Frequency Therapeutics — Hearing Loss Regeneration

[serendipity1996]

Regarding the normal audiograms and possible high frequency hearing loss that may be causing tinnitus, FX-322 just regenerates hair cells, doesn't it, and wouldn't address cochlear synaptopathy - where the synapses are damaged but the hearing cells are intact? That's why it may not work for tinnitus if one of the proposed theories of tinnitus is correct, i.e. tinnitus originates from synaptic damage and not hearing cells that have been damaged or destroyed?

FX-322 would address synaptopathy only where there is corresponding hair cell damage. I think tinnitus could originate from both hair cell loss and synaptopathy - anywhere there is a loss of input could result in tinnitus so it's not strictly one or the other.

 

[FGG]

FX-322 would address synaptopathy only where there is corresponding hair cell damage. I think tinnitus could originate from both hair cell loss and synaptopathy - anywhere there is a loss of input could result in tinnitus so it's not strictly one or the other.

This is why I wish Frequency Therapeutics would tone match tinnitus in their study.

If you have a 8000 Hz tone (for instance) from synaptopathy, and no hair cell loss in that area, the drug likely won't help. But if you have audiogram improvements in a specific frequency, you are at least addressing hair cells at that frequency so tinnitus should at least improve whether or not you had synaptopathy without IHC damage at that location.

 

[Diesel]

FX-322 would address synaptopathy only where there is corresponding hair cell damage. I think tinnitus could originate from both hair cell loss and synaptopathy - anywhere there is a loss of input could result in tinnitus so it's not strictly one or the other.

It seems that many here agree that it's highly likely that most people with hearing loss / tinnitus probably have a mixture of hair cell loss and synaptopathy.

It will be interesting to see in initial patients how much FX-322 repairing IHC/OHC improves hearing loss/tinnitus where the original in-tact hair cells with synaptopathy are unchanged.

Perhaps in some, the population of brand-new cells is enough to compensate in terms of signal for those that are still not functioning due to broken synapses?

I suppose without a proper way to test for hair-cell damage and synaptopathy, there would be no way to tell...

 

[Zugzug]

All of this discussion about hair cells and synaptopathy have left me with some questions:

1) If progenitor cells replace dead hair cells by morphing into them and leaving behind a copy of themselves, what does the body do with the original dead hair cells? Do they just stay there, possibly exasperating synaptopathy if the synapses are damaged? Does the body get rid of them?
2) Do the new hair cells just form new synapses? (I'm 99% sure the answer is yes to this one.)
3) What if the hair cell is damaged, but not destroyed? Do the support cells repair the hair cell without undergoing the process of leaving behind a copy and turning into a hair cell? Is there any chance that a repair (as opposed to replacement) would repair synapses?

I'm so confused. At the same rate, I agree with everyone's assessment that addressing synaptopathy is critical.

 

[Diesel]

I was just thinking about my previous comment, and was reminded of Will McLean's presentation in 2018. He discusses applying FX-322 to an intact cochlea. Quote:

"We found that you actually get more supporting cells, but you also get a doubling of inner and outer hair cells. Interestingly, if you culture longer, it seems to limit itself."

Frequency has not mentioned this at all in during the trials, because obviously it cannot be observed in live patients; unless they are able to extract cochleas for patients that happened to receive the drug in a trial, then pass away.

My hypothesis as it relates to synaptopathy:

Let's assume most people with hearing loss / tinnitus likely have some mixture of IHC/OHC damage/death and synaptopathy. Let's also assume Will's case is happening in live patients: that FX-322 applied to a living cochlea causes the IHC/OHC capacity to 'overproduce' cells at the site of action; upwards of 2X.

What would the organ do with this surplus of cells? We have been told that the PCA process causes the synapse to reconnect to "the" or "a" nerve...

In the case of a patient with "mixed pathology"... I hypothesize that perhaps the "surplus" of IHC/OHC cells may reconnect to those nerves that have cells broken synapses. The result would be a cell with a broken synapse still living in the cochlea, but a new adjacent cell connecting in its place.

