Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

I hear a lot about Frequency working with the FDA for fast tracking and such, is Audion doing something similar? It looks like the LY3056480 trials are happening in Europe. If the Phase II trial passes over there, does the FDA count it the same?

It's odd that Frequency has been very vocal while Audion seems under the radar (at least to me).

After reading this, my opinion is Audion seems inferior:

https://www.frontiersin.org/articles/10.3389/fncel.2018.00073/full#F1

 

[brokensoul]

I think there is a huge misconception that the stereocillia is the actual hair cell. It isn't. The stereocillia flops over because the cell degrades and can't hold it up "hair" of the hair cell anymore. This damaged cell sends out signals of damage and will be replaced just like damaged intestinal cells (where Karp and Langer modeled their progenitor cell activation treatment from).

Perhaps my question wasn't phrased perfectly clear. I know the stereocilia grows on top of the hair cell. For me this is clear. I don't know however what happens on the micro level when the stereocilia are damaged, but the hair cell is intact or if you can have a dysfunctional hair cell that remains in place. I haven't studied this at all. It's not clear to me, hence my questions.

So you think a hair cell with damaged stereocilia would be replaced by PCA?

Do damaged hair cells always get removed? This is the natural process? No grey area?

That's what I'm trying to understand. That would be great. One issue less to worry about.

Thanks so much for your insights.

You've been investigating this much longer than I am. So great to have your support!

 

[MrCrybaby]

After reading this, my opinion is Audion seems inferior:

https://www.frontiersin.org/articles/10.3389/fncel.2018.00073/full#F1

That's freaky! Wouldn't want my ears ending up like that...

Is there evidence that Frequency's technique maintains the normal/healthy hair cell arrangement?

 

[Chriscom]

20 years is such a long long time away. At least something will be in place, hopefully, for my children.

The joke I encountered when I first acquired hearing loss and tinnitus loss was something like, "a cure is just 5-10 years away, and always has been."

But solid advances really are being made now. It's absolutely not gonna be 20 years and in my opinion not even ten. What's happening with FX-322 is a first as far as I can tell: they've created new, functioning hair cells, restored hearing in mice, and mildly improved hearing in human subjects. More work is required to seriously boost that into substantial hearing gains, it remains to be seen how broadly successful it will be, and so on. But much of the mechanisms are understood and we're beginning to enter the refinement stage. They could have encountered grave obstacles before this point and seemingly haven't. Those include safety (cancerous growth after you've stimulated new growth) and, this occurred to me the other day, some other element in the hearing mechanism that, say, created more noise and weird artifacts rather than actually improving hearing. But that doesn't seem to be an issue--we have improved word recognition scores for example.

Lots of reasons to be optimistic. I think completely cracking the tinnitus code will be more difficult since it isn't as thoroughly understood. But it's not crazy to expect improved hearing will decrease if not completely eliminate tinnitus, a possible side benefit of FX-322, and of course there are other efforts on the direct tinnitus front.

I think both these afflictions will begin to be seriously tamed within 3-5 years.

 

[d'Wooluf]

At least they didn't mention anything about the delivery method challenge. I understand they are selling and avoid talking about the challenges (problems), but now I'm left wondering if they even have the intention to improve the delivery method to target <4kHz. The whole presentation seemed to be about improving sound clarity (intelligibility).

Like you say, they are selling. Their language changed after they released the phase 1b results. They used to talk about restoring hearing, now it's improving hearing. They are concentrating on the positives (word recognition improvements in some subjects) and glossing over the unknowns (improving thresholds below 8kHz). I think you can explain the new-found interest in higher frequencies as adding a new potential market (tinnitus sufferers) to keep things upbeat in the face of emerging doubts about their original- and most lucrative- market. Maybe I'm in post-Christmas cynic mode. Sorry.

I haven't given up on them, and I respect others' opinions on the whys and wherefores of them testing those higher frequencies. Time will tell.

By the way, I'm still not sure what they mean when they say that 4 out of 6 had 'statistically significant' improvements and 2 didn't. Statistical significance is applied to a group, not individuals in that group. That's the way I always understood it.

