Frequency Therapeutics — Hearing Loss Regeneration

[Bartoli]

Prednisone and all steroids have a *highly* variable intracochlear penetrance. So much so that Otonomy has a phase 3 drug that is just Dexamethasone in a penetrative gel which would be completely unnecessarily if steroids were easy to get in the cochlea.

Thanks.

I am aware of that. I meant it in the way that if one was to take steroids or other anti-inflammatory drugs orally (maybe for another purpose) and it made tinnitus lower for a while, it could give a clue as to whether inflammation would be (at least partly) responsible for tinnitus.
I believe the same coincidence led to the observation that IV lidocaine helped some people lower their tinnitus temporarily, again suggesting inflammation may be the cause.

Prednisone does nothing for me, but I guess someone could try and see if it helps in their case if feeling particularly curious and adventurous.

Not sure if one could get access to intratympanic Dexamethasone as easily, so it's not really a viable way to "experiment" with.

 

[FGG]

Thanks.

I am aware of that. I meant it in the way that if one was to take steroids or other anti-inflammatory drugs orally (maybe for another purpose) and it made tinnitus lower for a while, it could give a clue as to whether inflammation would be (at least partly) responsible for tinnitus.
I believe the same coincidence led to the observation that IV lidocaine helped some people lower their tinnitus temporarily, again suggesting inflammation may be the cause.

Prednisone does nothing for me, but I guess someone could try and see if it helps in their case if feeling particularly curious and adventurous.

Not sure if one could get access to intratympanic Dexamethasone as easily, so it's not really a viable way to "experiment" with.

Ah ok. Got it now I think.

You were saying it could provide clues with a positive response but not necessarily provide any diagnostic information with a neutral response then. In that case, I agree.

 

[tommyd87]

Thanks.

I am aware of that. I meant it in the way that if one was to take steroids or other anti-inflammatory drugs orally (maybe for another purpose) and it made tinnitus lower for a while, it could give a clue as to whether inflammation would be (at least partly) responsible for tinnitus.
I believe the same coincidence led to the observation that IV lidocaine helped some people lower their tinnitus temporarily, again suggesting inflammation may be the cause.

Prednisone does nothing for me, but I guess someone could try and see if it helps in their case if feeling particularly curious and adventurous.

Not sure if one could get access to intratympanic Dexamethasone as easily, so it's not really a viable way to "experiment" with.

If it is effective with tinnitus then I am sure you can get it off-label.

 

[Koz]

I'm sure this has been asked before but FX-322 is strictly for damaged cochlear hair cells, right?

If the sensorineural hearing loss is a result of a damaged auditory nerve then FX-322 wouldn't work?

If so, does anyone know if there's anything in the pipeline for that?

 

[Kendra]

QUOTE="Koz, post: 553967, member: 2621"]I'm sure this has been asked before but FX-322 is strictly for damaged cochlear hair cells, right?

If the sensorineural hearing loss is a result of a damaged auditory nerve then FX-322 wouldn't work?

If so, does anyone know if there's anything in the pipeline for that?[/QUOTE]
Correct. I don't believe it would help with auditory nerve damage. Frequency Therapeutics' MS program maybe might end up helping though.

https://www.frequencytx.com/pipeline-programs/multiple-sclerosis-program/

 

[FGG]

I'm sure this has been asked before but FX-322 is strictly for damaged cochlear hair cells, right?

If the sensorineural hearing loss is a result of a damaged auditory nerve then FX-322 wouldn't work?

If so, does anyone know if there's anything in the pipeline for that?

"Auditory Neuropathy" is usually damage to the synapse portion from everything I read and yes there are cochlear synaptopathy drugs in the works: OTO-413 is the furthest along of those.

There are exceptions to this with diseases like GBS which can affect the non synapse portions but those aren't very common and Rinri Therapeutics is the biotech to watch for that.

 

[tommyd87]

I'm sure this has been asked before but FX-322 is strictly for damaged cochlear hair cells, right?

If the sensorineural hearing loss is a result of a damaged auditory nerve then FX-322 wouldn't work?

If so, does anyone know if there's anything in the pipeline for that?

Rinri Pharmaceuticals is working on that. Although I don't think this will be an issue for most people. I think that the majority of people have issues with hair cells and/or the nerve ends/synapses.

Supposedly sometimes people refer to the hair cells/synapses as nerve issues which they technically are, although actually they really are not. Thus it is incredibly likely that the overwhelming majority of people will get benefit from FX-322 for their issue.