SOURCE:


Ref:

 

[Jurger]

I'm not so sure August had an update to that graphic [1]. Slide 17 looks the same in this document and it's dated for May of this year:

https://sec.report/Document/0001564590-20-025267/

However, I looked the document up on archive.org and noticed that there was a significant change (though in the opposite direction: from 3500Hz to 6500Hz - it's slide 22):

https://web.archive.org/web/2019120...ic-files/6d161090-16f5-49f4-9606-8caceb5a88a1

That change seems very significant. I wonder if the change was due to the results of their exploratory study into the delivery of FX-322 [2]. If it was, the good news is that we know their graphics are accurate. The bad news is that there's definitely a problem with getting to the lower frequencies. 6500Hz and above is still good, but it's kind of strange that they can't seem to get to the lower frequencies.

[1] https://investors.frequencytx.com/static-files/6d161090-16f5-49f4-9606-8caceb5a88a1
[2] https://investors.frequencytx.com/n...eutics-shares-clinical-data-exploratory-study

Not that strange. The apex of the cochlea, where the lower frequencies are located, is notoriously difficult to reach with intratympanic drug delivery. Getting drugs there in a sufficient, consistent and practical manner is one of the biggest hurdles in the inner ear field.

 

[serendipity1996]

All of this discussion about hair cells and synaptopathy have left me with some questions:

1) If progenitor cells replace dead hair cells by morphing into them and leaving behind a copy of themselves, what does the body do with the original dead hair cells? Do they just stay there, possibly exasperating synaptopathy if the synapses are damaged? Does the body get rid of them?
2) Do the new hair cells just form new synapses? (I'm 99% sure the answer is yes to this one.)
3) What if the hair cell is damaged, but not destroyed? Do the support cells repair the hair cell without undergoing the process of leaving behind a copy and turning into a hair cell? Is there any chance that a repair (as opposed to replacement) would repair synapses?

I'm so confused. At the same rate, I agree with everyone's assessment that addressing synaptopathy is critical.

I'm not sure exactly about hair cells that are damaged but not dead, but I recall reading that dead hair cells undergo apoptosis and are ejected by the body once dead.

 

[Rubenslash]

Not that strange. The apex of the cochlea, where the lower frequencies are located, is notoriously difficult to reach with intratympanic drug delivery. Getting drugs there in a sufficient, consistent and practical manner is one of the biggest hurdles in the inner ear field.

Correct, but it seems there is a lot of movement in this field. I came across this paper from 2020: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063177/

Here we present an efficient, quick, and simple method of cochlear pumping, through large-amplitude, low-frequency reciprocal oscillations of the stapes and round window, which can consistently and uniformly deliver drugs along the entire length of the intact cochlea within minutes without disrupting the cochlear boundaries. The method should facilitate novel ways of approaching the treatment of inner ear disorders because it overcomes the challenge of delivering therapeutics along the entire cochlear length.
[...]
A large number of methods, including intracochlear administration, cochleostomy, and canalostomy, have been proposed for solving the problem of uniform drug distribution along the cochlea, but only two current strategies address this problem without breaching the boundaries of the intact cochlea (e.g., see El Kechai et al., 2015). The first strategy relies on retaining drugs in contact with the RW to allow drug diffusion into the cochlear apex. Notable examples of devices designed for this purpose include microwicks, osmotic pumps, etc. Hydrogel-based drug delivery systems also allow retention of therapeutics in the middle ear in contact with the RW. The problem with this strategy is that retention of drugs at the RW leads to their establishing steady-state concentration gradients along the cochlea, which depend on the relationship between diffusion and clearing (Salt and Ma, 2001, Sadreev et al., 2019), but the base-to-apex gradients can still be very pronounced.

The second strategy, although relatively non-invasive to the cochlea, requires development of more complex drug formulations. The technique employs drug-loaded nanoparticles, which could be used to take advantage of the anatomical and cellular features of the cochlea, which enable drug uptake through routes and pathways other than the ST route (Buckiová et al., 2012, Glueckert et al., 2018). Magnetically driven, drug-loaded magnetic nanoparticle can also be actively distributed along the entire cochlea (Ramaswamy et al., 2017).

Here we demonstrate that cochlear pumping (CP), through pressure oscillations in the ear canal at frequencies low enough to avoid damage to the cochlear sensory apparatus, can consistently and uniformly deliver drugs along the entire length of the intact cochlea within minutes without disrupting the cochlear boundaries.

