Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Remember there was an article that stated that it will take a decade and the reason why they said that is because they didn't want to be sued.

If David said it will take a few years it could still be released quicker because he might not want to be sued.

There wasn't an article, just a discussion that publicly traded biotech companies in general have to make as conservative statements as possible to not be sued by investors later if there is a delay for any unforeseen reason.

The CEO said a few years is possible *depending on the FDA* in the latest interview.

 

[Lucifer]

There's really not a whole lot they can report at this time. They can't reveal any early outcomes from the Phase 2A trial, other than that they completed enrollment.

Hopefully they mention about completing enrollment soon.

Im praying everyday that it gets breakthrough therapy status and they can release the drug soon.

 

[Danad]

Regarding FX-322 and its uniqueness among the vast majority of drugs which are typically injected into tissue, sometimes intravenously, or taken orally.

Since they are not assessing systemic levels of the drug in phase 2a, their concern for possible adverse events seems limited to local abnormalities of the ear canal and patient reports. None are mentioned anywhere so far. Once safety and efficacy is proven, as should result from phase 2a, and there are no competing available treatments, one would expect a rather lean NDA with a timely FDA approval. The time frame from Karp and Langers breakthrough study has been a mere 3 years (Feb 2017)! They have moved incredibly fast on this breakthrough and I don't see any slowdown coming from Frequency Therapeutics.

I'm predicting approval mid 2021 and availability within a year afterward.

Some thoughts I have regarding phase 2a and its effects on tinnitus subjects. For those with bilateral hearing loss and bilateral tinnitus, an improvement in a single cochlea (injecting 1 ear only in subjects) may not be effective since my tinnitus (bilateral) can go from center to full left to full right depending on what my auditory pathway is up to at the moment. Hopefully they'll breakout results for unilateral tinnitus subjects (assuming they inject the affected side) yet, we have to remember this study is primarily concerned with hearing restoration. If not, the results for tinnitus benefit may be understandably mixed and we therefore should not lose any hope for FX-322.

 

[Lucifer]

Regarding FX-322 and its uniqueness among the vast majority of drugs which are typically injected into tissue, sometimes intravenously, or taken orally.

Since they are not assessing systemic levels of the drug in phase 2a, their concern for possible adverse events seems limited to local abnormalities of the ear canal and patient reports. None are mentioned anywhere so far. Once safety and efficacy is proven, as should result from phase 2a, and there are no competing available treatments, one would expect a rather lean NDA with a timely FDA approval. The time frame from Karp and Langers breakthrough study has been a mere 3 years (Feb 2017)! They have moved incredibly fast on this breakthrough and I don't see any slowdown coming from Frequency Therapeutics.

I'm predicting approval mid 2021 and availability within a year afterward.

Some thoughts I have regarding phase 2a and its effects on tinnitus subjects. For those with bilateral hearing loss and bilateral tinnitus, an improvement in a single cochlea (injecting 1 ear only in subjects) may not be effective since my tinnitus (bilateral) can go from center to full left to full right depending on what my auditory pathway is up to at the moment. Hopefully they'll breakout results for unilateral tinnitus subjects (assuming they inject the affected side) yet, we have to remember this study is primarily concerned with hearing restoration. If not, the results for tinnitus benefit may be understandably mixed and we therefore should not lose any hope for FX-322.

View attachment 36229

I think they are doing everything possible to get FX-322 FDA approved as fast as they can.

I remember reading on the FDA website that approval for breakthrough therapy status can take up to 60 days but if they consider FX-322 to be a life or death situation I imagine sooner. As soon as Phase 2a results come out they will apply straight away.

 

[FGG]

Regarding FX-322 and its uniqueness among the vast majority of drugs which are typically injected into tissue, sometimes intravenously, or taken orally.