I could be wrong and you could have a different situation, however when I look at what was the probable result of your tinnitus it is seeming like it is entirely possible that your case is from synapse issues. If it is the case that it is synapse issues then FX-322 won't work for you as it only regrows hair cells/synapses together when they are both busted. Therefore you would be using something like OTO-413, if successful, which is a nerve end/synapse treatment that redoes these when there is a hair cell there without a synapse.

 

[Koz]

"Auditory Neuropathy" is usually damage to the synapse portion from everything I read and yes there are cochlear synaptopathy drugs in the works: OTO-413 is the furthest along of those.

There are exceptions to this with diseases like GBS which can affect the non synapse portions but those aren't very common and Rinri Therapeutics is the biotech to watch for that.

Thank you, because I don't actually know if my sensorineural hearing loss is auditory nerve or cochlear hair cell related. My right ear is normal but my left ear is the damaged one with an audiogram that is practically flat all across the moderate to severe range (from 50 dB - 60 dB).

I haven't bothered trying to find out, there is no cure for either. I've always thought to leave it until whichever cure for one comes first. The ENT agreed.

 

[tommyd87]

Thank you, because I don't actually know if my sensorineural hearing loss is auditory nerve or cochlear hair cell related. My right ear is normal but my left ear is the damaged one with an audiogram that is practically flat all across the moderate to severe range (from 50 dB - 60 dB).

I haven't bothered trying to find out, there is no cure for either. I've always thought to leave it until whichever cure for one comes first. The ENT agreed.

This shows your problem is incredibly likely to be from both hair cell and synapse issues. Hair cell issue is indicated when you have hearing loss shown on the traditional audiogram. As a result, if you used a treatment like OTO-6XX or FX-322 for the hair cells, synapses would be regrown with these too. You wouldn't regrow busted synapses when a hair cell is functional though. Thus this might mean (and probably will mean) that you will need to use a synapse treatment like PIPE-505 because there would probably be a fair chance that you have some hair cells with no synapses as well.

 

[weab00]

Let's assume, for the sake of argument, that your tinnitus is 100% caused by missing hair cells (no damaged synapses). After getting FX-322, would your tinnitus instantaneously go away as soon as the hair cells were regenerated? Or would it slowly fade over the following months? I remember reading that people with tinnitus caused by colds or wax don't get full fading for up to a year sometimes.

 

[tommyd87]

Let's assume, for the sake of argument, that your tinnitus is 100% caused by missing hair cells (no damaged synapses). After getting FX-322, would your tinnitus instantaneously go away as soon as the hair cells were regenerated? Or would it slowly fade over the following months? I remember reading that people with tinnitus caused by colds or wax don't get full fading for up to a year sometimes.

I think that this is a hard one to quantify because firstly some people's tinnitus goes away immediately if they use a hearing aid and secondly it seems that no one knows what would happen when you regrow hair cells because no one has done this before.

I would say that this wouldn't happen immediately with regrown hair cells considering that there is a delayed effect between getting injected with FX-322 and the regrowth starting. Furthermore, you may need to get injected more than once before your your hair cells will completely and correctly regrow.

Thus I think that it is too early to tell exactly what would happen in people who have got tinnitus from hair cell loss, we will know only after you regrow those damaged hair cells.

 

[Michael01]

Thank you, because I don't actually know if my sensorineural hearing loss is auditory nerve or cochlear hair cell related.

Is there a way to find that out, as I understood that such things were beyond current diagnostic means? Just that it'd be nice to know so we know whether such things as FX-322 would work, instead of having to try everything and hope something works?

 

[tommyd87]

Is there a way to find that out, as I understood that such things were beyond current diagnostic means? Just that it'd be nice to know so we know whether such things as FX-322 would work, instead of having to try everything and hope something works?

I'd rather have the solutions . Although it is going to mean paying more money too. Totally agree with your point however.

 

[ThomasRobert]

Is there a way to find that out, as I understood that such things were beyond current diagnostic means? Just that it'd be nice to know so we know whether such things as FX-322 would work, instead of having to try everything and hope something works?

