unfortunately, there is no "mirror therapy" with the cochlea.

Do you think it's possible to argue that the partial relief a hearing aid can bring to some tinnitus sufferers is similar to using mirror therapy in phantom limb syndrome?

That by artificially saturating missing frequencies as much as possible, you're tricking the brain, at least for the duration of the trick, into thinking it still has input receptors that it's actually lost?

 

[FGG]

Do you think it's possible to argue that the partial relief a hearing aid can bring to some tinnitus sufferers is similar to using mirror therapy in phantom limb syndrome?

That by artificially saturating missing frequencies as much as possible, you're tricking the brain, at least for the duration of the trick, into thinking it still has input receptors that it's actually lost?

Yes. If hearing aids did more than just amplify I think you'd have a more profound effect. But a lot of people with tinnitus in the hearing aid range are helped and they wouldn't be if the brain only had the ability to respond with plasticity once.

 

[Jack V]

Yes. If hearing aids did more than just amplify I think you'd have a more profound effect. But a lot of people with tinnitus in the hearing aid range are helped and they wouldn't be if the brain only had the ability to respond with plasticity once.

Forgive me, I don't really follow.

With phantom limb syndrome, I believe the mirror trick provides relief while you're using the mirror.

Similarly, a hearing aid provides relief while you're using the hearing aid.

Both rely on plasticity working more than once, no?

 

[FGG]

Forgive me, I don't really follow.

With phantom limb syndrome, I believe the mirror trick provides relief while you're using the mirror.

Similarly, a hearing aid provides relief while you're using the hearing aid.

Both rely on plasticity working more than once, no?

I think you are misreading what I am saying. I was responding to and rejecting the idea that plasticity is stuck in one direction.

And yes hearing aids have an effect and I suspect they'd have a much better effect if they did more than amplify.

 

[Jack V]

I think you are misreading what I am saying. I was responding to and rejecting the idea that plasticity is stuck in one direction.

And yes hearing aids have an effect and I suspect they'd have a much better effect if they did more than amplify.

Thanks, I think I understand a bit more of what you mean, not completely, but more.

I know a researcher in a related field who used mirror therapy to help overcome his own leg amputation, and I relate some of his personal story and related research to what might be helpful for tinnitus.

For me, in the absence of something like a working FX-322, it makes sense to trick the brain into believing what's broken isn't broken. So if noise trauma kills hair cells in a certain frequency range, perhaps not all, but enough to trigger tinnitus, by using a hearing aid, it seems like you're trying to saturate the remaining hair cells with enough sound to trick the brain into thinking the area is less broken, that it has the sound it's searching for, thus relieving tinnitus to some extent. Incidentally, I've been experimenting with different eq curves to try to optimize the effect.

Obviously, FX-322, if it's effective, makes the hearing aid unnecessary. Or, if FX-322 is partially effective, and fixes some but not all broken inputs contributing to tinnitus, perhaps that might make a hearing aid more effective because there's more natural inputs to saturate, and more overall signal reaching the brain. You know, mix and match.

 

[tommyd87]

Unless we see a large improvement on the 10 dB threshold shift at 8 kHz, those of us who wear hearing aids now will still need hearing aids. If anything it might move people into that zone where hearing aids can actually do some good.

This is very accurate. However, I think that there is likely to be bigger shifts in either future clinical trials or using future dosing methods. I still think that there is a lot of theoretical evidence which indicates that FX-322 isn't the problem but rather the benefit obtained from dosing thus far.

From what we have seen from the lab evidence, FX-322 can regrow hair cells wherever in the ear. This means that the trouble isn't with FX-322 at all. I believe that this is quite well known by both those administering it and also by Frequency Therapeutics. Thus this is the reason that there is so much work being done by Frequency Therapeutics to try to get the dosing improved.

I don't want to derail the thread, but what is your hearing loss now?

Would FX-322 make a significant difference for someone with a 50 dB loss at 8 kHz, i.e. me?

Think about how much improvement you would actually get from a 50 dB increase at 8000 Hz. I would say that not only is this going to make a lot of sounds simply louder like birds, but it will also actually greatly improve clarity. This will be especially the case when you hear a kid's voice for example.

If the scenario does play out where people will still need hearing aids after FX-322 is released then every 10 dB improvement is inevitably going to make your use of them better. This is not only because they are going to have their functionality improved but also because this might mean that you can choose an alternative hearing aid type too.

 

[bobvann]

Similarly, a hearing aid provides relief while you're using the hearing aid.

I don't think a hearing aid does that. If it did, it may actually help.

 

[tommyd87]

No one knows yet what results can be expected with repetitive dosing.

Repetitive dosing apparently makes intracochlear dexamethasone much more effective (and is more important than concentration or total dose given) and phase 2A has a repetitive dosing schedule so it could make. Fx-322 likewise have a much more dramatic difference at 8000 Hz (I think it's almost a given that it has a much bigger effect at UHF considering the word score changes). We will know in about 6 months.