Since they are not assessing systemic levels of the drug in phase 2a, their concern for possible adverse events seems limited to local abnormalities of the ear canal and patient reports. None are mentioned anywhere so far. Once safety and efficacy is proven, as should result from phase 2a, and there are no competing available treatments, one would expect a rather lean NDA with a timely FDA approval. The time frame from Karp and Langers breakthrough study has been a mere 3 years (Feb 2017)! They have moved incredibly fast on this breakthrough and I don't see any slowdown coming from Frequency Therapeutics.

I'm predicting approval mid 2021 and availability within a year afterward.

Some thoughts I have regarding phase 2a and its effects on tinnitus subjects. For those with bilateral hearing loss and bilateral tinnitus, an improvement in a single cochlea (injecting 1 ear only in subjects) may not be effective since my tinnitus (bilateral) can go from center to full left to full right depending on what my auditory pathway is up to at the moment. Hopefully they'll breakout results for unilateral tinnitus subjects (assuming they inject the affected side) yet, we have to remember this study is primarily concerned with hearing restoration. If not, the results for tinnitus benefit may be understandably mixed and we therefore should not lose any hope for FX-322.

View attachment 36229

That's a really good point. I have completely symmetric bilateral tinnitus. Both of my two different tones are in both ears at the same volume. If they only treated one ear, how would my brainstem respond?

People with unilateral tinnitus would be better test subjects for this since they are only injecting one ear in the study. I hope they separate subjects out with these differences when they publish their phase 2 findings.

 

[Diesel]

Some thoughts I have regarding phase 2a and its effects on tinnitus subjects. For those with bilateral hearing loss and bilateral tinnitus, an improvement in a single cochlea (injecting 1 ear only in subjects) may not be effective since my tinnitus (bilateral) can go from center to full left to full right depending on what my auditory pathway is up to at the moment. Hopefully they'll breakout results for unilateral tinnitus subjects (assuming they inject the affected side) yet, we have to remember this study is primarily concerned with hearing restoration. If not, the results for tinnitus benefit may be understandably mixed and we therefore should not lose any hope for FX-322.

View attachment 36229

Interesting point that I had not considered. Speaking anecdotally, having bilateral tinnitus, if only one ear was treated with the drug and the symptom got quieter or went away, I would certainly notice it and it would likely improve(reduce) my TFI score. Perhaps not as much as someone who is experiencing the symptom unilaterally. As a treated group of bilateral and unilateral subjects, it still may be significant.

 

[Pink Noise]

Hi guys, I live in the UK and once FX-322 is commercially available I would like treatment ASAP.

Would I need to come to the US for treatment or would I need to wait for Astellas to distribute it worldwide? Speed is the important factor here. More days with less intrusive tinnitus is a life better spent.

I'm really suffering/struggling with loud extremely high pitch invasive tinnitus. I have allocated my savings for recovery, so looking for a timely solution.

 

[Mathieulh]

Regarding FX-322 and its uniqueness among the vast majority of drugs which are typically injected into tissue, sometimes intravenously, or taken orally.

Since they are not assessing systemic levels of the drug in phase 2a, their concern for possible adverse events seems limited to local abnormalities of the ear canal and patient reports. None are mentioned anywhere so far. Once safety and efficacy is proven, as should result from phase 2a, and there are no competing available treatments, one would expect a rather lean NDA with a timely FDA approval. The time frame from Karp and Langers breakthrough study has been a mere 3 years (Feb 2017)! They have moved incredibly fast on this breakthrough and I don't see any slowdown coming from Frequency Therapeutics.

I'm predicting approval mid 2021 and availability within a year afterward.

Some thoughts I have regarding phase 2a and its effects on tinnitus subjects. For those with bilateral hearing loss and bilateral tinnitus, an improvement in a single cochlea (injecting 1 ear only in subjects) may not be effective since my tinnitus (bilateral) can go from center to full left to full right depending on what my auditory pathway is up to at the moment. Hopefully they'll breakout results for unilateral tinnitus subjects (assuming they inject the affected side) yet, we have to remember this study is primarily concerned with hearing restoration. If not, the results for tinnitus benefit may be understandably mixed and we therefore should not lose any hope for FX-322.