Hopeful that eventually something will be found to get this drug into the entire cochlea.

 

[asey20]

Correct, but it seems there is a lot of movement in this field. I came across this paper from 2020: https://www.

Yay! Full drug delivery. Feeling like hearing loss and tinnitus will be cured within the next decade. Hehe

 

[Thuan]

Correct, but it seems there is a lot of movement in this field. I came across this paper from 2020: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063177/

Hopeful that eventually something will be found to get this drug into the entire cochlea.

That's an awesome article!

For those who are wondering what this cochlear pump is doing: they're proposing that a very, very low, 4 Hz (not kHz), frequency to mechanically move the stapes that's connected to the cochlea to induce fluid displacement inside the cochlea. Basically, they're sloshing the fluid inside the cochlear while the drugs at the round window slowly diffuses through. Very cool.

I hope Frequency Therapeutics reads about this.

 

[FGG]

That's an awesome article!

For those who are wondering what this cochlear pump is doing: they're proposing that a very, very low, 4 Hz (not kHz), frequency to mechanically move the stapes that's connected to the cochlea to induce fluid displacement inside the cochlea. Basically, they're sloshing the fluid inside the cochlear while the drugs at the round window slowly diffuses through. Very cool.

I hope Frequency Therapeutics reads about this.

This sounds really interesting but wouldn't apply to Frequency as their drug will be out before this goes through human trials (and they mentioned in the link having to tweak this a bit for the human cochlea).

The link did mention this being a non-invasive/non-surgical approach but keep in mind there is a surgery (canalostomy) that could be done now to reach the apex with any drug (can be diffused into endolymph or perilymph at that location without damage to cochlea).

They will be trialing surgeries like this soon for AAV genetic deafness therapies which need to be infused directly into the cochlea and the previous method (cochleostomy is destructive to the cochlea).

No one wants surgery but it is one possibility that would be imminently available.

 

[Thuan]

This sounds really interesting but wouldn't apply to Frequency as their drug will be out before this goes through human trials (and they mentioned in the link having to tweak this a bit for the human cochlea).

The link did mention this being a non-invasive/non-surgical approach but keep in mind there is a surgery (canalostomy) that could be done now to reach the apex with any drug (can be diffused into endolymph or perilymph at that location without damage to cochlea).

They will be trialing surgeries like this soon for AAV genetic deafness therapies which need to be infused directly into the cochlea and the previous method (cochleostomy is destructive to the cochlea).

No one wants surgery but it is one possibility that would be imminently available.

Out of curiosity, wouldn't something like canalostomy (which drills a hole through the canal into the endolymph) introduce risks for symptoms to cochlear hydrops? From what I understood of the hypothesized cause of cochlear hydrops is that the endolymph-perilymph membrane is broken that results in a cascade of factors. Given that if the cut heals, then it would be fine but if it doesn't that's a huge load of scary symptoms after surgery.

In another note, if one is opting for surgery, why not just use a needle to inject the drug directly through the round window? Doing this will be similar to canalostomy except the entry point is the round window, which from what I gathered isn't bony but a membrane. I would imagine a direct injection into the round window is less destructive.

 

[Gb3]

Does anyone know if sudden sensorineural hearing loss includes cochlear synaptopathy or is it just damage to the hair cells?

 

[FGG]

Out of curiosity, wouldn't something like canalostomy (which drills a hole through the canal into the endolymph) introduce risks for symptoms to cochlear hydrops? From what I understood of the hypothesized cause of cochlear hydrops is that the endolymph-perilymph membrane is broken that results in a cascade of factors. Given that if the cut heals, then it would be fine but if it doesn't that's a huge load of scary symptoms after surgery.

In another note, if one is opting for surgery, why not just use a needle to inject the drug directly through the round window? Doing this will be similar to canalostomy except the entry point is the round window, which from what I gathered isn't bony but a membrane. I would imagine a direct injection into the round window is less destructive.

It's in a different location. The canalostomy is in the semi-circular canal. The risk here is vestibular but as someone who has virtually no vestibular function on my right side and is clinically normal (though I probably can't go on roller coasters again) after PT, it's worth the risk imo.

As far as i know, puncturing the round window directly is damaging (and I'm not sure offers much advantage over IT injection), as it is very small and prone to damage but maybe there is some way they could do that safely that I'm not aware of.