That being said, even a 10 dB difference would be very noticeable to you.

The other thing is that we don't know where the repeat dose ceiling actually sits.

Should this repeat dosing benefit be effective, we (and Frequency Therapeutics for that matter too) don't know if giving someone just say 8 doses is going to provide an even bigger benefit. Basically I would be very interested to see if Frequency Therapeutics was looking to increase the number of doses someone got if they had success with the repeat dosing in the current trial.

 

[FGG]

The other thing is that we don't know where the repeat dose ceiling actually sits.

Should this repeat dosing benefit be effective, we (and Frequency Therapeutics for that matter too) don't know if giving someone just say 8 doses is going to provide an even bigger benefit. Basically I would be very interested to see if Frequency Therapeutics was looking to increase the number of doses someone got if they had success with the repeat dosing in the current trial.

I think if it shows enough efficacy for approval at 4 doses they will let ENTs experiment with additional dosing off label rather than take time finding the "perfect dose" pre-approval which would just delay things.

 

[tommyd87]

I think if it shows enough efficacy for approval at 4 doses they will let ENTs experiment with additional dosing off label rather than take time finding the "perfect dose" pre-approval which would just delay things.

With the way Frequency Therapeutics does things and how they have been foremost focused on getting FX-322 out to people, I wouldn't be surprised with this at all.

At this stage Frequency Therapeutics gives me the feeling that they are all about getting FX-322 out for use ASAP and playing around with the dosing and getting better benefit for people later on (hence their redosing plans). This definitely seems like an easier and quicker approach.

 

[Jack V]

I don't think a hearing aid does that. If it did, it may actually help.

It helps some people

 

[Lilah]

I presume there are forces out there, i.e. interested parties like the hearing aid industry, that will do everything in their power to make sure FX-322 doesn't hit the market, or if it does, to make sure it fails somehow.

What theoretically could they do to achieve their goal?

They can file a lot of petitions to the FDA citing safety concerns and request additional clinical trials before the product enters the market. I think all they can do is delay the process.

One good thing that might happen is that they might have an incentive to lower the price of hearing aids, so that they remain competitive.

 

[Lucifer]

They can file a lot of petitions to the FDA citing safety concerns and request additional clinical trials before the product enters the market. I think all they can do is delay the process.

This is my worst fear. I'm scared that this will happen which will delay the treatment to millions of people.

 

[tommyd87]

I don't think a hearing aid does that. If it did, it may actually help.

I think that this depends on the cause of tinnitus. For example, some people with a hair cell loss can get relief from a hearing aid because it has been found that hearing aids provide the lost auditory stimulation. So this lost stimulation is actually the cause of their tinnitus.

There's a theory now that there could be other causes of tinnitus than just hair cell loss. For example, inflammation and synapses. Since neither of these can be artificially stimulated in the same way that tinnitus caused by hair cell loss can be, hearing aids are ineffective for these indications.

Basically this means that you would need to fix the underlying cause to get relief from tinnitus caused by those things.

 

[Jack V]

This is my worst fear. I'm scared that this will happen which will delay the treatment to millions of people.

I don't see how opposition from a potential competitor in another part of the field enters into the FDA's decision. I'm just speculating, but I'm not worried about that at all.

 

[dan]

I don't see how opposition from a potential competitor in another part of the field enters into the FDA's decision. I'm just speculating, but I'm not worried about that at all.

Bribes.

 

[dan]

Can you imagine how many people would be out of a job if hearing loss was cured?

Hearing aid manufacturers + research + marketing jobs + audiology (sales people) + TRT clinicians.

This a multi billion dollar/year industry! Do you guys really think they are going to go down easy? It's much better for them if something like RL-81 cured tinnitus but left hearing loss alone.

Curing hearing loss + tinnitus together? That's BIG.

 

[tommyd87]

They can file a lot of petitions to the FDA citing safety concerns and request additional clinical trials before the product enters the market. I think all they can do is delay the process.

One good thing that might happen is that they might have an incentive to lower the price of hearing aids, so that they remain competitive.

I think that this could happen, however I hope it does not happen. I think that the reality is that those opposing the release of FX-322 or any other similar medicine would have to provide good reasons for them to have to go through further trials. The thing is it would be very interesting to see how any group could claim FX-322 is unsafe when it is already proven to be extremely safe and also almost risk free.

This is my worst fear. I'm scared that this will happen which will delay the treatment to millions of people.

So am I. I could see some opposing bodies try and claim that it is unsafe, however something says that Frequency Therapeutics might be prepared for this to happen.

If the reasons given to try and delay the release of FX-322 are like those in that article which presented a negative view of Frequency Therapeutics, there is not much of a chance that they will succeed in delaying the release. Right now I think that most of the information which is being used to give a negative opinion of FX-322 is appearing to be quite vague and also quite questionable.

