Frequency Therapeutics — Hearing Loss Regeneration

[tommyd87]

From what we know so far, three factors play a role in how effective FX-322 will be treating the individual's condition:

- Depth of damage in the cochlea that FX-322 can treat. Right now, it seems to be anything above 8 kHz on the audiogram. This may change with multiple doses, but it still probably won't reach the lowest frequencies from the Phase 2A results.

- Extent of damage in the cochlea. So far, we know that FX-322 can treat moderately severe cases, but it is unknown whether areas of severe or profound losses can be regenerated.

- Type of damage. Hair cell loss or synaptopathy. FX-322 will treat those damaged hair cells, but not those that are healthy but with broken synapses.

Expectations should be that most probably have some degree of wear/damage at all three bullets above. One or all of these conditions may be a factor contributing to their tinnitus.

In terms of outcomes, I don't think anyone should think that FX-322 will alone bring them back to complete silence in a quiet room wearing earplugs. It can't go deep enough, and treat all conditions of wear/tear to be a 'cure' back to a day-zero cochlea.

However, it's likely that FX-322 will give patients much needed relief, even if partial.

Assuming most patients have a combination of the above bullet points, let's say distributed equally between all 3. FX-322 should help restore their frequencies at the higher ranges where hair cells are missing, they should recover some level of hearing bringing them up at least 10 dB. It cannot treat synaptopathy where the hair cells are 'healthy', but likely repair adjacent hair cells that have acquired damage.

So, in this case, and for many of our cases, maybe it won't eliminate the tinnitus and fully restore hearing, but it'll be the first treatment to begin the reversal process.

As it relates to tinnitus, I would imagine many on here would be thrilled if FX-322 perhaps did even one of the following:

- Reduced 1 or more tones / static / hissing / clicking / popping / humming, but left some remaining
- Reduced the overall loudness of all the tinnitus by 25%, 30%, 50%
- Made the tinnitus less annoying on a daily basis, i.e. made it softer
- Reduced reactivity of their tinnitus

I think that there is one thing you missed out and that is that the issue with FX-322 is not that it can't go deep enough, but rather that the current delivery method and/or formula for FX-322 won't go deep enough. Essentially we have already seen that FX-322 can provide full regrowth in the lab work.

What we will see is FX-322 most probably get redosed and/or reformulated to work with wider hearing ranges. Really the issue isn't FX-322 in any way but rather the dosing.

 

[AfroSnowman]

- Type of damage. Hair cell loss or synaptopathy

I'm sure this has been covered more than once but how do we self-diagnose or what test do we need to determine if our hearing loss/tinnitus is due to hair cell loss or synaptopathy?

 

[tommyd87]

I'm sure this has been covered more than once but how do we self-diagnose or what test do we need to determine if our hearing loss/tinnitus is due to hair cell loss or synaptopathy?

Determining the cause can be difficult to do (especially with some form of accuracy) due to testing not being robust and there is no scan or anything right now to show what the issue(s) happen to be.

At present, we know that an audiogram can indicate issues with the hair cells and a speech in noise test can indicate any issues with the synapses. However, even with the current diagnostic methods, there is still a lot of uncertainty about what it actually is. It is therefore the reason why you may need to use both a synapse and a hair cell treatment and trial treat.

 

[FGG]

I think that there is one thing you missed out and that is that the issue with FX-322 is not that it can't go deep enough, but rather that the current delivery method and/or formula for FX-322 won't go deep enough. Essentially we have already seen that FX-322 can provide full regrowth in the lab work.

What we will see is FX-322 most probably get redosed and/or reformulated to work with wider hearing ranges. Really the issue isn't FX-322 in any way but rather the dosing.

There are studies that show repeat injections increase intratympanic drug penetrance (not just with FX-322 but with Dexamethasone too).

Let's see what the results are for Phase 2. It may be a lot better than we think.

 

[FGG]

I'm sure this has been covered more than once but how do we self-diagnose or what test do we need to determine if our hearing loss/tinnitus is due to hair cell loss or synaptopathy?

There isn't a great method. Unless you have obvious audiogram changes, most people are probably going to have to "trial treat."

 

[serendipity1996]

I couldn't imagine being stuck waiting for care if it's urgent and could actually help. Thousands of people from Canada come to Detroit all the time for care. I have talked to people waiting over a year to see a neurologist.

Our medical system in the U.S is fucked up and expensive but at least you can see a doctor if you need to.

You will get seen fairly quickly if it's urgent, at least in Scotland...