 

[serendipity1996]

Does anyone know if sudden sensorineural hearing loss includes cochlear synaptopathy or is it just damage to the hair cells?

It can be both. Unfortunately there's no way to image the inner ear and diagnostics haven't really caught up yet, particularly for cochlear synaptopathy. The key finding to come out of the discovery of cochlear synaptopathy, however, is that the synapses are even more vulnerable to damage than the hair cells - you can have significant synaptic loss before it starts affecting hearing thresholds, according to Liberman and Kujawa.

 

[tommyd87]

Not that strange. The apex of the cochlea, where the lower frequencies are located, is notoriously difficult to reach with intratympanic drug delivery. Getting drugs there in a sufficient, consistent and practical manner is one of the biggest hurdles in the inner ear field.

Correct, but it seems there is a lot of movement in this field. I came across this paper from 2020: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063177/

Hopeful that eventually something will be found to get this drug into the entire cochlea.

I'd argue one of the major reasons that it remains difficult to deliver medicine using intratympanic injection throughout the ear is because until now there has been no research into improving this. This is largely because previously there have been very few, if any, treatments using intratympanic injection requiring the medicine reaching the full area in the cochlea.

Research in the pharma field is a lot like doing maintenance on a house. You only do things when you need to. Hence why Frequency Therapeutics only employed someone to improve dosing when they identified the need.

Therefore due to the development of FX-322 and the wider interest in creating similar treatments, there is now an actual reason to improve intratympanic injections and their reach in the cochlea. Therefore, further investments in this area can be expected from pharma companies manufacturing ear medicines, and from companies providing ancillary services to those pharma companies.

 

[tommyd87]

That's an awesome article!

For those who are wondering what this cochlear pump is doing: they're proposing that a very, very low, 4 Hz (not kHz), frequency to mechanically move the stapes that's connected to the cochlea to induce fluid displacement inside the cochlea. Basically, they're sloshing the fluid inside the cochlear while the drugs at the round window slowly diffuses through. Very cool.

I hope Frequency Therapeutics reads about this.

It's in a different location. The canalostomy is in the semi-circular canal. The risk here is vestibular but as someone who has virtually no vestibular function on my right side and is clinically normal (though I probably can't go on roller coasters again) after PT, it's worth the risk imo.

As far as i know, puncturing the round window directly is damaging (and I'm not sure offers much advantage over IT injection), as it is very small and prone to damage but maybe there is some way they could do that safely that I'm not aware of.

Couldn't it be possible that Frequency Therapeutics might actually investigate using this type of treatment down the track? I am aware that they are evaluating dosing and delivery too as part of their process.

Hopefully the proposed vestibular treatment actually succeeds.

 

[Lilah]

What is considered hearing loss by Frequency Therapeutics? Anything above 20 dB in a given frequency?

 

[weab00]

I'm just now learning about FX-322, so this may have already been covered at some point in the thread.

From what I've seeing they are only accepting people with mild-to-moderate hearing loss as candidates. I have moderate tinnitus and hyperacusis and am obviously excited by the results of the drug and would like to try it once it's on the market.

However, my audiogram shows near perfect hearing; would I be rejected on grounds of having "not enough hearing loss"?

 

[FGG]

Couldn't it be possible that Frequency Therapeutics might actually investigate using this type of treatment down the track? I am aware that they are evaluating dosing and delivery too as part of their process.

Maybe but it would be extremely premature of them to look into something before it's even in pre-clinical to eventually be tried in humans.

 

[FGG]

I'm just now learning about FX-322, so this may have already been covered at some point in the thread.

From what I've seeing they are only accepting people with mild-to-moderate hearing loss as candidates. I have moderate tinnitus and hyperacusis and am obviously excited by the results of the drug and would like to try it once it's on the market.

However, my audiogram shows near perfect hearing; would I be rejected on grounds of having "not enough hearing loss"?

Probably unless your extended audiogram had a lot of abnormalities as it is first and foremost a hearing loss drug for the purposes of the FDA trials.

 

[FGG]

What is considered hearing loss by Frequency Therapeutics? Anything above 20 dB in a given frequency?