View attachment 36229

You can get bilateral tinnitus from damage to a single cochlea because it often drives inflammation to the auditory cortex, which then creates phantom noises in the other ear (or in your head/center) even if the signaling is deficient/defective only in one ear, you would most likely notice stronger/louder tinnitus from your affected ear though.

Such is the case for me, I started as unilateral tinnitus on the left ear, eventually noise started on the right ear as well after months of it being unilateral, albeit at a much milder volume.

Of course if you fix the affected ear, chronic inflammation of your auditory cortex should eventually stop (probably within weeks at the most) as you removed the cause for the inflammation to begin with, and thus your tinnitus should stop along with it.

If you don't target the damaged ear/cochlea however, it most likely will have no effect on your tinnitus, assuming the damage is unilateral.

 

[MrCrybaby]

Hey @FGG I have an FDA question. If the experimental arm in 2a finds a solid impact on tinnitus, would they be able to apply for breakthrough status as a tinnitus treatment? Tinnitus, like sound clarity, is unmet so I'm curious if that's an avenue they can pursue.

 

[Diesel]

I see they're presenting at Cowen on March 2nd. Looks like the garden-variety company overview. Unfortunately, the Q&A won't be webcast. Anyone know anybody at Cowen?

 

[FGG]

Hey @FGG I have an FDA question. If the experimental arm in 2a finds a solid impact on tinnitus, would they be able to apply for breakthrough status as a tinnitus treatment? Tinnitus, like sound clarity, is unmet so I'm curious if that's an avenue they can pursue.

They can't because their IND on which the FDA approved the trials was for hearing loss.

Frequency knows that, that's why they are of studying TFI (Tinnitus Functional Index) as the only measure of tinnitus in phase 2. This would not be rigorous enough for approval *for* tinnitus but FX-322 can't be given Breakthrough status or even approved for an indication they didn't file the IND for anyway. Frequency adding TFI to phase 2 wasn't pointless though, it will let people know they can use it for tinnitus too once approved for hearing loss.

To give you another example of what I mean: the FDA couldn't have approved Trobalt for tinnitus if it didn't work for epilepsy. But, once released for epilepsy, it could be prescribed off label for tinnitus.

To use a more famous, unrelated example, they knew in clinical trials from patient testimonials that Rogaine re-grew hair in bald men but it had to show effects on blood pressure to release it. The drug is hardly used for blood pressure but is very commonly used for hair loss. But, before it became an OTC topical, it was prescribed off label for hair loss. To my knowledge it was never actually trialed separately and approved specifically for hair loss.

Anyway, within this framework, I am trying to write the FDA to encourage them to use as many different *hearing loss* end point surrogates (i.e. let's give word scores as much or more weight than standard audiograms if they don't go fully into the speech range even) knowing that, in doing so, they may be benefiting a huge tinnitus population as well while still acting well within the rules of the FDA.

In other words, they can't approve this drug or grant Breakthrough for tinnitus when it wasn't the indication that was applied for. But they should know that, if approved or given Breakthrough status for hearing loss they will be helping tinnitus patients, too, and maybe that will provide extra motivation to do so.

 

[MrCrybaby]

They can't because their IND on which the FDA approved the trials was for hearing loss.

Frequency knows that, that's why they are of studying TFI (Tinnitus Functional Index) as the only measure of tinnitus in phase 2. This would not be rigorous enough for approval *for* tinnitus but FX-322 can't be given Breakthrough status or even approved for an indication they didn't file the IND for anyway. Frequency adding TFI to phase 2 wasn't pointless though, it will let people know they can use it for tinnitus too once approved for hearing loss.

To give you another example of what I mean: the FDA couldn't have approved Trobalt for tinnitus if it didn't work for epilepsy. But, once released for epilepsy, it could be prescribed off label for tinnitus.

