Frequency Therapeutics — Hearing Loss Regeneration

[Jurger]

It doesn't though. The lines on an audiogram are to show a pattern. It doesn't indicate every frequency was measured. Each time you press the button, you are indicating when you hear one single frequency.

True, it's an estimate. By testing 8000 Hz you get a rough estimate of 7500 Hz. Or 7660 Hz. It's possible that someone has perfect hearing at 8000 Hz and has severely damaged hearing at 7500 Hz, but it's unlikely.

 

[tommyd87]

I mean that a normal audiogram roughly shows where you are at at every frequency between 250 Hz and 8000 Hz. So yes, including 3000 Hz, 5000 Hz and 7000 Hz.

Not necessarily true because an audiogram tests you at 250 Hz, 500 Hz,1000 Hz, 2000 Hz, 3000 Hz, 4000 Hz, 6000 Hz, 8000 Hz.

 

[FGG]

True, it's an estimate. By testing 8000 Hz you get a rough estimate of 7500 Hz. Or 7660 Hz. It's possible that someone has perfect hearing at 8000 Hz and has severely damaged hearing at 7500 Hz, but it's unlikely.

Correct. Extremely. But if you have more mild hearing loss...

 

[Jurger]

Not necessarily true because an audiogram tests you at 250 Hz, 500 Hz,1000 Hz, 2000 Hz, 3000 Hz, 4000 Hz, 6000 Hz, 8000 Hz.

I'm not sure if this is true. Just because not every frequency is displayed separately on an audiogram, doesn't mean that only the frequencies that are displayed are actually tested. But of course I'm not an audiologist. But I heard a helluva lot more tones in my tests than the 8 you're summing up.

 

[Jurger]

Correct. Extremely. But if you have more mild hearing loss...

We've talked about this before but: ideally you would have diagnostic capabilities to see what the cochlea of a patient looks like. You could then use an audiogram to see if it corresponds with what you saw on the scan.

 

[Paulmanlike]

Are there any companies working with Frequency Therapeutics to better get FX-322 further into the cochlea? It seems one of the hardest things to do, they have the molecules (FX-322) to multiply progenitor cells and turn into hair cells, but the hard part is delivery and getting it to reach all the frequencies.

How can they do this as nothing is out there yet?

 

[Diesel]

You're referring to a picture they have in their corporate presentation. I believe it showed the drug getting to a little under 8000 Hz (about 6500 Hz I think). I think that's just an estimate, extrapolated from their Phase 1/2 results. Frequency Therapeutics hopes multiple injections will result in the drug improving more frequencies. We'll see what happens. If not, they have a problem on their hands. At least as a hearing loss treatment.

If not, they have a drug that restores high frequency hearing loss only; which still has a huge, unserved market.

Good problem to have.

 

[tommyd87]

If they can get 10 dB improvement in multiple frequencies it might be significant for some patients, but 10 dB only in the 8 kHz frequency is really not that great. Now, improvements in ultra high frequencies might result in additional benefit, but it's not entirely clear yet how that works. Audiologists don't test those frequencies, hearing aids don't cover them. What we ultimately need is something that has the ability to improve the entire 250-8000 Hz range.

Three points that I can take away from this post:

1. The phase 1 was a safety trial and used a safety dose. Thus there is a significantly higher chance that the outcomes achieved are actually not reflective of what the true capabilities/performance of FX-322 is. Although we only saw a 10 dB improvement in the phase 1 trial, there are likely to have been further improvements recorded in other areas such as the very high frequency regions, and tinnitus. Thus this is exactly why the testing has been broadened in the current trial to include other things and also it should be noted that the dosing method used was not even the most prudent option. Obviously there is a lot of information which suggests that this treatment approach using PCA will deliver better outcomes when it is dosed multiple times.

2. There will be a reformulation/redosing. I believe this is guaranteed and Frequency Therapeutics will be working hard to ensure that this ends up happening. There has already been broad and also extensive research implemented to look at improving the delivery of medicine in the ear. Essentially I believe that once the dosing has been improved, the performance of FX-322 will be better.

3. I think the fact that Frequency Therapeutics has been able to show that they can deliver full regrowth demonstrates that the issue is not the performance of the medicine, but rather the issue is reformulation/dosing.