From their clinical trials page inclusion criteria:

"Pure Tone Audiometry (PTA) within 26-70 dB in the ear to be injected."

 

[weab00]

Probably unless your extended audiogram had a lot of abnormalities as it is first and foremost a hearing loss drug for the purposes of the FDA trials.

I more so meant once the drug is actually commercially available.

And if that were the case, wouldn't it defeat the purpose of all the buzz it's been getting on Tinnitus Talk? It seems to me that many people with tinnitus don't have hearing loss. Hopefully Frequency Therapeutics will come to see how much profit they can make off tinnitus/hyperacusis sufferers alone.

 

[FGG]

I more so meant once the drug is actually commercially available.

And if that were the case, wouldn't it defeat the purpose of all the buzz it's been getting on Tinnitus Talk? It seems to me that many people with tinnitus don't have hearing loss. Hopefully Frequency Therapeutics will come to see how much profit they can make off tinnitus/hyperacusis sufferers alone.

The buzz is because it can and will be used off label. But of course not everyone will qualify for the clinical trial. But clinical trials are never the whole of people who will benefit from a drug.

If you have tinnitus from cochlear injury (e.g., noise, ototoxins), you have hearing loss even if your standard audiogran looks normal. But obviously FX-322 won't benefit non-cochlear causes (e.g., TMJ, ETD).

 

[BBakkers]

I more so meant once the drug is actually commercially available.

And if that were the case, wouldn't it defeat the purpose of all the buzz it's been getting on Tinnitus Talk? It seems to me that many people with tinnitus don't have hearing loss. Hopefully Frequency Therapeutics will come to see how much profit they can make off tinnitus/hyperacusis sufferers alone.

Just read this article about Hidden Hearing Loss and all will make sense:

https://leader.pubs.asha.org/doi/10.1044/leader.FTR1.22072017.48

Just some quotes from this article:
"You can lose 50 percent of your synapses in minutes after a noise exposure, but it might take you a full lifetime to lose that number with aging."

"And while the causes and extent of HHL in humans and its implications for public health are still up for debate, the notion that it could soon be time for audiologists to expand their standard assessment arsenal beyond pure-tone audiometry in quiet is less controversial."

 

[Charburchar]

"You can lose 50 percent of your synapses in minutes after a noise exposure

Damn. When I was 21 I once practiced with my band in a small little room with no ear plugs and a very loud drummer. I bet I lost a hell of a load of synapses.

 

[Lucifer]

Just read this article about Hidden Hearing Loss and all will make sense:

https://leader.pubs.asha.org/doi/10.1044/leader.FTR1.22072017.48

Just some quotes from this article:
"You can lose 50 percent of your synapses in minutes after a noise exposure, but it might take you a full lifetime to lose that number with aging."

"And while the causes and extent of HHL in humans and its implications for public health are still up for debate, the notion that it could soon be time for audiologists to expand their standard assessment arsenal beyond pure-tone audiometry in quiet is less controversial."

It sucks that OTO-413 and Hough Pill are so far behind in their trials to help restore synapses. I just hope hyperacusis and tinnitus are caused by OHCs and IHCs rather than synapses so that FX-322 will definitely help everyone with noise damage.

 

[xyz]

"You can lose 50 percent of your synapses in minutes after a noise exposure, but it might take you a full lifetime to lose that number with aging."

How did they know the synapse count after noise exposure? Probably this were some animals that were tested. As far as I know you can look at the synapses only if you surgically remove the cochlea. But anyhow it might give a hint what happens in humans.

 

[Jurger]

The buzz is because it can and will be used off label. But of course not everyone will qualify for the clinical trial. But clinical trials are never the whole of people who will benefit from a drug.

If you have tinnitus from cochlear injury (e.g., noise, ototoxins), you have hearing loss even if your standard audiogran looks normal. But obviously FX-322 won't benefit non-cochlear causes (e.g., TMJ, ETD).

Since this drug is tested for hearing loss across the 250 Hz - 16000 Hz range, I hardly see any room for off label prescription. They're basically covering everything now, aside from ultra, ultra high frequency hearing loss.

 

[Jurger]

Does anyone know if sudden sensorineural hearing loss includes cochlear synaptopathy or is it just damage to the hair cells?

From the research they did on temporal bones, it can be both, but usually mostly hair cells.