 

[Jack V]

Can you imagine how many people would be out of a job if hearing loss was cured?

Hearing aid manufacturers + research + marketing jobs + audiology (sales people) + TRT clinicians.

This a multi billion dollar/year industry! Do you guys really think they are going to go down easy? It's much better for them if something like RL-81 cured tinnitus but left hearing loss alone.

Curing hearing loss + tinnitus together? That's BIG.

Great! TRT clinicians can transition to selling electric vehicles.

That said, antibiotics didn't put doctors out of business. Things evolve

 

[d'Wooluf]

I don't want to derail the thread, but what is your hearing loss now?

Would FX-322 make a significant difference for someone with a 50 dB loss at 8 kHz, i.e. me?

Mine's a bit worse than yours. I don't think 10 dB at 8 kHz will make a huge difference, but the possibly greater improvements above that might help with speech comprehension - especially in noise. Until we know more, FX-322 isn't going to help me hear the crickets on a summer night, but might help me participate in dinner conversation (with the help of hearing aids). Without going back and checking, I think that only one of the people with improved word recognition scores might get by without a hearing aid. Their scores were doubled but still not great.

 

[Jack V]

The thing is it would be very interesting to see how any group could claim FX-322 is unsafe when it is already proven to be extremely safe and also almost risk free.

I don't see how a 3rd party does that either.

But I'm also not sure FX-322 has "already proven to be extremely safe and also almost risk free."

It's shown that in a small number of people with severe hearing damage, it was safe, and safe enough to proceed to a larger Phase II trial. But there are drugs that progress from Phase I to II to III, each with progressively larger numbers of participants, that only show dangerous side effects in Phase III.

Just look at the recent AstraZeneca COVID-19 vaccine trial that seemed to cause a serious neurological reaction only once it progressed to tens of thousands of participants in Phase III. And still other drugs manifest side effects only after they've been released into the marketplace. I forget the name of it, for example, but there was a drug I read about in this forum that helped some people with tinnitus, was FDA approved, and taken off the market due to serious side effects that showed up only after it was in the market for a few years.

The sheer length of this thread is a testament to how hopeful we all are that FX-322 will help us, and how eager we all are to try it. I mean, hell yeah, sign me up! Given the suffering, I'm eager to take it as soon as I can if it continues to generate good results. But if I'm fortunate enough to get access to it as part of a compassionate use program before it's completed a Phase III trial, there's still unknown risk. I'm no less a guinea pig than any other guinea pig in the trial.

 

[tomytl]

What do guys think is the reason, that people in the Phase 1/2 didn't get more than 10-15 dB improvement at 8 kHz?

Does it mean that FX-322 didn't regenerate outer hair cells, which normally act as amplifiers?

Or did the single dose administered "only" generate very few new hair cells, like a bundle with just a few new hair cells...?

Or could it be because the hair cells won't regrow in the very exact position as the damaged or missed hair cell do?

Every added dB is a miracle, but I just wonder why there isn't more improvement.

 

[tommyd87]

Mine's a bit worse than yours. I don't think 10 dB at 8 kHz will make a huge difference, but the possibly greater improvements above that might help with speech comprehension - especially in noise. Until we know more, FX-322 isn't going to help me hear the crickets on a summer night, but might help me participate in dinner conversation (with the help of hearing aids). Without going back and checking, I think that only one of the people with improved word recognition scores might get by without a hearing aid. Their scores were doubled but still not great.

1. One individual got 47/50 words or 94% after FX-322, compared to their mid-20 words in the initial test.

2. Improvement above 8000 Hz probably will help with clarity/comprehension. Currently this is a fairly reasonable assumption to make based off of the testing results from the inaugural trial.

There are two questions which are still not answered regarding how FX-322 benefits with hearing in noise:

- Does the word clarity improve the ability for someone to hear in background noise better?

- Does FX-322 provide enough benefit to someone's synapses to allow them to hear better in background noise?

The evidence tends to suggest that there is benefit to clarity based on the word score improvements and the research outcomes showed that FX-322 also reconnects synapses. Thus it is highly likely that if you could hear more clearly and/or you could hear better in background noise then you would have benefit when it comes to conversations.

However the question that is not answered is whether FX-322 would provide sufficient synapse recovery to allow you to have full restoration of the speech in noise benefit in the same way which a synapse restoration medicine would?

We don't know the answer to this yet and from what has been hinted, FX-322 does not actually provide the same benefit to synapses as a specific synapse medicine would.

The dosing is seemingly the only inhibitor to getting improved results in the ear. Based off of the results we saw in the lab there is the possibility that FX-322 can provide full regrowth in the ear, however this will just depend upon getting the sufficient dose and correct method organised to enable this.