 

[tommyd87]

If the first formulation can penetrate below 8000 Hz due to multiple doses, that would have massive implications on the hearing world. If not, treating high frequencies is still a game changer as high and low frequencies would be able to be helped at least in some regard (hearing aids, FX-322, etc.) We know a reformulation will be made to get deeper into the cochlea at some point. The company has expressed their interest in doing so. Right now, they are focused on delivering strong Phase 2a results that warrant Breakthrough Therapy designation from the FDA. If that's granted as I expect it to be, we will be that much closer to reducing the severity of our tinnitus affliction.

This sums up the performance of FX-322 now. If FX-322 does work in the 250-8000 Hz range in the current form then this is a big winner and will provide a bigger benefit from the first version of FX-322 than what would have maybe been expected. Even solely treating to 8000 Hz will have a benefit because not only will it give patients their very high frequency function again, it will also provide them with a buffer in their ear with more functional hair cells.

The reality is that while we know that Frequency Therapeutics might not get FX-322 working throughout the ear, we do know that there definitely will be a redosing/reformulation at some point. Particularly when the evidence indicates that FX-322 has the capabilities to provide full regrowth too.

The opinion I have right now is that Frequency Therapeutics's top concern is to get the medicine approved and be able to release it to patients. Currently Frequency Therapeutics knows that once FX-322 is approved, they are then able to play around with this in terms of dosing and better its outcomes. However without the FDA approval they simply won't have the money or the ability to use FX-322 freely to work on outcomes.

 

[tommyd87]

I'm not sure if this is true. Just because not every frequency is displayed separately on an audiogram, doesn't mean that only the frequencies that are displayed are actually tested. But of course I'm not an audiologist. But I heard a helluva lot more tones in my tests than the 8 you're summing up.

Hearing tests use a standard set here because the frequencies from 250 Hz-6000 Hz are the speech frequencies, then 8000 Hz is done for high frequency testing/the fact that there are actually a few regular sounds that are heard at 8000 Hz.

 

[serendipity1996]

Are there any companies working with Frequency Therapeutics to better get FX-322 further into the cochlea? It seems one of the hardest things to do, they have the molecules (FX-322) to multiply progenitor cells and turn into hair cells, but the hard part is delivery and getting it to reach all the frequencies.

How can they do this as nothing is out there yet?

Isn't Otomagnetics working on this?

 

[tommyd87]

If not, they have a drug that restores high frequency hearing loss only; which still has a huge, unserved market.

Good problem to have.

Although I feel that there will be a redosing at some point where Frequency Therapeutics can get this treatment working throughout the cochlea, I still 100% agree with you that the ability to provide treatment to the very high frequencies will work wonderfully for many individuals.

This could effectively eliminate a large portion of the need for hearing aids and associated treatments, as FX-322 could be used to deal with the very high frequency hearing loss early on if it is detected.

Thus either way we will see great benefit from FX-322.

 

[FGG]

Hearing tests use a standard set here because the frequencies from 250 Hz-6000 Hz are the speech frequencies, then 8000 Hz is done for high frequency testing/the fact that there are actually a few regular sounds that are heard at 8000 Hz.

It's that way in the US too. They usually test 250 Hz, 500 Hz, 1000 Hz, 2000 Hz, 4000 Hz, 6000 Hz and 8000 Hz and sometimes 125 Hz too.

Where do you live again @Jurger?

 

[Diesel]

Are there any companies working with Frequency Therapeutics to better get FX-322 further into the cochlea? It seems one of the hardest things to do, they have the molecules (FX-322) to multiply progenitor cells and turn into hair cells, but the hard part is delivery and getting it to reach all the frequencies.

How can they do this as nothing is out there yet?

Frequency Therapeutics may be trying to improve the delivery method themselves, as some have noted the jobs they are hiring for.

It's highly likely if Frequency Therapeutics is establishing any type of partnership to improve delivery, it won't be public knowledge until after FX-322 is an approved therapy. Reason being, many may opt to wait for the new and improved version, and will choose to bypass the first iteration.

 

[tommyd87]

Frequency Therapeutics may be trying to improve the delivery method themselves, as some have noted the jobs they are hiring for.

It's highly likely if Frequency Therapeutics is establishing any type of partnership to improve delivery, it won't be public knowledge until after FX-322 is an approved therapy. Reason being, many may opt to wait for the new and improved version, and will choose to bypass the first iteration.

