Frequency Therapeutics — Hearing Loss Regeneration

[Gabriel5050]

This basically sums up all the rules regarding this, the requirements, the responsibilities of all parties pertaining to treatment through Expanded Access.

https://www.fda.gov/news-events/expanded-access/expanded-access-information-patients#what-is-it

Although a doctor can choose to refuse access to you, I do not actually see why they would and I think that there would be multiple doctors willing to grant Expanded Use.

So this Expanded Access is only available to US citizens? If that's the case, the rest of the world still have a longer wait.

 

[FGG]

So this Expanded Access is only available to US citizens? If that's the case, the rest of the world still have a longer wait.

I don't see a citizen requirement but it seems likely you may need a US doctor.

 

[Diesel]

Maybe this is wishful thinking, but I wonder if curing/reducing tinnitus is FX-322's ace in the hole. Carl LeBel mentioned that several Phase I/II patients told their ENTs that FX-322 improved their tinnitus. This leaves me with several questions:

* How many of the 15 patients treated with FX-322 had tinnitus?
* How many of these tinnitus suffers experienced a reduction? (all we know is that it was more than 1)
* How big of a reduction did they experience?
* Why did a reduction in tinnitus occur? (if tinnitus is being reduced, it probably means that theory about the brain memorizing the sound is wrong)

Hearing restoration may be the bigger market, but if this drug improves tinnitus then they'll want to go full steam ahead in making sure ENTs know.

I can't find the source, but I specifically recall a stat that 40%-60% of patients with diagnosed hearing loss of mild or worse on the standard audiogram reported some level of tinnitus. I'll see if I can dig it up.

The patients could have reported any range of responses, from, my tinnitus got quieter, a high-frequency tone went away, or it went away completely. It probably depends on the severity of hearing loss. I would expect that the mild group may have had more "qualitative" feedback for their ENTs, since Frequency Therapeutics doesn't focus on them much at all in the presentation.

Why did the reduction occur? Because hair cells grew back, and the auditory system/brain got a signal as nature intended. Therefore, the tinnitus symptom was probably reduced/eliminated.

Side comment:
As promising as it is to learn that simply restoring hair cells may help reduce/eliminate tinnitus symptoms for SNHL/NIHL; it is extremely frustrating to see the amount of mis-directed funds and time on research, information, and false conclusions in circulation stating a bunk reason for the cause of tinnitus in these cases.

I really hope as part of the FX-322 program; Frequency Therapeutics makes an effort to draw a clear connection between eliminating tinnitus and hair-cell restoration. Seems like there needs to be a good 40+ years of bad / unhealthy research to be corrected.

#Rantover

 

[Sven]

I haven't read the entire thread (hardly anything, actually), but if you don't suffer from loss of hearing but just have tinnitus caused by loud noise/music, will this help, should it work?

I doubt very much that my tinnitus will be cured before I die in hopefully around 50 years, but if I'm wrong I'd be very happy.

 

[Pink Noise]

I'm thinking about getting a FX-322 tattoo...

Could be a good hearing protection reminder.

 

[FGG]

I haven't read the entire thread (hardly anything, actually), but if you don't suffer from loss of hearing but just have tinnitus caused by loud noise/music, will this help, should it work?

I doubt very much that my tinnitus will be cured before I die in hopefully around 50 years, but if I'm wrong I'd be very happy.

Acoustic trauma causes hearing loss whether you see it on an audiogram or not. Whether FX-322 will help you depends on whether you have hair cell loss or just broken synapses.

Unfortunately, there aren't great diagnostic tests for this but there are a few "synaptopathy" drugs in clinical trials as well (OTO-413, PIPE-505 and the Hough Pill).

If the drug is proven safe, a lot of people will just resort to trial and error with these two classes of treatments.

If you haven't already, get an extended audiogram up to 16000 Hz. This will at least tell you whether you have significant outer hair cell damage (though it won't address less diffuse damage, or inner hair cell damage).

 

[WillBeNimble]

I haven't read the entire thread (hardly anything, actually), but if you don't suffer from loss of hearing but just have tinnitus caused by loud noise/music, will this help, should it work?

I doubt very much that my tinnitus will be cured before I die in hopefully around 50 years, but if I'm wrong I'd be very happy.