 

[FGG]

That's freaky! Wouldn't want my ears ending up like that...

Is there evidence that frequency's technique maintains the normal/healthy hair cell arrangement?

FX-322 should IMO based on their results and based on the fact that their platform uses an entirely different method preserving the support cells for better architecture and also they aren't trying to biochemically retrofit a support cell into a hair cell.

 

[mrbrightside614]

20 years is such a long long time away. At least something will be in place, hopefully, for my children.

This was a super old quote from me, and highly conservative.

I think FX-322 is going to be the real deal. @brokensoul has valid questions that make me wonder, for sure though. I think 18-30 months with barriers like pending a phase 3 conditional approval (as one poster here referenced its precedent of first-in-class drugs) will be the biggest piece in deciding its earlier availability.

 

[Joeseph Stope]

New to the group but long time tinnitus sufferer (Easter 1992).

It strikes me that the question may be transposing itself now to: "What sort of damage do I have"?
i.e. is it ribbon synapse damage? Is it hair cell damage? Is it nerve damage? Is it some combination of these? Stereocilia anyone?

How to figure this out without being sacrificed and dissected (post mortem) would be kind of crucial.

Then you could plug for the right treatment for your own particular auditory damage... Frequency, Adion, Novartis etc.

May I say that I am amazed at how far advanced the whole field of tinnitus research has developed since the 1990s. And how far tinnitus sufferers have come organizing themselves.

Best.

 

[FGG]

Perhaps my question wasn't phrased perfectly clear. I know the stereocilia grows on top of the hair cell. For me this is clear. I don't know however what happens on the micro level when the stereocilia are damaged, but the hair cell is intact or if you can have a dysfunctional hair cell that remains in place. I haven't studied this at all. It's not clear to me, hence my questions.

So you think a hair cell with damaged stereocilia would be replaced by PCA?

Do damaged hair cells always get removed? This is the natural process? No grey area?

That's what I'm trying to understand. That would be great. One issue less to worry about.

Thanks so much for your insights.

You've been investigating this much longer than I am. So great to have your support!

I agree that not all damage destroys the stereocilia completely, but I haven't seen any evidence of damaged stereocilia without at least some hair cell damage.

 

[FGG]

To the Otomagnetics folks: I love the interest in it and it looks very intriguing but i don't think it will be necessary to get regenerative drugs all the way to the apex.

Otonomy and Pipeline both use a surfactant called Poloaxomer 407 and through an email exchange I have confirmation that Pipeline's drug will fully reach the apex with their formulation. Otonomy has the patent so I imagine Pipeline would have to pay them for its use.

Frequency needs a better hydrogel for this and in fact they appear to be hiring for just that purpose. I expect a FX-322 2.0 to hit the market not long after approval.

 

[mrbrightside614]

I think you can explain the new-found interest in higher frequencies as adding a new potential market (tinnitus sufferers) to keep things upbeat in the face of emerging doubts about their original- and most lucrative- market. Maybe I'm in post-Christmas cynic mode. Sorry.

I haven't given up on them, and I respect others' opinions on the whys and wherefores of them testing those higher frequencies. Time will tell.

I actually think the market would be stronger for tinnitus sufferers, considering hearing aids can greatly benefit for those with losses from 250 Hz-8 kHz. Between augmenting your hearing in the ranges from 3.5 kHz and up from FX-322 and being able to benefit from hearing aids for the other frequencies, combination therapy for the hearing loss population should be very effective.

Tinnitus sufferers are typically plagued by the severely high pitched noises which probably comes from loss in the extended frequencies—something that hearing aids will not be able to come close to anytime soon. I think there is a much bigger market in tinnitus sufferers when your drug targets 3.5 kHz+, with likely the best results at the highest frequencies due to those frequencies' location being more proximal to drug penetration site.

 

[serendipity1996]

The joke I encountered when I first acquired hearing loss and tinnitus loss was something like, "a cure is just 5-10 years away, and always has been."