Yes there is a way to find out... "Synchrotron Phase-Contrast Imaging and Histology"

"But as yet, it is not possible to study living patients with this technique. The radiation is too strong, the technology can be modified in the future to achieve better resolution than today, says Helge Rask-Andersen"

Link:
Ear's inner secrets revealed with new technology

This video explains clearly how the Synchrotron scanner system works:

 

[Michael01]

Synchrotron Phase-Contrast Imaging and Histology

Pity that it's too strong to use on living patients, as I understand it. I'd very much like to know what's going on with my ears.

 

[weab00]

Yes there is a way to find out... "Synchrotron Phase-Contrast Imaging and Histology"

"But as yet, it is not possible to study living patients with this technique. The radiation is too strong, the technology can be modified in the future to achieve better resolution than today, says Helge Rask-Andersen"

Link:
Ear's inner secrets revealed with new technology

That is probably so loud it would blow every hair cell and synapse out.

 

[Koz]

Is there a way to find that out, as I understood that such things were beyond current diagnostic means? Just that it'd be nice to know so we know whether such things as FX-322 would work, instead of having to try everything and hope something works?

My ENT said it wasn't possible. I thought Otoacoustic Emissions test and Auditory Brainstem Response test were exactly the tests to help figure if your problem is from dead hair cells or from a damaged acoustic nerve. But maybe not? Like @tommyd87 said, i'ts very likely both hair cell and synapse if you have visible loss on an audiogram (like me).

I didn't dive deep into it once again as I say, it would be nice to know but what is the point? There is no cure as it stands. I would like to investigate further if possible once the first cure for sensorineural hearing loss comes out whether its FX-322 or OTO-6XX etc.

Edit: Funny enough I've just realised I have done an Auditory Brainstem Response test in the past (aka Auditory Evoked Potential) - and the conclusion result is normal. "Stimulate ears with 80dB nHL (Burst/Clicking Sound) and the waves of I, III, V are induced. The latency period of waves I, III, V and the interpeak interval of wave I-V are normal."

 

[briano]

At the moment, is FX-322 our best chance to restore our hearing loss?

 

[tommyd87]

At the moment, is FX-322 our best chance to restore our hearing loss?

I wouldn't say that the term best chance is appropriate or accurate at all. At this stage I would think that FX-322 is showing some significant promise and also actually has a good chance of giving good hearing restoration. It is at present the furthest ahead in terms of development it seems and also the furthest into the trials process.

FX-322 isn't the only treatment however for hair cell growth. OTO-6XX is at present probably very close to commencing trials since they have now sorted that agreement. Then there tends to be about 5 other companies at least which were working on or will be working on a hair cell treatment at some point.

Thus the terrific fact is that by having multiple companies work with hair cell regrowth it is inevitably going to make it much more likely that there will be a suitable treatment that works and that there will possibly also be multiple medicines doing the same thing.

 

[briano]

I wouldn't say that the term best chance is appropriate or accurate at all.

Yes, you are correct. "Best chance" was a poor use of words. I guess what I meant to ask was if FX-322 was the front runner at the moment. Thanks for giving me the answer to that question. Have you heard if anyone experienced higher than 10 dB increases during the trials?

 

[Pete88]

Just curious about something.

Remember how Frequency Therapeutics injected cochleas that were being extracted from people and they concluded that "therapeutic levels of the drug" were found in the entire cochlea after splitting them open?

Does anyone know how many shots these cochleas got? Just wondering if they did multiple injections which supports the theory being trialed now that numerous injections allows FX 322 to reach deeper into the cochlea?

Also I may have messed up my facts on this so feel feel to correct any errors.

 

[Lucifer]

Just curious about something.

Remember how Frequency Therapeutics injected cochleas that were being extracted from people and they concluded that "therapeutic levels of the drug" were found in the entire cochlea after splitting them open?

Does anyone know how many shots these cochleas got? Just wondering if they did multiple injections which supports the theory being trialed now that numerous injections allows FX 322 to reach deeper into the cochlea?

Also I may have messed up my facts on this so feel feel to correct any errors.

I completely forgot about this. I assume it was just one shot but they didn't say. Anyone know the answer to this question?

 

[FGG]

Just curious about something.

Remember how Frequency Therapeutics injected cochleas that were being extracted from people and they concluded that "therapeutic levels of the drug" were found in the entire cochlea after splitting them open?

Does anyone know how many shots these cochleas got? Just wondering if they did multiple injections which supports the theory being trialed now that numerous injections allows FX 322 to reach deeper into the cochlea?

Also I may have messed up my facts on this so feel feel to correct any errors.

