Frequency Therapeutics — Hearing Loss Regeneration

[brokensoul]

Did anyone of you ever do a DPOAE test?

https://en.wikipedia.org/wiki/Otoacoustic_emission

"Studies have found that exposure to noise can cause a decline in OAE responses. OAEs are a measurement of the activity of outer hair cells in the cochlea, and noise-induced hearing loss occurs as a result of damage to the outer hair cells in the cochlea. Therefore the damage or loss of some outer hair cells will likely show up on OAEs before showing up on the audiogram. Studies have shown that for some individuals with normal hearing that have been exposed to excessive sound levels, fewer, reduced, or no OAEs can be present. This could be an indication of noise-induced hearing loss before it is seen on an audiogram."

My audiologist claimed I had no hair cell damage after that test.

My audiogram looks reasonable as well and is in line with what is expected for someone my age according to all the ENTs I consulted. I only have a 25 dB notch at 8 kHz on the left side and 20 dB on the right side. It's possible my high frequency tinnitus is at that frequency, but I'm not really sure.

I'm not sure at all if FX-322 will do anything for me.

So, I'm left wondering if I have tinnitus due to cochlear synaptopathy or if I simply have some form of brain damage (referring to Dr. Rauschecker; malfunctioning filter, TRN in the thalamus), but he stated that it is very rare in his opinion to have tinnitus without some form of hearing damage. Hope he is right.

 

[patorjk]

So how do you interpret that? They also said they saw "trends" in those measures with both mild and moderate to moderately severe groups.

Since they also said neither they nor the FDA was concerned with any side effects, trends surely means positive trends, right?

At first I agreed with Chriscom, but going back and re-listening a few times, I think I've changed my mind. Here's what I think is being said (I'm having trouble making out the actual question):

Q: And just a follow up on that, do you see benefit on those secondary end points on the mild hearing loss category?
A: We saw trends across the population.

That answer actually makes it sound like in the Phase I study they saw trends for those secondary end-points across the population, which is why they're now testing for them. It could be a mis-intrepretation, but it is interesting.

 

[FGG]

Another thing I'm thinking is that Frequency Therapeutics is working on hair cell regeneration and this is only one element of the hearing regeneration puzzle. Even if they can solve the delivery challenge, and I think they will since other companies can already do it, we are still left wondering about synapse regeneration and auditory nerve repair.

Are we assuming downstream reparation after hair cell regeneration? I know Stanford said the nerve 'magically' reconnects so that's great, presuming the nerve is still functional enough to do so (there could be an issue perhaps). Are we also assuming or hoping that the synapses will regrow as well? Has Frequency Therapeutics stated anything in that regard?

We also have PIPE working on synapse regeneration, in case not all required synapses regrow, but this is a different company. So I suspect that after FX-322 we may still have to wait for PIPE to come through with a working solution to fix the complete auditory system (excluding the brain) and find some synergy between both solutions.

It's a pity we don't have a large concern working on all the elements of the puzzle.

Even if FX-322 works well they are going to move on to other diseases. I understand though, their company is PCA technology and they will expand that into all possible treatments and synapse regeneration is not done through PCA.

Anyhow, first thing first, let's see if their already promising results improve in their second trial, otherwise we're probably still in it for the long haul.

Frequency has said that their newly created hair cells will form normal synapses. So at least where hair death occurs, synatopathy should improve. However, many people have synaptic damage without hair cell death and would clearly benefit more from PIPE-505, Hough pill, and intratympanic BDNF (OTO-413).

I suspect, though, that since everyone past childhood has some age related hair cell death (worse towards base of cochlea usually), that there will be *some* improvement with his drug (may be slight, but an improvement non the less, I am not sure) even in cases thought to be primarily synaptopathy cases because there will be more hairs (percentage wise) with normal synaptic connections after the age-related lost hairs are restored.

 

[FGG]

At first I agreed with Chriscom, but going back and re-listening a few times, I think I've changed my mind. Here's what I think is being said (I'm having trouble making out the actual question):

Q: And just a follow up on that, do you see benefit on those secondary end points on the mild hearing loss category?
A: We saw trends across the population.

That answer actually makes it sound like in the Phase I study they saw trends for those secondary end-points across the population, which is why they're now testing for them. It could be a mis-intrepretation, but it is interesting.

This is my take and it definitely seems like a really vague but subtle hint that they *have* seen evidence of tinnitus improvement in phase 1.