To use a more famous, unrelated example, they knew in clinical trials from patient testimonials that Rogaine re-grew hair in bald men but it had to show effects on blood pressure to release it. The drug is hardly used for blood pressure but is very commonly used for hair loss. But, before it became an OTC topical, it was prescribed off label for hair loss. To my knowledge it was never actually trialed separately and approved specifically for hair loss.

Anyway, within this framework, I am trying to write the FDA to encourage them to use as many different *hearing loss* end point surrogates (i.e. let's give word scores as much or more weight than standard audiograms if they don't go fully into the speech range even) knowing that, in doing so, they may be benefiting a huge tinnitus population as well while still acting well within the rules of the FDA.

In other words, they can't approve this drug or grant Breakthrough for tinnitus when it wasn't the indication that was applied for. But they should know that, if approved or given Breakthrough status for hearing loss they will be helping tinnitus patients, too, and maybe that will provide extra motivation to do so.

Thanks, that's very informative! I'm so grateful that you share all your knowledge here on Tinnitus Talk!

 

[Joeseph Stope]

They can't because their IND on which the FDA approved the trials was for hearing loss.

Frequency knows that, that's why they are of studying TFI (Tinnitus Functional Index) as the only measure of tinnitus in phase 2. This would not be rigorous enough for approval *for* tinnitus but FX-322 can't be given Breakthrough status or even approved for an indication they didn't file the IND for anyway. Frequency adding TFI to phase 2 wasn't pointless though, it will let people know they can use it for tinnitus too once approved for hearing loss.

To give you another example of what I mean: the FDA couldn't have approved Trobalt for tinnitus if it didn't work for epilepsy. But, once released for epilepsy, it could be prescribed off label for tinnitus.

To use a more famous, unrelated example, they knew in clinical trials from patient testimonials that Rogaine re-grew hair in bald men but it had to show effects on blood pressure to release it. The drug is hardly used for blood pressure but is very commonly used for hair loss. But, before it became an OTC topical, it was prescribed off label for hair loss. To my knowledge it was never actually trialed separately and approved specifically for hair loss.

Anyway, within this framework, I am trying to write the FDA to encourage them to use as many different *hearing loss* end point surrogates (i.e. let's give word scores as much or more weight than standard audiograms if they don't go fully into the speech range even) knowing that, in doing so, they may be benefiting a huge tinnitus population as well while still acting well within the rules of the FDA.

In other words, they can't approve this drug or grant Breakthrough for tinnitus when it wasn't the indication that was applied for. But they should know that, if approved or given Breakthrough status for hearing loss they will be helping tinnitus patients, too, and maybe that will provide extra motivation to do so.

Yes, it would make sense that if many tinnitus patients benefit from hearing aids, they would benefit in a somewhat similar way from improved natural hearing.

The whole shebang about getting FDA approval seems to have taken on the aura of a chess game. Do I have some right to be angry or annoyed? Far from it. I can see that TPTB (the powers that be) have to adopt a cautious approach to issuing OK. We have had the tragic case of poor ChrisBoyMonkey just a month or two back and we are still waiting to hear whether he got the real thing or just a placebo. Incidents like this should be studiously avoided (but sadly chit happens).

 

[FGG]

Their Cowen meeting on March 2nd will be followed by a Q and A which will be posted on their website:

https://finance.yahoo.com/news/frequency-therapeutics-present-40th-annual-133000134.html

 

[Lucifer]

Their Cowen meeting on March 2nd will be followed by a Q and A which will be posted on their website:

https://finance.yahoo.com/news/frequency-therapeutics-present-40th-annual-133000134.html

I wonder if this is the event where they will state that the clinical trials for Phase 2a have finished enrollment and when they expect the results to be released.

 

[FGG]

I wonder if this is the event where they will state that the clinical trials for Phase 2a have finished enrollment and when they expect the results to be released.

There is no way they will say that since some centers haven't even started enrolling.