 

[Gb3]

Unless you have obvious audiogram changes, most people are probably going to have to "trial treat."

What do you mean by obvious audiogram changes?

 

[Diesel]

Sorry to focus on this point, as the rest of the post is great, but wasn't the delivery method already confirmed to sufficiently travel the cochlea? Or is this still an ongoing problem?

Were you talking specifically about a single initial dose? I thought the general idea was that multiple doses would indeed allow the depths of the cochlea to be reached. Perhaps that number may even be x4 as that's the maximum doses being tested in the current trial.

The single dose from the Phase 1/2 was observed to diffuse deep enough in the cochlea perilymph to show hearing improvements at 8 kHz (and presumably above).

They are assuming that multiple doses will cause FX-322 to diffuse deeper into the cochlea in "waves." It's also believed that additional doses of FX-322 will bypass areas already treated and be "consumed" by progenitors adjacent to damaged hair cells deeper in the cochlea. If this assumption is correct, then multiple doses should show a stratified improvement at lower frequency bands. Ie: 2x doses showed improvements down to 10 dB at 6 kHz; 4x doses down to 4 kHz.

In vitro, FX-322 has been observed restoring hair cells at all frequencies in donated human cochlea.

Short answer: the delivery gel is probably a hurdle, or maybe some will need more than 4x doses of accumulated FX-322 in their cochleas to get to lower frequencies.

 

[FGG]

What do you mean by obvious audiogram changes?

Meaning outside of normal limits denotes OHC loss at least (but normal doesn't rule it out).

 

[serendipity1996]

I think that there could be treatment offered for ear related medicines through government funded medical systems in countries like the UK, Sweden and Australia actually a lot sooner than that, provided that the medicines get demonstrated to provide better benefits than current options such as hearing aids provide. Presently most governments which offer health care options cover cochlear implants or hearing aids and as a result are likely to cover substitute treatments for these.

Something I actually thought to add to this. The recent Emerging Hearing Medicines Landscape webinars were UK-based and organised and were actually discussing how the standard of healthcare is going to change in the near future (in the UK presumably) with the introduction of these medicines - FX-322 was in fact discussed as being particularly promising. I can't remember if any of the speakers were NHS-affiliated although I think there may have been some audiologists. Regardless, these developments are being closely watched which is encouraging. I actually just found this document of Q&As where this question is answered.

Many of the people that I support who have hearing loss cannot afford private health care, do you believe that the things discussed would be available on the NHS at some point?

"The NHS has an excellent system for evaluating treatments by cost and efficacy, called the National Institute for Clinical Excellence (NICE). For example, NICE has just published a review of treatments for tinnitus. when new treatments for hearing loss are available, I would expect them to be reviewed by NICE, and if clinical efficacy and cost-effectiveness can be demonstrated, for the to be available on the NHS."

https://s3.eu-west-1.amazonaws.com/...4085308/HMDS-Webinar-Unanswered-Questions.pdf​

One thing we do know is that untreated hearing loss can have a massive economic burden - current treatment options are pretty poor and that many people fitted with hearing aids don't wear them. We also know that FX-322 shouldn't be too difficult to manufacture. It's also a pretty straightforward clinical procedure compared to something like gene therapy. So I think from a logical standpoint there would be many good reasons for government healthcare to embrace it.

 

[Drachen]

Short answer: the delivery gel is probably a hurdle, or maybe some will need more than 4x doses of accumulated FX-322 in their cochleas to get to lower frequencies.

So theoretical improvements to FX-322 are likely going to focus on delivery, such as the gel or dosage size, rather than the chemical itself?

This is good, right? I would assume logistics is less of an issue than the formula itself.

As I am ignorant about drug protocol, I do have another question: when FX-322 ends up on the market, is it locked to a certain number of doses and capacity of each dose? I am not sure if they have to go through the trial process yet again if they want to tinker with the numbers. Otherwise, it seems like the ENT should just be able to give you more FX-322 in the shot, which should invalidate any concerns of delivery.

 

[Lucifer]

Something I actually thought to add to this. The recent Emerging Hearing Medicines Landscape webinars were UK-based and organised and were actually discussing how the standard of healthcare is going to change in the near future (in the UK presumably) with the introduction of these medicines - FX-322 was in fact discussed as being particularly promising. I can't remember if any of the speakers were NHS-affiliated although I think there may have been some audiologists. Regardless, these developments are being closely watched which is encouraging. I actually just found this document of Q&As where this question is answered.