But solid advances really are being made now. It's absolutely not gonna be 20 years and in my opinion not even ten. What's happening with FX-322 is a first as far as I can tell: they've created new, functioning hair cells, restored hearing in mice, and mildly improved hearing in human subjects. More work is required to seriously boost that into substantial hearing gains, it remains to be seen how broadly successful it will be, and so on. But much of the mechanisms are understood and we're beginning to enter the refinement stage. They could have encountered grave obstacles before this point and seemingly haven't. Those include safety (cancerous growth after you've stimulated new growth) and, this occurred to me the other day, some other element in the hearing mechanism that, say, created more noise and weird artifacts rather than actually improving hearing. But that doesn't seem to be an issue--we have improved word recognition scores for example.

Lots of reasons to be optimistic. I think completely cracking the tinnitus code will be more difficult since it isn't as thoroughly understood. But it's not crazy to expect improved hearing will decrease if not completely eliminate tinnitus, a possible side benefit of FX-322, and of course there are other efforts on the direct tinnitus front.

I think both these afflictions will begin to be seriously tamed within 3-5 years.

Agreed! I realise the whole ' only 5-10 years!' away timeline has become a bit of a tiresome meme but I do feel we've reached a critical tipping point when it comes to the future of hearing regeneration. For so long it feels like this has only been discussed in an abstract sense but it's a testament to the tremendous amount of progress that has been made that we now have companies in clinical trials for commercial treatments.

I look back at when I first joined the forum back in 2016, so only 4 years ago and there wasn't nearly as much going on as there is now. Sure, I don't necessarily think that the first generation of treatments will be absolutely perfect and restore us to the hearing of a 5 year old but it's all coming together now!

 

[brokensoul]

To the Otomagnetics folks: I love the interest in it and it looks very intriguing but i don't think it will be necessary to get regenerative drugs all the way to the apex.

I agree. It seems also that it is something that is still very much proof of concept. If they can ever get this to work, then it's great, but I'm not at all waiting for it as the solution to get to the apex.

Otonomy and Pipeline both use a surfactant called Poloaxomer 407 and through an email exchange I have confirmation that Pipeline's drug will fully reach the apex with their formulation. Otonomy has the patent so I imagine Pipeline would have to pay them for its use.

Exactly this. If Pipeline can already do it, then we know it's perfectly doable and it's only a matter of time when Frequency Therapeutics comes up with their own solution to reach the apex.

That's why I was sort of surprised to seem them gloss over this 'challenge'. Just one sentence that they are actively working on optimising or developing an even better hydrogel would have looked better in my opinion instead of avoiding it and lowering expectations to high frequency restoration only. It seemed odd to me, even if they were in sell mode.

Frequency needs a better hydrogel for this and in fact they appear to be hiring for just that purpose. I expect a FX-322 2.0 to hit the market not long after approval.

This would be great. How do you deduct from their hiring that they intend to build their own solution to reach the apex?

I mean it makes perfect sense to me that they would be looking into that and I presume they are aware of Pipeline's solution to reach the apex, but did you see any specific hiring that draws you to that conclusion?

 

[mrbrightside614]

I look back at when I first joined the forum back in 2016, so only 4 years ago and there wasn't nearly as much going on as there is now. Sure, I don't necessarily think that the first generation of treatments will be absolutely perfect and restore us to the hearing of a 5 year old but it's all coming together now!

A common theme here is that our members usually register as little-to-no hearing loss between the standard frequencies. Since we're not too far gone, I really think that tinnitus relief will be more achievable compared to complete hearing restoration. I could care less if I never heard 13 kHz again... but my brain sure does want to.

Kill it with stem cells!

 

[Momme]

To the Otomagnetics folks: I love the interest in it and it looks very intriguing but i don't think it will be necessary to get regenerative drugs all the way to the apex.

Otonomy and Pipeline both use a surfactant called Poloaxomer 407 and through an email exchange I have confirmation that Pipeline's drug will fully reach the apex with their formulation. Otonomy has the patent so I imagine Pipeline would have to pay them for its use.