 

[FGG]

I just looked it up, the following sites haven't even started recruiting for the trial yet:

Amhearst, NY
SLC, Utah
San Antonio, TX
Richmond, VA

That's 4/16 sites where recruitment has yet to begin.

They also have two sites in San Antonio for some reason.

I hope this won't delay data read out too much but i also hope the increase in sites is to bolster their data to the FDA for quicker approval.

 

[Joly]

I do not see that this subject has been approached. I have read the whole thread and have found nothing.

My questions are:
- Do you think FX-322 could restore dead hair cells that have died from ototoxic drugs?
- I think ototoxic drugs are more devastating than loud sound and can kill supporting cells, right?
- Is it possible to have damaged hair cells which remain but which no longer function? At that point FX-322 will not act on these cells?

 

[mrbrightside614]

I do not see that this subject has been approached. I have read the whole thread and have found nothing.

My questions are:
- Do you think FX-322 could restore dead hair cells that have died from ototoxic drugs?
- I think ototoxic drugs are more devastating than loud sound and can kill supporting cells, right?
- Is it possible to have damaged hair cells which remain but which no longer function? At that point FX-322 will not act on these cells?

1) Yes.
2) Ototoxic drugs don't preferentially kill the OHC like acoustic trauma seems to and could pose more harm to support cells, but synthesizing the info from this thread that's mostly a guess.
3) It's highly doubtful IMO. Even healthy hair cells are sometimes subject to cell death following traumatic events. Most likely all damaged hair cells are subject to apoptosis.

 

[mrbrightside614]

I'd like to mention that for those of whom are concerned about widespread support cell depletion, StemCells21 could be a viable option for both improving your tinnitus in addition to possibly replenishing support cells. If the timeline for FX-322/Shore doesn't seem favorable by the end of the year I'm probably going to go to Bangkok for this.

 

[FGG]

I do not see that this subject has been approached. I have read the whole thread and have found nothing.

My questions are:
- Do you think FX-322 could restore dead hair cells that have died from ototoxic drugs?
- I think ototoxic drugs are more devastating than loud sound and can kill supporting cells, right?
- Is it possible to have damaged hair cells which remain but which no longer function? At that point FX-322 will not act on these cells?

If all your LGr+ supporting cells are destroyed, yes it won't work, but that usually would only happen in severe to profound deafness I imagine because all your hair cells would be completely gone in that region without support cells. It might be one reason they aren't testing in people with over 70dB loss.

I wish I could remember where I read or heard it but I distinctly remember them saying "damaged or destroyed hair cells" and it seems if the hair is truly non functional apoptosis should kick in anyway.

As far as ototoxicity, some of the pre-clinical work was done on aminoglycoside damaged cells, so there is a good chance unless your ototoxin was Cisplatin (the retained platinum is anti mitotic), this will work for you too imo.

 

[Diesel]

I just looked it up, the following sites haven't even started recruiting for the trial yet:

Amhearst, NY
SLC, Utah
San Antonio, TX
Richmond, VA

That's 4/16 sites where recruitment has yet to begin.

They also have two sites in San Antonio for some reason.

I hope this won't delay data read out too much but i also hope the increase in sites is to bolster their data to the FDA for quicker approval.

The optimist in me thinks that having two sites in San Antonio is to increase the volume of participants in the trial and as a result, increase the data/level of evidence to support the primary outcomes in Phase2A. Its mentioned on the FDA website that a sponsor seeking the Breakthrough Designation has to meet higher level of evidence than the Fast Track designation.

Speculation: The strategy may be to gather more data in the Phase 2A, which may elongate it past the 9/30 deadline. However, in doing so gaining the Breakthrough Designation and expediting the overall product development timeline.

 

[FGG]

The optimist in me thinks that having two sites in San Antonio is to increase the volume of participants in the trial and as a result, increase the data/level of evidence to support the primary outcomes in Phase2A. Its mentioned on the FDA website that a sponsor seeking the Breakthrough Designation has to meet higher level of evidence than the Fast Track designation.