If I was going to announce that I had formed a partnership or if I was going to form a partnership then I too would wait until after FDA approval to announce such agreements. At least this way you are not actually bound to do stuff until the agreement actually becomes relevant.

Right now I wouldn't be surprised if Frequency Therapeutics hired an internal employee to deal with the reformulation/redosing aspect of the treatment. Even if Frequency Therapeutics worked with a partner to assist with this, they would still need someone internally who can advise and liaise between the company and the external provider. This has happened with the individual that they have hired to take on the pricing issue. It is incredibly likely that they will need to liaise with groups like the ENTs who will be administering FX-322.

 

[kiki]

You're referring to a picture they have in their corporate presentation. I believe it showed the drug getting to a little under 8000 Hz (about 6500 Hz I think). I think that's just an estimate, extrapolated from their Phase 1/2 results. Frequency Therapeutics hopes multiple injections will result in the drug improving more frequencies. We'll see what happens. If not, they have a problem on their hands. At least as a hearing loss treatment.

It was 3500 Hz in the October 2019 slide. The damage caused by noise occurs especially at 4000 Hz.

I think Frequency Therapeutics has set its first goal at 4000 Hz.

 

[tommyd87]

It was 3500 Hz in the October 2019 slide. The damage caused by noise occurs especially at 4000 Hz.

I think Frequency Therapeutics has set its first goal at 4000 Hz.

If Frequency Therapeutics could get FX-322 to these low frequencies using the current dosing method then this would be a major winner. We would not only see the very high frequencies get treated but we would also see a number of the key speech frequencies get treated. From what I understand this frequency range will probably assist the overwhelming majority of people.

 

[Lucifer]

It's a shame we have to wait until May next year to find out if multiple doses benefit more than a single dose.

I do hope that half of the patients who got 4 doses of FX-322 benefited more than those with a single dose.

 

[tommyd87]

It's a shame we have to wait until May next year to find out if multiple doses benefit more than a single dose.

I do hope that half of the patients who got 4 doses of FX-322 benefited more than those with a single dose.

It is annoying, although I am fairly optimistic that there would be bigger benefits from more doses. I believe that the evidence stating that there needs to be a dose to kickstart the PCA process is sound since there is a fair bit of research indicating this.

The other point worth mentioning is that there seems to be evidence that the hair cells need to be functional or activated in order for FX-322 to bypass these. Thus with the possibility of people having high levels of busted hair cells in the very high frequencies, I think that FX-322 might initially need to do a lot of work in those areas in some. Subsequently this might mean it takes a bit of time to get the regrowth in the lower frequencies.

Furthermore from what we can work out based on the information provided to us by Frequency Therapeutics, we can assume that there should be better improvements in the individuals who got multiple doses. If this does indeed happen, Frequency Therapeutics might look at seeing if they can attain more benefit with even more doses outside the clinical trial.

For example Frequency Therapeutics might leave this to the doctors to work out by encouraging and also allowing them to inject 5 or 6 or even more doses as needed to see if they can come up with a bigger response. This way Frequency Therapeutics can simply finish the trials ASAP, get FX-322 out and allow doctors to start treating patients. Frequency Therapeutics might also look at this in more depth in the form a side study after they commence the phase 2b trial. Frequency Therapeutics could consider using some of these positively treated multi dose patients to get more injections in the side study and actually see whether they get further benefit from getting more FX-322 when their trial time ends. Essentially this would allow the benefit of even further multi dosing to be established before release and actually give Frequency Therapeutics and also those who will treat patients further information about multi dosing outcomes and also benefits.

 

[kiki]

If Frequency Therapeutics could get FX-322 to these low frequencies using the current dosing method then this would be a major winner. We would not only see the very high frequencies get treated but we would also see a number of the key speech frequencies get treated. From what I understand this frequency range will probably assist the overwhelming majority of people.

Isn't 4000 Hz a high frequency?

https://www.britannica.com/science/ear/Transmission-of-sound-within-the-inner-ear

https://www.researchgate.net/figure...velopment-across-the-frequency_fig1_270054612

 

[tommyd87]

Isn't 4000 Hz a high frequency?

https://www.britannica.com/science/ear/Transmission-of-sound-within-the-inner-ear

https://www.researchgate.net/figure...velopment-across-the-frequency_fig1_270054612

Yes it is. I think the question has been to what extent can FX-322 treat within the high frequencies. From what I understand and based off of Australian standards, high frequencies are down to 2 kHz. Therefore this would mean that FX-322 could treat the majority of high frequencies if it can treat to 3500 Hz, however it means it wouldn't treat all of them.