Frequency needs a better hydrogel for this and in fact they appear to be hiring for just that purpose. I expect a FX-322 2.0 to hit the market not long after approval.

When do you think Pipeline is going to come out?

 

[mrbrightside614]

To the Otomagnetics folks: I love the interest in it and it looks very intriguing but i don't think it will be necessary to get regenerative drugs all the way to the apex.

Otonomy and Pipeline both use a surfactant called Poloaxomer 407 and through an email exchange I have confirmation that Pipeline's drug will fully reach the apex with their formulation. Otonomy has the patent so I imagine Pipeline would have to pay them for its use.

Frequency needs a better hydrogel for this and in fact they appear to be hiring for just that purpose. I expect a FX-322 2.0 to hit the market not long after approval.

I don't know how you've managed to get such great correspondence with them because they seem to be holding their cards close to the vest, but I love you for it. I feel like these companies have a moral obligation to be sharing information but that's just not how it works in capitalist society. I'm also interested as to how you gleaned the information from their hiring practices. It'd be really great to see if they've made efforts to improve their drug suspension methods, or even corresponded with other drug companies to improve it.

 

[FGG]

I agree. It seems also that it is something that is still very much proof of concept. If they can ever get this to work, then it's great, but I'm not at all waiting for it as the solution to get to the apex.

Exactly this. If Pipeline can already do it, then we know it's perfectly doable and it's only a matter of time when Frequency Therapeutics comes up with their own solution to reach the apex.

That's why I was sort of surprised to seem them gloss over this 'challenge'. Just one sentence that they are actively working on optimising or developing an even better hydrogel would have looked better in my opinion instead of avoiding it and lowering expectations to high frequency restoration only. It seemed odd to me, even if they were in sell mode.

This would be great. How do you deduct from their hiring that they intend to build their own solution to reach the apex?

I mean it makes perfect sense to me that they would be looking into that and I presume they are aware of Pipeline's solution to reach the apex, but did you see any specific hiring that draws you to that conclusion?

Here was the phrasing for one of their posts:

"Responsibilities: Design and carry out experiments to develop novel polymer-based, small molecule delivery systems for otic and other routes of administration"

I'm just reading between the lines.

 

[FGG]

I don't know how you've managed to get such great correspondence with them because they seem to be holding their cards close to the vest, but I love you for it. I feel like these companies have a moral obligation to be sharing information but that's just not how it works in capitalist society. I'm also interested as to how you gleaned the information from their hiring practices. It'd be really great to see if they've made efforts to improve their drug suspension methods, or even corresponded with other drug companies to improve it.

I don't know either but I think it's maybe because Pipeline is very excited about their product and doesn't have an outlet to share this excitement yet.

 

[Chriscom]

To the Otomagnetics folks: I love the interest in it and it looks very intriguing but i don't think it will be necessary to get regenerative drugs all the way to the apex.

Otonomy and Pipeline both use a surfactant called Poloaxomer 407 and through an email exchange I have confirmation that Pipeline's drug will fully reach the apex with their formulation. Otonomy has the patent so I imagine Pipeline would have to pay them for its use.

Frequency needs a better hydrogel for this and in fact they appear to be hiring for just that purpose. I expect a FX-322 2.0 to hit the market not long after approval.

I didn't realize any such drug could fully reach the apex, that's amazing, and great!

 

[brokensoul]

It strikes me that the question may be transposing itself now to: "What sort of damage do I have"?
i.e. is it ribbon synapse damage? Is it hair cell damage? Is it nerve damage? Is it some combination of these? Stereocilia anyone?

How to figure this out without being sacrificed and dissected (post mortem) would be kind of crucial.

Hi and welcome!

Hearing damage scenarios:

Hearing loss can happen at different points in the auditory system. It is likely that damage happens on several layers. It is however known that synapses are more fragile than hair cells.

You can have damaged stereocilia on the hair cells and perhaps you can also have dysfunctional hair cells that are still present. Lastly, you can simply have dead hair cells that are entirely removed from the epithelium after some time.