Many of the people that I support who have hearing loss cannot afford private health care, do you believe that the things discussed would be available on the NHS at some point?

"The NHS has an excellent system for evaluating treatments by cost and efficacy, called the National Institute for Clinical Excellence (NICE). For example, NICE has just published a review of treatments for tinnitus. when new treatments for hearing loss are available, I would expect them to be reviewed by NICE, and if clinical efficacy and cost-effectiveness can be demonstrated, for the to be available on the NHS."

https://s3.eu-west-1.amazonaws.com/...4085308/HMDS-Webinar-Unanswered-Questions.pdf​

One thing we do know is that untreated hearing loss can have a massive economic burden - current treatment options are pretty poor and that many people fitted with hearing aids don't wear them. We also know that FX-322 shouldn't be too difficult to manufacture. It's also a pretty straightforward clinical procedure compared to something like gene therapy. So I think from a logical standpoint there would be many good reasons for government healthcare to embrace it.

This is great to hear, hopefully FX-322 gets fully covered under insurance. It is such a shame that most insurance companies don't cover the full cost of hearing aids.

 

[Drachen]

One thing we do know is that untreated hearing loss can have a massive economic burden - current treatment options are pretty poor and that many people fitted with hearing aids don't wear them. We also know that FX-322 shouldn't be too difficult to manufacture. It's also a pretty straightforward clinical procedure compared to something like gene therapy. So I think from a logical standpoint there would be many good reasons for government healthcare to embrace it.

And that is all in addition to the immense quality-of-life improvements that comes with improving hearing loss and reducing or silencing tinnitus.

There would legitimately be zero reason for governments worldwide to not jump on this given the opportunity. We now have the science to restore parts our of bodies. Further endorsements and perhaps even cash injections from them could even make the job of Frequency Therapeutics, Otonomy, and others in the field of regenerative medicine that much easier.

I am honestly surprised the U.S. Department of Defense is not investing more money into this given how both hearing loss and tinnitus are major complaints for our veterans. I'm wondering if we could perhaps expect more support from them following successful and favorable trial results this year? I'm sure the more financial support they get, the better that will be for patients in the end.

 

[serendipity1996]

And that is all in addition to the immense quality-of-life improvements that comes with improving hearing loss and reducing or silencing tinnitus.

There would legitimately be zero reason for governments worldwide to not jump on this given the opportunity. We now have the science to restore parts our of bodies. Further endorsements and perhaps even cash injections from them could even make the job of Frequency Therapeutics, Otonomy, and others in the field of regenerative medicine that much easier.

I am honestly surprised the U.S. Department of Defense is not investing more money into this given how both hearing loss and tinnitus are major complaints for our veterans. I'm wondering if we could perhaps expect more support from them following successful and favorable trial results this year? I'm sure the more financial support they get, the better that will be for patients in the end.

Yeah - I mean, if FX-322 succeeds it's going to be huge. This is not some obscure arduous treatment that costs like hundreds of thousands a head. I feel like there's every reason for governments around the world to get on board with this.

 

[Diesel]

So theoretical improvements to FX-322 are likely going to focus on delivery, such as the gel or dosage size, rather than the chemical itself?

This is good, right? I would assume logistics is less of an issue than the formula itself.

As I am ignorant about drug protocol, I do have another question: when FX-322 ends up on the market, is it locked to a certain number of doses and capacity of each dose? I am not sure if they have to go through the trial process yet again if they want to tinker with the numbers. Otherwise, it seems like the ENT should just be able to give you more FX-322 in the shot, which should invalidate any concerns of delivery.

This is very good news for FX-322. The delivery gel is a limitation right now.

Ideally the gel should be 'extended release' that diffuses enough concentrated FX-322 to reach the entire cochlea. But, it may not exist / may need re-formulated. If FX-322 continues to show improvement with multiple doses, there may be a version "2.0" that utilizes an extended release gel. So, fewer injections are needed.

In one of Frequency Therapeutics' most recent Patents for FX-322, the dosage amounts are described in a number of scenarios that are outside of the scope of 4 doses spread across 4 weeks like the Phase 2A. So I am speculating that they are planning on making some type of matrix/dosage plan for ENTs to assess the hearing function and determine the proper dosage schedule, and that needs to be a patented component along with the drug itself.

I think it's probable that if 4x injections shows a significant stepped improvement per dose cohort, that they'll investigate 6x, 8x, etc.

If FX-322 continues to show a favorable safety profile through the Phase 3, I don't see why they won't recommend to ENTs that they just keeping giving the drug until improvements are no longer detected on the standard clinical assessments. That should make the stockholders happy...