 

[kiki]

It is annoying, although I am fairly optimistic that there would be bigger benefits from more doses. I believe that the evidence stating that there needs to be a dose to kickstart the PCA process is sound since there is a fair bit of research indicating this.

The other point worth mentioning is that there seems to be evidence that the hair cells need to be functional or activated in order for FX-322 to bypass these. Thus with the possibility of people having high levels of busted hair cells in the very high frequencies, I think that FX-322 might initially need to do a lot of work in those areas in some. Subsequently this might mean it takes a bit of time to get the regrowth in the lower frequencies.

Furthermore from what we can work out based on the information provided to us by Frequency Therapeutics, we can assume that there should be better improvements in the individuals who got multiple doses. If this does indeed happen, Frequency Therapeutics might look at seeing if they can attain more benefit with even more doses outside the clinical trial.

For example Frequency Therapeutics might leave this to the doctors to work out by encouraging and also allowing them to inject 5 or 6 or even more doses as needed to see if they can come up with a bigger response. This way Frequency Therapeutics can simply finish the trials ASAP, get FX-322 out and allow doctors to start treating patients. Frequency Therapeutics might also look at this in more depth in the form a side study after they commence the phase 2b trial. Frequency Therapeutics could consider using some of these positively treated multi dose patients to get more injections in the side study and actually see whether they get further benefit from getting more FX-322 when their trial time ends. Essentially this would allow the benefit of even further multi dosing to be established before release and actually give Frequency Therapeutics and also those who will treat patients further information about multi dosing outcomes and also benefits.

Is it something like the following?

Two molecules reach low frequencies.

However, there is not enough capacity.

With multiple doses, the molecules accumulate and the needed effect occurs.

Will the molecule survive for several weeks?

 

[tommyd87]

Is it something like the following?

Two molecules reach low frequencies.

However, there is not enough capacity.

With multiple doses, the molecules accumulate and the needed effect occurs.

Will the molecule survive for several weeks?

If it is like what I have seen, the issue hasn't got anything to do with FX-322 but rather the problem is with delivery due to the make up of the ear. The theory that Frequency Therapeutics has given is that they need to make FX-322 move further into the ear before it releases in order to get to the low frequency section. Thus they are looking at methods like cochlear pumping which actually had good results recorded in the research trials done by a group who works with medicine delivery/dosing.

The other obvious one is to get FX-322 to release later so this means it can still be injected but the gel will release a lot later than what it does now. FX-322 has no issues in working with any section of the ear because the work pre-clinical trials demonstrated this. Thus this is why we will likely see either an external company or Frequency Therapeutics engage in drug redosing after they know that FX-322 will pass the the clinical trial requirements set by FDA.

 

[kiki]

One more, which direction is the lymph flow in the cochlea? I only know that it's very slow.

 

[tommyd87]

One more, which direction is the lymph flow in the cochlea? I only know that it's very slow.

Now that's something that I cannot answer. I'll ask @FGG if she knows that.

 

[kiki]

If it is like what I have seen, the issue hasn't got anything to do with FX-322 but rather the problem is with delivery due to the make up of the ear. The theory that Frequency Therapeutics has given is that they need to make FX-322 move further into the ear before it releases in order to get to the low frequency section. Thus they are looking at methods like cochlear pumping which actually had good results recorded in the research trials done by a group who works with medicine delivery/dosing.

The other obvious one is to get FX-322 to release later so this means it can still be injected but the gel will release a lot later than what it does now. FX-322 has no issues in working with any section of the ear because the work pre-clinical trials demonstrated this. Thus this is why we will likely see either an external company or Frequency Therapeutics engage in drug redosing after they know that FX-322 will pass the the clinical trial requirements set by FDA.

Thank you for your kind and polite answer.

I would like Frequency Therapeutics to publish information on drug delivery by pumping the cochlea on its homepage.

 

[FGG]

Now that's something that I cannot answer. I'll ask @FGG if she knows that.

I believe endolymph flows towards the apex, perilymph flows towards the base.

 

[tommyd87]

Thank you for your kind and polite answer.