What makes you think you don't have hearing loss? If you have only taken the standard audiogram, then you're missing the high frequency and ultra high frequency ranges. So long as you have support cells there, meaning less than 90 dB of loss, you should be able to at least reduce it.

 

[Jurger]

So this Expanded Access is only available to US citizens? If that's the case, the rest of the world still have a longer wait.

FDA can't approve expanded access outside US territories. Besides, Astellas holds the outside US-license. So you'd probably need Astellas and the regulatory agency from the country you're in to get expanded access.

By the way, expanded access is not an exclusive US entity. See for the EU: https://www.ema.europa.eu/en/human-regulatory/research-development/compassionate-use

 

[Emgee]

I haven't read the entire thread (hardly anything, actually), but if you don't suffer from loss of hearing but just have tinnitus caused by loud noise/music, will this help, should it work?

I doubt very much that my tinnitus will be cured before I die in hopefully around 50 years, but if I'm wrong I'd be very happy.

If your tinnitus was caused by noise exposure, you have some degree of hearing damage/loss. Have you been tested via an extended audiogram? You may have high-frequency hearing loss, or even synapse damage that is undetected on a standard audiogram up to 8000 Hz. Also, hearing damage may not even show on an audiogram at all.

 

[serendipity1996]

I haven't read the entire thread (hardly anything, actually), but if you don't suffer from loss of hearing but just have tinnitus caused by loud noise/music, will this help, should it work?

I doubt very much that my tinnitus will be cured before I die in hopefully around 50 years, but if I'm wrong I'd be very happy.

If your tinnitus was caused by noise then it is a form of hearing damage. Audiograms are considered quite primitive measures of hearing loss amongst the research community - you can score well within the 'normal range' on a 250 Hz - 8000 Hz audiogram but have significant damage in the ultra high-frequency range. In that case, FX-322 should help. You could also have 'hidden hearing loss' - there are a few drugs in the pipeline for this too! OTO-414 and PIPE-505.

 

[FGG]

FDA can't approve expanded access outside US territories. Besides, Astellas holds the outside US-license. So you'd probably need Astellas and the regulatory agency from the country you're in to get expanded access.

By the way, expanded access is not an exclusive US entity. See for the EU: https://www.ema.europa.eu/en/human-regulatory/research-development/compassionate-use

I know this is about clinical trials (and this link discusses cancer) but it says US citizens and permanent residents are given priority but it's not a requirement.

https://ccr.cancer.gov/clinical-trials/patients/faq

Pure speculation but I imagine the same would be true for expanded access. I can't find anything anywhere that says US citizenship is a requirement. But I do agree that it needs to occur in the US/territories which is why I suspect a US doctor would need to be involved.

Edit: your point about European expanded use was a good one. That's probably an easier route for most (depending on Astellas).

 

[Zugzug]

Complex question: For patients with autoimmune inner ear disease, their immune system keeps attacking the hair cells. Let's assume that they take FX-322, the progenitor cells get activated, and the immune system targets the progenitor cells. The patient then takes more FX-322. Can it actually keep cycling in the sense of:

hair cells dies ---> progenitor cell is activated -->progenitor cell dies ---> progenitor cell gets reactivated.

To make this question more general, once an activated progenitor cell dies, is that the end? i.e. patients get another chance at avoiding acoustic truama, but not a bunch of them?

EDIT: From reading the website (and this was mentioned in the podcast transcription), the analogy here is that progenitor cells recycle in the gut every few days. I wonder if a similar process could occur in the ear.

Does the human body keep creating progenitor cells in the ear, or are they also a one time deal?

 

[Jurger]

I know this is about clinical trials (and this link discusses cancer) but it says US citizens and permanent residents are given priority but it's not a requirement.

https://ccr.cancer.gov/clinical-trials/patients/faq

Pure speculation but I imagine the same would be true for expanded access. I can't find anything anywhere that says US citizenship is a requirement. But I do agree that it needs to occur in the US/territories which is why I suspect a US doctor would need to be involved.

Edit: your point about European expanded use was a good one. That's probably an easier route for most (depending on Astellas).