 

[Diesel]

And that is all in addition to the immense quality-of-life improvements that comes with improving hearing loss and reducing or silencing tinnitus.

There would legitimately be zero reason for governments worldwide to not jump on this given the opportunity. We now have the science to restore parts our of bodies. Further endorsements and perhaps even cash injections from them could even make the job of Frequency Therapeutics, Otonomy, and others in the field of regenerative medicine that much easier.

I am honestly surprised the U.S. Department of Defense is not investing more money into this given how both hearing loss and tinnitus are major complaints for our veterans. I'm wondering if we could perhaps expect more support from them following successful and favorable trial results this year? I'm sure the more financial support they get, the better that will be for patients in the end.

The US Department of Defense has already granted Frequency Therapeutics money for the development of FX-322 in 2018. Also, they collaborated with the US Army to develop the PCA approach early on, probably also in 2018.

There will be worldwide interest in buying FX-322 for governments and militaries.

 

[Lucifer]

The US Department of Defense has already granted Frequency Therapeutics money for the development of FX-322 in 2018. Also, they collaborated with the US Army to develop the PCA approach early on, probably also in 2018.

There will be worldwide interest in buying FX-322 for governments and militaries.

Do you have the specific article on that? I didn't even know US Department of Defence has given Frequency Therapeutics money.

 

[Diesel]

Do you have the specific article on that? I didn't even know US Department of Defence has given Frequency Therapeutics money.

U.S. Department of Defense Awards $2M Grant to Frequency Therapeutics

 

[twa]

Do you have the specific article on that? I didn't even know US Department of Defence has given Frequency Therapeutics money.

Yes, to help vets with tinnitus. In comparison to the overall budget, it seems small considering the number of vets who acquire tinnitus during military service.

 

[Drachen]

U.S. Department of Defense Awards $2M Grant to Frequency Therapeutics

Ah, yeah. I remember seeing this before. Thank you for reminding me of it.

I suppose more specifically I should have said that I would like to see them invest a bit more into the cause. $2 million is great money, for sure, but considering how much of an issue this is for soldiers, I see an even greater potential for them to help out. I guess I would expect this to come in the form of deals once it is accepted by the FDA.

I don't know how much money Frequency Therapeutics actually needs, but I can assume that early cash infusions will help make the process of producing and selling the drug much more appealing to both them, the shareholders, and the consumers. If you have the more of the money now, there's less need to try and make it back after it goes to market, yeah?

I also wonder about the Department of Veterans Affairs. Since they are receiving a budget of $243 billion, I can't imagine they'd want to keep handing out hearing aids like candy when they could instead offer a much better solution with FX-322. Based off what I've read here, it should be financially beneficial to the department to pursue this route as well.

 

[Jrblovsky]

And that is all in addition to the immense quality-of-life improvements that comes with improving hearing loss and reducing or silencing tinnitus.

There would legitimately be zero reason for governments worldwide to not jump on this given the opportunity. We now have the science to restore parts our of bodies. Further endorsements and perhaps even cash injections from them could even make the job of Frequency Therapeutics, Otonomy, and others in the field of regenerative medicine that much easier.

I am honestly surprised the U.S. Department of Defense is not investing more money into this given how both hearing loss and tinnitus are major complaints for our veterans. I'm wondering if we could perhaps expect more support from them following successful and favorable trial results this year? I'm sure the more financial support they get, the better that will be for patients in the end.

It's because the Department of Defense doesn't care. If you serve you country and have hearing loss you should not have to give up your quality of life. The current treatments are laughable. Absolutely worthless. The doctors say vets kill themselves due to PTSD and depression. Maybe if they removed their heads from their asses they see tinnitus is tied to a lot of other conditions and is serious.

 

[Lucifer]

U.S. Department of Defense Awards $2M Grant to Frequency Therapeutics

Since that happened in 2018, do you reckon the US Department of Defense will give Frequency Therapeutics more money?

 

[Diesel]

Since that happened in 2018, do you reckon the US Department of Defense will give Frequency Therapeutics more money?

When FX-322 is approved by the FDA, yes I do, in the form of a purchase order.

 

[FGG]

Since that happened in 2018, do you reckon the US Department of Defense will give Frequency Therapeutics more money?

Their trials are fully funded by the way. More money won't speed anything up at this point.

 

[xyz]

Their trials are fully funded by the way. More money won't speed anything up at this point.