I would like Frequency Therapeutics to publish information on drug delivery by pumping the cochlea on its homepage.

It is incredibly unlikely that Frequency Therapeutics would put something about drug delivery on their website at this time though for two reasons:

1. At this time the drug delivery method is still going to be intratympanic injections until the time that the trials finish. Frequency Therapeutics will do this because it means that the trial process will be able to be completed as quickly as possible because it will likely deliver the outcomes that the trials need to deliver to get FDA approval for FX-322.

2. The delivery/redosing information is not yet finalised probably for two reasons.

Firstly, there are a number of methods that are actually being looked at for redosing at present. For example cochlear pumping is just one method that Frequency Therapeutics can maybe utilise to improve the dosing. There are also a few other options which can be used like using a delivery method that releases FX-322 slowly but is still administered intratympanically, which will end up FX-322 working deeper in the ear.

Secondly, there is a real possibility of there already being a deal with a drug delivery/dosing company or person, however Frequency Therapeutics probably isn't likely to announce this until after FX-322 can be released to the market. Also Frequency Therapeutics still don't have the final details of how FX-322 performs currently with the use of the intratympanic injections techniques or more than one injection until the trials are finished.

Thus I very much think that there will certainly be redosing work being done quite rapidly, however this might not happen before the current trial is finished. That's when Frequency Therapeutics knows what action and dosing to take next with FX-322. Frequency Therapeutics knows this treatment works well, the issue is that they need to make FX-322 reach all areas within the ear.

 

[Billy_Shears]

It is annoying, although I am fairly optimistic that there would be bigger benefits from more doses. I believe that the evidence stating that there needs to be a dose to kickstart the PCA process is sound since there is a fair bit of research indicating this.

The other point worth mentioning is that there seems to be evidence that the hair cells need to be functional or activated in order for FX-322 to bypass these. Thus with the possibility of people having high levels of busted hair cells in the very high frequencies, I think that FX-322 might initially need to do a lot of work in those areas in some. Subsequently this might mean it takes a bit of time to get the regrowth in the lower frequencies.

Furthermore from what we can work out based on the information provided to us by Frequency Therapeutics, we can assume that there should be better improvements in the individuals who got multiple doses. If this does indeed happen, Frequency Therapeutics might look at seeing if they can attain more benefit with even more doses outside the clinical trial.

For example Frequency Therapeutics might leave this to the doctors to work out by encouraging and also allowing them to inject 5 or 6 or even more doses as needed to see if they can come up with a bigger response. This way Frequency Therapeutics can simply finish the trials ASAP, get FX-322 out and allow doctors to start treating patients. Frequency Therapeutics might also look at this in more depth in the form a side study after they commence the phase 2b trial. Frequency Therapeutics could consider using some of these positively treated multi dose patients to get more injections in the side study and actually see whether they get further benefit from getting more FX-322 when their trial time ends. Essentially this would allow the benefit of even further multi dosing to be established before release and actually give Frequency Therapeutics and also those who will treat patients further information about multi dosing outcomes and also benefits.

Concerning the systemic drug delivery that was utilized in Phase 2a, are you inferring that the first dose of FX-322 administered will cover the frequencies that are expected (say, from 20 kHz to 8 kHz) and a second dose will bypass these frequencies (if PCA has occurred) and commence activating cellular frequencies advancing toward 6 kHz to 2 kHz and so forth- eventually reaching 250 Hz with each additional dose?

Also, aside from an FDA-approved trial in the United States, it is unlikely ENT physicians will break protocol and inject more doses than the four that have been outlined beforehand - perhaps that is for another day. Frequency Therapeutics desires to expedite this wonder drug to market as soon as possible but they are also conducting their research in a rather keen and conservative manner. Nonetheless, the testing you hypothesize will come about in due time in my opinion.

 

[kiki]

I believe endolymph flows towards the apex, perilymph flows towards the base.

Thank you very much. I always think your knowledge is wonderful.

If the effect really depends on the number of injections, FX-322 is a promising drug.

The invention of being able to regenerate hair cells and connecting synapses is a huge step.

That is, 0 → 1.

Next, improvement of delivery, etc., 1 → 2, 3, ... 10...

I think the really difficult thing is 0 → 1.

I want to believe that the evolution of technology, for development from 1, be surprisingly straightforward.

I am grateful for everyone's courage writing in this thread.