 

[brokensoul]

We don't know what their audiograms looked like. It's possible only 4 people had damage there.

It's also probable imo that since it was a smaller dose used for phase 1, it just didn't travel very far distal to the round window and it "barely" made it to 8000 Hz in a few individuals. There are small individual differences in middle ear size and in round window diffusion, too.

I think the "space" theory would be more likely if they had seen improvements at 6000 Hz for some and 8000 Hz for others etc...

You're right, we don't even know if it got as far as 8kHz for everyone. This probably makes the most sense.

Can't help thinking though it remains strange they didn't go for extended audiograms. It was a safety study, but they did test efficacy.

It's possible indeed they wanted a history of audiogram tests to show the hearing loss was stable and since 8kHz audiograms are still the standard, that's how they proceeded, knowing it was not ideal for the efficacy test, but good enough for safety?

Then again wouldn't you need to test the full spectrum to validate safety from the point of view of potential ototoxicity. It's like saying some cancer therapy drug is not ototoxic, but only testing up to 8kHz.

Anyhow, it'll remain a mystery I guess.

 

[brokensoul]

Q: And just a follow up on that, do you see benefit on those secondary end points on the mild hearing loss category?
A: We saw trends across the population.

That answer actually makes it sound like in the Phase I study they saw trends for those secondary end-points across the population, which is why they're now testing for them. It could be a mis-intrepretation, but it is interesting.

Dear God, let it be true for all of us!

I'll make some time to listen to it tomorrow.

 

[MRItechssuck]

Great work everyone, thank you for digesting this for us. I couldn't focus enough to listen all the way through.

Thanks.

 

[brokensoul]

However, many people have synaptic damage without hair cell death and would clearly benefit more from PIPE-505, Hough pill, and intratympanic BDNF (OTO-413).

I suspect this as well, from what I've read so far. It's been stated that the synapses are actually more fragile than the hair cells, isn't it? I've seen a scientist state that cochlear synaptopathy is the more likely cause of tinnitus. Nobody is sure though.

What I'm really afraid of though is that there is something additional ongoing in the brain itself (thalamus). I'm hoping though this is due to maladaptive neuroplasticity somehow affecting the inhibitory functionality of the thalamus and that it will be reversed after restoring hearing.

 

[ChrisBoyMonkey]

So how do you interpret that? They also said they saw "trends" in those measures with both mild and moderate to moderately severe groups.

Since they also said neither they nor the FDA was concerned with any side effects, trends surely means positive trends, right?

My first, most logical thought of a "trend" that can't be a negative is that tinnitus would improve when the specific frequency's hair cells are regenerated.

Just one possibility, but it's the first one that comes to my mind given the fact it can't be a bad trend.

 

[FGG]

I suspect this as well, from what I've read so far. It's been stated that the synapses are actually more fragile than the hair cells, isn't it? I've seen a scientist state that cochlear synaptopathy is the more likely cause of tinnitus. Nobody is sure though.

What I'm really afraid of though is that there is something additional ongoing in the brain itself (thalamus). I'm hoping though this is due to maladaptive neuroplasticity somehow affecting the inhibitory functionality of the thalamus and that it will be reversed after restoring hearing.

I think it's like phantom limb, which also involved the thalamus:

https://www.ncbi.nlm.nih.gov/pubmed/9450753/

But with phantom limb, there is evidence that neuroplasticity that is initially maladaptive, can readapt when given more normal stimuli (e.g.. as with mirror therapy for phantom limb).

 

[ChrisBoyMonkey]

Did anyone of you ever do a DPOAE test?

https://en.wikipedia.org/wiki/Otoacoustic_emission

"Studies have found that exposure to noise can cause a decline in OAE responses. OAEs are a measurement of the activity of outer hair cells in the cochlea, and noise-induced hearing loss occurs as a result of damage to the outer hair cells in the cochlea. Therefore the damage or loss of some outer hair cells will likely show up on OAEs before showing up on the audiogram. Studies have shown that for some individuals with normal hearing that have been exposed to excessive sound levels, fewer, reduced, or no OAEs can be present. This could be an indication of noise-induced hearing loss before it is seen on an audiogram."

My audiologist claimed I had no hair cell damage after that test.

My audiogram looks reasonable as well and is in line with what is expected for someone my age according to all the ENTs I consulted. I only have a 25 dB notch at 8 kHz on the left side and 20 dB on the right side. It's possible my high frequency tinnitus is at that frequency, but I'm not really sure.