Maybe with additional money they could do a pure tinnitus & hyperacusis trial and inject FX-322 in both ears, just for fun.

 

[HootOwl]

With the recent discussion surrounding the blind spots of audiograms and other current cochlear diagnostics, I thought I would contribute this little anecdotal piece of info.

Some may remember that I've posted my extended (up to 20 kHz) audiogram in the past. On this audiogram I have a flat line running from 9 kHz to 12.5 kHz. Out of the 4 tested frequencies, each came back at 0 dB.

I've written in the past about sweep testing at my lower tinnitus frequencies and finding mild-moderate notches; however this was along intervals with designated mild loss (5-15 dB). I thought let's do the same thing, but this time do it at this high frequency interval where the data markers literally read as "you have no hearing loss. At all."

And, well, turns out I actually have several (probably 2-3) substantial notches from 9 kHz-12.5 kHz as well.

The kind of notch substantial enough where my hearing would dip out in one ear or the other depending on its place along that interval. I'm a pretty good tone matcher, and I believe the notch at 12.2 kHz might actually be one of my static tones.

Ultimately the frequencies tested on an 8 kHz audiogram are arbitrary. They're still useful, since a 1 kHz-3 kHz interval between testing points will usually yield an adequate assessment of widespread OHC loss (and by extension support cell loss) - but it's very rough around the edges for anything else. Hell, you could replace the tested frequencies with other random, but adjacent frequencies, and get the same snapshot.

Ex. 500 Hz with 646 Hz, 1 kHz with 1,094 Hz, etc. etc.

This is my very long winded way of adding my n=1 to the notion of interval notches, and that theoretically you could have a 0 dB flat line across your entire audiogram, and still easily have structural damage all along your cochlea in the form of OHC loss/IHC loss, synaptic loss, or even inflammation (which will later cause the deterioration of the aforementioned structures).

 

[FGG]

Maybe with additional money they could do a pure tinnitus & hyperacusis trial and inject FX-322 in both ears, just for fun.

I suppose they could do a proof of concept study for bilateral injections and tinnitus (and/or hyperacusis) but they haven't expressed interest in that.

They already have tinnitus as a measure in the current trial.

People will learn very quickly its effects for those when the drug is released.

 

[FGG]

With the recent discussion surrounding the blind spots of audiograms and other current cochlear diagnostics, I thought I would contribute this little anecdotal piece of info.

Some may remember that I've posted my extended (up to 20 kHz) audiogram in the past. On this audiogram I have a flat line running from 9 kHz to 12.5 kHz. Out of the 4 tested frequencies, each came back at 0 dB.

I've written in the past about sweep testing at my lower tinnitus frequencies and finding mild-moderate notches; however this was along intervals with designated mild loss (5-15 dB). I thought let's do the same thing, but this time do it at this high frequency interval where the data markers literally read as "you have no hearing loss. At all."

And, well, turns out I actually have several (probably 2-3) substantial notches from 9 kHz-12.5 kHz as well.

The kind of notch substantial enough where my hearing would dip out in one ear or the other depending on its place along that interval. I'm a pretty good tone matcher, and I believe the notch at 12.2 kHz might actually be one of my static tones.

Ultimately the frequencies tested on an 8 kHz audiogram are arbitrary. They're still useful, since a 1 kHz-3 kHz interval between testing points will usually yield an adequate assessment of widespread OHC loss (and by extension support cell loss) - but it's very rough around the edges for anything else. Hell, you could replace the tested frequencies with other random, but adjacent frequencies, and get the same snapshot.

Ex. 500 Hz with 646 Hz, 1 kHz with 1,094 Hz, etc. etc.

This is my very long winded way of adding my n=1 to the notion of interval notches, and that theoretically you could have a 0 dB flat line across your entire audiogram, and still easily have structural damage all along your cochlea in the form of OHC loss/IHC loss, synaptic loss, or even inflammation (which will later cause the deterioration of the aforementioned structures).

I agree with all of this except even widespread hearing loss doesn't mean any support cells are lost, unless it's profound hearing loss.

 

[UHPTS]

As for better delivery of FX-322 into the cochlea a patient could:

- be rotated in various directions
- listen to sounds
- have ultrasound/infrasound waves applied to cochlea
- combination of the above

A cochlea mock-up could be created to research what kind of rotation/sounds would move the FX-322 molecules in cochlear liquid the best.

 

[Trevor_phillips]

Will FX-322 be available first in the US and then later on in Europe through Astellas?

Or will it be available at the same time in the US and EU?