Speculation: The strategy may be to gather more data in the Phase 2A, which may elongate it past the 9/30 deadline. However, in doing so gaining the Breakthrough Designation and expediting the overall product development timeline.

100% my thought process as well because otherwise why would you have so many sites so close together if you are simply just having trouble enrolling and that was the reason to add locations.

For instance, these sites are all within easy driving distance of each other:

Richmond and Winston Salem

Winston Salem and Mathews

Orangeburg and Mathews
(If you live in Central NC, for instance you could go to any of these above 4 locations pretty easily)

Sarasota and Tampa (these cities are literally just across a bridge from each other)

And finally two separate locations in San Antonio.

 

[all to gain]

I'd like to mention that for those of whom are concerned about widespread support cell depletion, StemCells21 could be a viable option for both improving your tinnitus in addition to possibly replenishing support cells. If the timeline for FX-322/Shore doesn't seem favorable by the end of the year I'm probably going to go to Bangkok for this.

Keep me posted on what you decide. I might need to go that route too.

 

[FGG]

I'd like to mention that for those of whom are concerned about widespread support cell depletion, StemCells21 could be a viable option for both improving your tinnitus in addition to possibly replenishing support cells. If the timeline for FX-322/Shore doesn't seem favorable by the end of the year I'm probably going to go to Bangkok for this.

Can you explain how that would regenerate support cells?

 

[Diesel]

As I was reading about the Breakthrough Therapy designation. I stumbled upon the 'Regenerative Medicine Advanced Therapy Designation,' or "RMAT."

https://www.fda.gov/vaccines-blood-...erative-medicine-advanced-therapy-designation

Here's a description of the program in detail: https://www.fda.gov/media/120267/download

And products that have received the RMAT designation: https://bioinformant.com/rmat/

It appears that the RMAT designation offers additional expedited benefits beyond the Breakthrough designation. IMHO, based on other products that have received RMAT designation, that FX-322 may be a fit to be accepted.

Questions:
- Does FX-322 fit the RMAT acceptance criteria?
- Why would Frequency indicate they are only seeking a Breakthrough Therapy designation and not RMAT?

 

[mrbrightside614]

Can you explain how that would regenerate support cells?

I'd imagine stem cells would differentiate into all kinds of cells related to the cochlea if they functionally regenerate some facets of it like in the cases of @attheedgeofscience and @undecided.

 

[FGG]

I'd imagine stem cells would differentiate into all kinds of cells related to the cochlea if they functionally regenerate some facets of it like in the cases of @attheedgeofscience and @undecided.

Isn't the benefit of distally injected stem cells from the exosomes providing an anti inflammatory effect and not direct cellular integration? Is there a type of distal stem cell (i.e. not locally delivered into the cochlea) therapy that does lead to cellular integration?

 

[Lucifer]

As I was reading about the Breakthrough Therapy designation. I stumbled upon the 'Regenerative Medicine Advanced Therapy Designation,' or "RMAT."

https://www.fda.gov/vaccines-blood-...erative-medicine-advanced-therapy-designation

Here's a description of the program in detail: https://www.fda.gov/media/120267/download

And products that have received the RMAT designation: https://bioinformant.com/rmat/

It appears that the RMAT designation offers additional expedited benefits beyond the Breakthrough designation. IMHO, based on other products that have received RMAT designation, that FX-322 may be a fit to be accepted.

Questions:
- Does FX-322 fit the RMAT acceptance criteria?
- Why would Frequency indicate they are only seeking a Breakthrough Therapy designation and not RMAT?

I thought Breakthrough Therapy status was the best but now it might be possible to achieve RMAT. Hopefully someone could explain to me what the difference is between the two and if FX-322 would be allowed to get RMAT status.

 

[all to gain]

I wonder what order, if any, a person who requires the whole shebang (FX-322 and OTO-413 and/or Pipeline or the Hough pill) would need to take these drugs in order for them to work their, hopefully, magic? Would it make a difference?