You have multiple synapse ribbons per hair cell. It is possible to have a functional hair cell with only one synapse ribbon instead of three for example (not sure about the maximum per hair cell).

It's also possible that the nerve endings to the hair cells are retracted, but I'm not sure if the hair cells remain alive when that happens.

It is obviously also possible that something is wrong upstream in the brainstem or beyond that, but my knowledge is limited in that regard.

Maybe someone can complement on all the possible scenarios.

How to test your hearing to have an idea what is damaged:

Hair cell functionality is tested with a pure tone audiometry, and it's obviously best to have an extended audiogram. It's a very basic test and my main problem with it is that they only test intervals instead of all frequencies. You could have gaps between the intervals and the test would not reveal that at all (even if they say it's not necessary I'm still in doubt).

To my knowledge, and this is common in my country, you can test hair cells also by doing a DPOAE test, which is objective and not subjective as is the case with an audiogram. Both tests should give you a rough idea to what extent you have hair cell damage. I believe the DPOAE test is more solid than an audiogram, but my research shows it is perhaps only for outer hair cells. This point is not entirely clear to me. My audiologist did not mention anything about that, but Wikipedia refers to OHCs and not IHCs as well.

To test if you may have cochlear synaptopathy, you should do a word recognition test, as well as a word in noise test. This is also a subjective test, but it gives you a rough idea if you have synapse degradation. The reasoning behind it, is that you need to have multiple synapses working per hair cell (at a certain frequency) to have a higher (better or more clear) understanding of what is being said. This is something that an audiogram will never be able to tell.

I do not know to what extent you can detect nerve damage or partial neuropathy. Perhaps you can test this to a certain degree with a FMRI done by a neurotologist. I have not done so.

I believe there is something called an Auditory Brain Response (ABR) test which could tell you if you have an issue in your brainstem. I did not take this test as I believe they briefly blast your ears with high volume sound. No thanks.

The more tests you do, the better you will know what type of damage you may have and what solution may work the best in the future to restore your hearing.

Again, it's logical to assume you have various levels of damage.

Lastly, these are all hearing regeneration solutions we are talking about and it remains a hypothesis if this will actually alleviate the tinnitus or not. We hope so, but until we get there, we don't really know for sure. At least that's my opinion. Most people seem to think it will help to reduce tinnitus.

If anyone wants to elaborate on that, please do.

 

[FGG]

When do you think Pipeline is going to come out?

Well they are about to start phase 1. As far as an exact timeline, maybe 3-5 years? Pure guess.

 

[Momme]

Well they are about to start phase 1. As far as an exact timeline, maybe 3-5 years? Pure guess.

Didn't it start in 2019?

"A Phase 1b/2a study of PIPE-505 in SNHL is expected to begin in 4Q 2019, with topline results expected in late 2020."

Source:
https://www.pipelinetherapeutics.com/news/Pipeline-SeriesBFinancingRelease.pdf

 

[brokensoul]

I could care less if I never heard 13 kHz again... but my brain sure does want to.

I'm sure it's the case for many tinnitus sufferers. I cannot say at all if I have any degradation to my hearing. I seemingly hear perfectly well and the tests seem to confirm that. If something is wrong it must be too subtle for me to notice and cannot be objectified through current hearing tests, as far as I can tell.

The multiple sounds tinnitus though is wrecking me. I don't want hearing regeneration per se, I want the tinnitus gone.

 

[brokensoul]

Here was the phrasing for one of their posts:

"Responsibilities: Design and carry out experiments to develop novel polymer-based, small molecule delivery systems for otic and other routes of administration"

I'm just reading between the lines.

Haha, that's quite literally it! Awesome!

 

[HootOwl]

Perhaps my question wasn't phrased perfectly clear. I know the stereocilia grows on top of the hair cell. For me this is clear. I don't know however what happens on the micro level when the stereocilia are damaged, but the hair cell is intact or if you can have a dysfunctional hair cell that remains in place. I haven't studied this at all. It's not clear to me, hence my questions.

So you think a hair cell with damaged stereocilia would be replaced by PCA?