I can't imagine there would be a legal issue for a non-US citizen to get permission from a US ENT, FDA and Frequency to get the drug administered in the US. However, with regards to administering outside the US, the FDA has no power. And the same probably goes for Frequency per the licensing agreement with Astellas.

 

[FGG]

Complex question: For patients with autoimmune inner ear disease, their immune system keeps attacking the hair cells. Let's assume that they take FX-322, the progenitor cells get activated, and the immune system targets the progenitor cells. The patient then takes more FX-322. Can it actually keep cycling in the sense of:

hair cells dies ---> progenitor cell is activated -->progenitor cell dies ---> progenitor cell gets reactivated.

To make this question more general, once an activated progenitor cell dies, is that the end? i.e. patients get another chance at avoiding acoustic truama, but not a bunch of them?

EDIT: From reading the website (and this was mentioned in the podcast transcription), the analogy here is that progenitor cells recycle in the gut every day. I wonder if a similar process could occur in the ear.

There is no net depletion with FX-322, unlike other methods (e.g. Audion).

Progenitor cell activated...two daughter cells through an asymmetrical mitosis (one is another identical progenitor cell and one is a hair cell).

 

[WillBeNimble]

Complex question: For patients with autoimmune inner ear disease, their immune system keeps attacking the hair cells. Let's assume that they take FX-322, the progenitor cells get activated, and the immune system targets the progenitor cells. The patient then takes more FX-322. Can it actually keep cycling in the sense of:

hair cells dies ---> progenitor cell is activated -->progenitor cell dies ---> progenitor cell gets reactivated.

To make this question more general, once an activated progenitor cell dies, is that the end? i.e. patients get another chance at avoiding acoustic truama, but not a bunch of them?

EDIT: From reading the website (and this was mentioned in the podcast transcription), the analogy here is that progenitor cells recycle in the gut every day. I wonder if a similar process could occur in the ear.

Does the human body keep creating progenitor cells in the ear, or are they also a one time deal?

So, what you're describing is pretty much what happens in every other vertebrate besides mammals in the animal kingdom. However, this therapy would not be able to force the constant reactivation of progenitor cells. That would require another level, something akin to genetic therapy. Which, although would be the holy grail of auditory science, is much further away.

It can slow down the process of deafness, and with consistent application, perhaps stave it off for the rest of the patient's life, but not constant reactivation.

Rereading the question, this drug causes the progenitor to split and then differentiate into a progenitor and hair cell. So, it will not deplete the support cells. As for the cells themselves dying off, my understanding is that happens with hearing loss and the lack of structure in the epithelial cells after deafness. @FGG is much better to ask about that one.

 

[Diesel]

Complex question: For patients with autoimmune inner ear disease, their immune system keeps attacking the hair cells. Let's assume that they take FX-322, the progenitor cells get activated, and the immune system targets the progenitor cells. The patient then takes more FX-322. Can it actually keep cycling in the sense of:

hair cells dies ---> progenitor cell is activated -->progenitor cell dies ---> progenitor cell gets reactivated.

To make this question more general, once an activated progenitor cell dies, is that the end? i.e. patients get another chance at avoiding acoustic truama, but not a bunch of them?

EDIT: From reading the website (and this was mentioned in the podcast transcription), the analogy here is that progenitor cells recycle in the gut every few days. I wonder if a similar process could occur in the ear.

Does the human body keep creating progenitor cells in the ear, or are they also a one time deal?

As it relates to the cochlea:

1. The progenitor is activated.
2. It "becomes" a hair cell and connects it to the nerve.
3. It leaves a copy of itself behind.
4. A new hair cell and progenitor remain.

If the progenitor is gone, the cycle can't continue. There isn't much revealed at this point about "reactivating" progenitors multiple times after multiple losses of the same hair cell. I assume they have some limit to how many times this cycle can occur.

 

[Zugzug]

@FGG @Diesel @WillBeNimble

You all answered my question. I think what I was looking for was that the progenitor becomes a hair cell, while leaving behind a copy of itself. On a theoretical level, it sounds like people can just keep taking this over and over again after hearing damage. This is some real science, folks, whether FX-322 is the promised land or not. We are finally getting what we want. It's exciting to see how this research will build.