I haven't seen number of injections reported for that.

 

[tommyd87]

Just curious about something.

Remember how Frequency Therapeutics injected cochleas that were being extracted from people and they concluded that "therapeutic levels of the drug" were found in the entire cochlea after splitting them open?

Does anyone know how many shots these cochleas got? Just wondering if they did multiple injections which supports the theory being trialed now that numerous injections allows FX 322 to reach deeper into the cochlea?

Also I may have messed up my facts on this so feel feel to correct any errors.

I thought it was only one shot.

Seems that they tried doing multiple shots when they got to the phase 2 trial.

 

[patorjk]

Just curious about something.

Remember how Frequency Therapeutics injected cochleas that were being extracted from people and they concluded that "therapeutic levels of the drug" were found in the entire cochlea after splitting them open?

Does anyone know how many shots these cochleas got? Just wondering if they did multiple injections which supports the theory being trialed now that numerous injections allows FX 322 to reach deeper into the cochlea?

Also I may have messed up my facts on this so feel feel to correct any errors.

They only got 1 shot:

In the study, seven subjects received a single dose of FX-322 at the same dose level given in the Company's Phase 1/2 study and its ongoing Phase 2a study.

Ref: https://investors.frequencytx.com/n...eutics-shares-clinical-data-exploratory-study

However, you make a good point - I wonder why they didn't dose some of them with multiple injections. That would have given us a preview of what Phase 2a may offer.

 

[Gb3]

Just curious about something.

Remember how Frequency Therapeutics injected cochleas that were being extracted from people and they concluded that "therapeutic levels of the drug" were found in the entire cochlea after splitting them open?

Does anyone know how many shots these cochleas got? Just wondering if they did multiple injections which supports the theory being trialed now that numerous injections allows FX 322 to reach deeper into the cochlea?

Also I may have messed up my facts on this so feel feel to correct any errors.

I don't think they split their cochlea open. What they did is they took cochlear implant candidates and injected them with FX-322 and were somehow able to measure the level of the drug through inserting the cochlear implant. I could be wrong.

 

[FGG]

I don't think they split their cochlea open. What they did is they took cochlear implant candidates and injected them with FX-322 and were somehow able to measure the level of the drug through inserting the cochlear implant. I could be wrong.

They removed perilymph during CI insertion and measured drug amount. The perilymph layer is where the drug eventually drains into.

 

[Diesel]

I don't think they split their cochlea open. What they did is they took cochlear implant candidates and injected them with FX-322 and were somehow able to measure the level of the drug through inserting the cochlear implant. I could be wrong.

There are two separate issues here that are being confused. I'll go in chronological order:

1. Frequency Therapeutics has confirmed that they have been able to demonstrate growing hair cells in entire donated cochleas in vitro. David Lucchino mentioned in-vitro testing included "hundreds" of donated human cochleas tested in vitro, in the lab, that showed all frequencies generated, prior to starting clinical trials. So, they have observed FX-322 will activate progenitors throughout entire cochleas donated from dead people, used in the lab.

2. The perilymph study, revealed earlier in 2020 demonstrated that a single dose of FX-322 applied through intratympanic injection was indeed entering the cochlea, and at therapeutic levels needed to activate progenitor cells. Frequency Therapeutics worked with a German cochlear implant firm that did the injection on live patients, then took a sample of the perilymph after the drug had diffused in the cochlea.

The takeaways here are:

1. FX-322 has been observed to activate progenitor cells throughout the cochlea. (All frequencies activated).
2. The drug is entering the live cochlea, as predicted, at levels high enough activate progenitors and make hair cells.

 

[Margus]

1. FX-322 has been observed to activate progenitor cells throughout the cochlea. (All frequencies activated).
2. The drug is entering the live cochlea, as predicted, at levels high enough activate progenitors and make hair cells.

And yet the study results unfortunately are not proving it so far. Let's hope for the best for Phase 2a, but I think the fact they have started look into hidden hearing and tinnitus as possible new secondary outcome targets is sign of desperation. You wouldn't need that if you have a confidence to achieve primary target.

 

[GBB]

And yet the study results unfortunately are not proving it so far. Let's hope for the best for Phase 2a, but I think the fact they have started look into hidden hearing and tinnitus as possible new secondary outcome targets is sign of desperation. You wouldn't need that if you have a confidence to achieve primary target.

You might be right although I think for insurance coverage those other indicators are also meaningful.