Do damaged hair cells always get removed? This is the natural process? No grey area?

That's what I'm trying to understand. That would be great. One issue less to worry about.

Thanks so much for your insights.

You've been investigating this much longer than I am. So great to have your support!

So I emailed Dr. Karp who is on the scientific advisory board for Frequency Therapeutics asking him this exact question and he directed me to Dr. Jeffery Holt from Harvard Medical.

I spoke with Dr. Holt on the phone and he said that in mice and rat models they see what he called "nonfunctional" hair cells die within 3 months. Although he didn't know for sure he said that flopped over/disfigured stereocillia wouldn't be transmitting their signals properly and would likely be considered non-functional by the body. If the rodent model stands correct they would also be removed in 3 months time or so.

I hope to hear back from Dan (Pipeline) on his thoughts as well. He might direct me to Heller though, we'll see.

 

[brokensoul]

I don't know how you've managed to get such great correspondence with them because they seem to be holding their cards close to the vest, but I love you for it.

@FGG

I agree with @mrbrightside614, it is awesome that you actively reach out to companies to get more info.

Tons of respect for your efforts.

 

[FGG]

Hi and welcome!

Hearing damage scenarios:

Hearing loss can happen at different points in the auditory system. It is likely that damage happens on several layers. It is however known that synapses are more fragile than hair cells.

You can have damaged stereocilia on the hair cells and perhaps you can also have dysfunctional hair cells that are still present. Lastly, you can simply have dead hair cells that are entirely removed from the epithelium after some time.

You have multiple synapse ribbons per hair cell. It is possible to have a functional hair cell with only one synapse ribbon instead of three for example (not sure about the maximum per hair cell).

It's also possible that the nerve endings to the hair cells are retracted, but I'm not sure if the hair cells remain alive when that happens.

It is obviously also possible that something is wrong upstream in the brainstem or beyond that, but my knowledge is limited in that regard.

Maybe someone can complement on all the possible scenarios.

How to test your hearing to have an idea what is damaged:

Hair cell functionality is tested with a pure tone audiometry, and it's obviously best to have an extended audiogram. It's a very basic test and my main problem with it is that they only test intervals instead of all frequencies. You could have gaps between the intervals and the test would not reveal that at all (even if they say it's not necessary I'm still in doubt).

To my knowledge, and this is common in my country, you can test hair cells also by doing a DPOAE test, which is objective and not subjective as is the case with an audiogram. Both tests should give you a rough idea to what extent you have hair cell damage. I believe the DPOAE test is more solid than an audiogram, but my research shows it is perhaps only for outer hair cells. This point is not entirely clear to me. My audiologist did not mention anything about that, but Wikipedia refers to OHCs and not IHCs as well.

To test if you may have cochlear synaptopathy, you should do a word recognition test, as well as a word in noise test. This is also a subjective test, but it gives you a rough idea if you have synapse degradation. The reasoning behind it, is that you need to have multiple synapses working per hair cell (at a certain frequency) to have a higher (better or more clear) understanding of what is being said. This is something that an audiogram will never be able to tell.

I do not know to what extent you can detect nerve damage or partial neuropathy. Perhaps you can test this to a certain degree with a FMRI done by a neurotologist. I have not done so.

I believe there is something called an Auditory Brain Response (ABR) test which could tell you if you have an issue in your brainstem. I did not take this test as I believe they briefly blast your ears with high volume sound. No thanks.

The more tests you do, the better you will know what type of damage you may have and what solution may work the best in the future to restore your hearing.

Again, it's logical to assume you have various levels of damage.

Lastly, these are all hearing regeneration solutions we are talking about and it remains a hypothesis if this will actually alleviate the tinnitus or not. We hope so, but until we get there, we don't really know for sure. At least that's my opinion. Most people seem to think it will help to reduce tinnitus.

If anyone wants to elaborate on that, please do.

My summary:

You have OHCs in larger numbers which connect to IHCs which finally synapse (ribbon synapses) with the spiral ganglion.