 

[WillBeNimble]

There isn't much revealed at this point about "reactivating" progenitors multiple times after multiple losses of the same hair cell. I assume they have some limit to how many times this cycle can occur.

Something like 40-60 times according to the hayflick limit.

 

[tommyd87]

Could be a good hearing protection reminder.

Having hearing protection would be very necessary after FX-322. Because even when hearing is restored you don't want to be paying potentially $5,000 for the dose as compared to $200 for good earplugs.

 

[Sven]

Those of you who answered me, I suppose you're correct. I didn't think of it like that.

Thanks.

 

[Jurger]

Complex question: For patients with autoimmune inner ear disease, their immune system keeps attacking the hair cells. Let's assume that they take FX-322, the progenitor cells get activated, and the immune system targets the progenitor cells. The patient then takes more FX-322. Can it actually keep cycling in the sense of:

hair cells dies ---> progenitor cell is activated -->progenitor cell dies ---> progenitor cell gets reactivated.

To make this question more general, once an activated progenitor cell dies, is that the end? i.e. patients get another chance at avoiding acoustic truama, but not a bunch of them?

EDIT: From reading the website (and this was mentioned in the podcast transcription), the analogy here is that progenitor cells recycle in the gut every few days. I wonder if a similar process could occur in the ear.

Does the human body keep creating progenitor cells in the ear, or are they also a one time deal?

I think it would be more worthwhile to try to get the auto-immune disease under control (low-dose prednisone?) as much as possible and once that's accomplished, try to regenerate hearing. Otherwise you'll be fighting a lifelong, uphill battle.

 

[Sloth]

Something like 40-60 times according to the hayflick limit.

But that only applies to normal cells, no? I'm not a biologist so I genuinely don't know, but aren't progenitor cells a type of stem cell and can therefore divide more often?

I mean, Frequency Therapeutics said that the ear's progenitors are kind of like close cousins to the intestinal progenitors. And the intestinal lining is basically regenerating itself once a week if I recall correctly, so I doubt that progenitors have the same limit.

 

[tommyd87]

But that only applies to normal cells, no? I'm not a biologist so I genuinely don't know, but aren't progenitor cells a type of stem cell and can therefore divide more often?

I mean, Frequency Therapeutics said that the ear's progenitors are kind of like close cousins to the intestinal progenitors. And the intestinal lining is basically regenerating itself once a week if I recall correctly, so I doubt that progenitors have the same limit.

https://www.clinmedjournals.org/articles/ijscrt/ijscrt-5-053-table1.html

This is an interesting table that tells what a progenitor cell does. It does seem that there is a limit looking at the information on how many times a progenitor can be regenerated although we don't know how many times that is then.

The other thing I find fairly interesting is that the table says it is able to recover damaged or dead cells. This makes me wonder whether the ability to regrow is much wider than first thought.

Thus I wonder whether the people who were not showing an increase in their testing outcomes had actually gained benefit by taking FX-322. It just wasn't as widespread because they needed either more or a bigger dose to treat their situation as opposed to those who showed improvement.

 

[Zugzug]

I think it would be more worthwhile to try to get the auto-immune disease under control (low-dose prednisone?) as much as possible and once that's accomplished, try to regenerate hearing. Otherwise you'll be fighting a lifelong, uphill battle.

I asked because getting the disease under control is a nightmare. For people with autoimmune inner ear disease, they basically need high dose steroids all of the time. There's going to be periods where they have to get off steroids for their health. I was mostly trying to better understand how the drug worked. But yeah, I certainly agree that one's strategy shouldn't be to take FX-322 every day.

 

[GregCA]

There is a procedure being worked at in Australia called ClearDrum Implant where they can patch the hole with a film made of silk directly through the ear. It is another surgery but it is apparently about as straight-forward and riskless as inserting a grommet. It will have further clinical trials soon.

I'm also aware of a new tech that is a kind of "gel" substance that is meant to "cover" the ear drum (and the hole in it), to promote proper regrowth, requiring no surgery, as it would be applied via the ear canal as if one was to "paint" the ear drum. Sadly, this tech hasn't even started trials. See:

https://atlanticpediatricdeviceconsortium.org/perf-fix-nonsurgical-eardrum-repair

Unfortunately that means that in the short term (next few years at least), this is a pretty tricky procedure. Ugh.