Further up you have the axon of the cochlear nerve which synapses at the brainstem (DCN) and then eventually the auditory cortex in the brain is where this signal is "heard."

The overwhelming majority of people who get tinnitus injured their cochlea in some way. Typically this happens through similar mechanisms: Neuro excitation and oxidative stress regardless of the cause.

The synapses and OHCs are more prone to this damage but some things (certain ototoxins, perhaps viral etc) damage the IHCs more. By the time you have audiogram changes, you have probably damaged multiple cochlear structures at that point.

Audiograms are very good at detecting OHC loss. There is some evidence that extended audiogram changes are a good additional tool to tell if you have synaptopathy in the typical audiogram range because if you have moderate damage above 10000 Hz, it is reasonable that the more sensitive synapses may be damaged further down.

I think everyone should get an extended audiogram personally.

Frequency restores OHC and it seems some IHC too from one of their publications. There is a link between loudness hyperacusis and IHC damage being a trigger for central gain so I wish they would test this on hyperacusis too! It may work for many cases imo.

Pipeline, Hough and Otonomy have synaptopathy drugs in trial.

Frequency will restore synapses if there are damaged or destroyed hair cells at that location.

As far as brainstem damage, that would usually be from things trauma, stroke or the rare ototoxin (I believe I am at least partially affected from Macrolide ototoxicity). A solution here would come from channel opening drugs. Or maybe CNS regeneration.

And, finally, Dr. Chen at Harvard is working on regenerating the entire cochlea, including support cells for the very severe cases. He's still in pre clinical but he told me he hopes to have something within a decade to market.

 

[FGG]

Didn't it start in 2019?

"A Phase 1b/2a study of PIPE-505 in SNHL is expected to begin in 4Q 2019, with topline results expected in late 2020."

Source:
https://www.pipelinetherapeutics.com/news/Pipeline-SeriesBFinancingRelease.pdf

It was supposed to. I have heard there is a slight delay but recruitment is imminent.

 

[FGG]

@FGG

I agree with @mrbrightside614, it is awesome that you actively reach out to companies to get more info.

Tons of respect for your efforts.

@HootOwl is super good at doing this, too! Just wanted to make sure she got the recognition she deserved on this.

 

[brokensoul]

So I emailed Dr. Karp who is on the scientific advisory board for Frequency Therapeutics asking him this exact question and he directed me to Dr. Jeffery Holt from Harvard Medical.

I spoke with Dr. Holt on the phone and he said that in mice and rat models they see what he called "nonfunctional" hair cells die within 3 months. Although he didn't know for sure he said that flopped over/disfigured stereocillia wouldn't be transmitting their signals properly and would likely be considered non-functional by the body. If the rodent model stands correct they would also be removed in 3 months time or so.

Blown away that you just take contact with these people. So incredibly awesome. Having input from their side provides us with so much more insight. Otherwise it's just laymen talking to other laymen here. We do our best, but have our limits, right?

I understood as well that the hair cell is supposed to die off after some weeks or some months. It's the potential grey area I am wondering about.

Ok, so rodent models demonstrate that when stereocilia no longer transmit any signal they are also removed.

Question is what happens if they still do emit a signal. Flopped over permanently means they can't vibrate anymore and hence no longer transduce a signal? I'm not sure. I think they still vibrate and transduce, but not a signal as expected. I Suspect there are some variations here and I'm wondering if flopped over or entangled stereocilia do actually still emit a faulty signal and are therefore technically not considered eligible for replacement. So they would remain in place and transduce a non perfect signal. Maybe these dysfunctional (but not dead) stereocilia are also contributing to tinnitus. At least they would cause some distortion to the overall auditory signal, I presume.

I hope to hear back from Dan (Pipeline) on his thoughts as well. He might direct me to Heller though, we'll see.

Thanks so much for reaching out to have more insight into this question.

I'm simply wondering about this in regards to FX-322 and hearing regeneration in general. Frequency Therapeutics will consider these hair cells and stereocilia as working and not touch them I suppose. Possibly an additional problem to tackle. I do not know at all, so thanks everyone for insights and efforts.

Greetings.