 

[FGG]

I asked because getting the disease under control is a nightmare. For people with autoimmune inner ear disease, they basically need high dose steroids all of the time. There's going to be periods where they have to get off steroids for their health. I was mostly trying to better understand how the drug worked. But yeah, I certainly agree that one's strategy shouldn't be to take FX-322 every day.

Otonomy has a long acting (effects last 90 days) intratympanic dexamethasone in phase 3. It's being labelled for Meniere's but I imagine it can be used off label. I imagine you could do something like that, then get a regenerative injection, and then maintain with intratympanic long acting Dex a few times a year if high dose steroids work for you.

 

[Diesel]

I'm also aware of a new tech that is a kind of "gel" substance that is meant to "cover" the ear drum (and the hole in it), to promote proper regrowth, requiring no surgery, as it would be applied via the ear canal as if one was to "paint" the ear drum. Sadly, this tech hasn't even started trials. See:

https://atlanticpediatricdeviceconsortium.org/perf-fix-nonsurgical-eardrum-repair

Unfortunately that means that in the short term (next few years at least), this is a pretty tricky procedure. Ugh.

Breakthroughs in any industry often jumpstart demand for complementary innovations. This may be the case for FX-322. Consider the exponential increase in demand for intratympanic injections and new measurements for hearing loss that FX-322 can actually treat.

It's likely that many of the early patients receiving FX-322 in the clinical setting may assume additional risk from the procedure. However, by the time the "full cochlea" FX-322 2.0 hits the shelves, application and measurements may have improved accordingly.

 

[Zugzug]

Otonomy has a long acting (effects last 90 days) intratympanic dexamethasone in phase 3. It's being labelled for Meniere's but I imagine it can be used off label. I imagine you could do something like that, then get a regenerative injection, and then maintain with intratympanic long acting Dex a few times a year if high dose steroids work for you.

Have you ever considered joining one of the research teams? Lol.

 

[tommyd87]

I'm also aware of a new tech that is a kind of "gel" substance that is meant to "cover" the ear drum (and the hole in it), to promote proper regrowth, requiring no surgery, as it would be applied via the ear canal as if one was to "paint" the ear drum. Sadly, this tech hasn't even started trials. See:

https://atlanticpediatricdeviceconsortium.org/perf-fix-nonsurgical-eardrum-repair

Unfortunately that means that in the short term (next few years at least), this is a pretty tricky procedure. Ugh.

Apparently at this time it seems that they are actually very close to commencing clinical trials as they are on their final stage of research. Considering it takes 10 to 15 years to get something like this to the market it is pretty consistent with this timeframe.

Once they can prove that there is positive benefit and it is safe, then the treatment can be approved to be used in the interim.

I would take a punt and say that this treatment would fall in this category since it is very safe and it is also a treatment which will enhance people's lives. Therefore I can see it getting Fast Tracked and being out there in a year or so.

This is unlike a medicine that needs to go through several trials. There is also the possibility that the treatment trials could get combined as it is quite impossible to not test the effect of this treatment while testing safety.

I hope I could enroll in the clinical trial if they run one.

Breakthroughs in any industry often jumpstart demand for complementary innovations. This may be the case for FX-322. Consider the exponential increase in demand for intratympanic injections and new measurements for hearing loss that FX-322 can actually treat.

It's likely that many of the early patients receiving FX-322 in the clinical setting may assume additional risk from the procedure. However, by the time the "full cochlea" FX-322 2.0 hits the shelves, application and measurements may have improved accordingly.

This is a fairly accurate point. However, I reckon that the risk of the procedure would be pretty low when we compare it to a number of other procedures.

We might need to have several doses of the treatment to get benefit because of the limitations in dosing and hence the dosing reformulation. However, I don't see anyone viewing this as a major concern because it is clear that the focus of everyone involved is providing maximum benefit to people.

 

[FGG]

Have you ever considered joining one of the research teams? Lol.

There are a lot of veterinarians who do biomedical research but they usually have done lab animal residencies (I haven't) or also have a PhD in the subspecialty of the research. I don't have the health to pursue either. Otherwise I would definitely consider it honestly.