I'm not sure at all if FX-322 will do anything for me.

So, I'm left wondering if I have tinnitus due to cochlear synaptopathy or if I simply have some form of brain damage (referring to Dr. Rauschecker; malfunctioning filter, TRN in the thalamus), but he stated that it is very rare in his opinion to have tinnitus without some form of hearing damage. Hope he is right.

Most audiograms don't cover high frequencies that most of our tinnitus probably is in.

 

[brokensoul]

Most audiograms don't cover high frequencies that most of our tinnitus probably is in.

I've done an extended audiogram up to 16kHz. My thresholds are actually lower above 8kHz, than below 8kHz. So my hearing above 8kHz is actually better than below 8kHz according to the audiogram. Which was a huge surprise to me, since the hair cells near the base are the first to die off. Everything however looks good up to 15kHz and then I have a slope downwards until 16kHz, which is perfectly normal for my age. According to my audiologist it cannot be objectified that I have hearing damage aside from some small notch at 8kHz.

I can assure you though that I have tinnitus with multiple sounds and my high frequency sound is very intrusive and only somewhat maskable at 75dB.

Everybody here should do an extended audiogram and DPOAE test.

 

[Lucifer]

If FX-322 does regrow new hair cells and synapses shouldn't this help with the majority of us who have tinnitus or hyperacusis?

 

[Pink Noise]

Those slides bring so much hope to me... even if tinnitus is just marginally mentioned.

As I'm a sound engineer restoring those high frequencies is worth it even if the tinnitus doesn't go away. Hearing more sound will help mask the tinnitus just like a hearing aid.

 

[FGG]

If FX-322 does regrow new hair cells and synapses shouldn't this help with the majority of us who have tinnitus or hyperacusis?

It only regrows the synapses associated with the new hair cells. It's not a "synaptopathy" treatment per se if you had hypothetically zero damage to hair cells.

 

[john paul]

Did anyone of you ever do a DPOAE test?

https://en.wikipedia.org/wiki/Otoacoustic_emission

"Studies have found that exposure to noise can cause a decline in OAE responses. OAEs are a measurement of the activity of outer hair cells in the cochlea, and noise-induced hearing loss occurs as a result of damage to the outer hair cells in the cochlea. Therefore the damage or loss of some outer hair cells will likely show up on OAEs before showing up on the audiogram. Studies have shown that for some individuals with normal hearing that have been exposed to excessive sound levels, fewer, reduced, or no OAEs can be present. This could be an indication of noise-induced hearing loss before it is seen on an audiogram."

My audiologist claimed I had no hair cell damage after that test.

My audiogram looks reasonable as well and is in line with what is expected for someone my age according to all the ENTs I consulted. I only have a 25 dB notch at 8 kHz on the left side and 20 dB on the right side. It's possible my high frequency tinnitus is at that frequency, but I'm not really sure.

I'm not sure at all if FX-322 will do anything for me.

So, I'm left wondering if I have tinnitus due to cochlear synaptopathy or if I simply have some form of brain damage (referring to Dr. Rauschecker; malfunctioning filter, TRN in the thalamus), but he stated that it is very rare in his opinion to have tinnitus without some form of hearing damage. Hope he is right.

Chances are after 8 kHz your audiogram starts to drop off a cliff.

 

[john paul]

If FX-322 does regrow new hair cells and synapses shouldn't this help with the majority of us who have tinnitus or hyperacusis?

This is a multi billion dollar question that nobody knows or is allowed to say right now.

Theory suggests it will but there are bound to be complications. The fact that the high frequencies are the easiest to treat and are no doubt the cause of most people's suffering is a good thing though and we should only be positive.

 

[Lucifer]

If Audion Therapeutics were to release their drug first before Frequency Therapeutics, which one would you take?

 

[FGG]

If Audion Therapeutics were to release their drug first before Frequency Therapeutics, which one would you take?

Frequency, without question. Audion depletes support cells for one and Frequency doesn't.

This paper also scared me about Audion:
https://www.frontiersin.org/articles/10.3389/fncel.2018.00073/full#F1

I believe the second compound they tested in this is Audion's gamma secretase inhibitor.

Reading that made me nervous enough to email Pipeline this study to ask if their drug (also a gamma secretase inhibitor like Audion but theirs effects Notch a bit differently) would do the same. Pipeline said their regenerated hair cells and synapses looked proper and were oriented correctly. Sigh of relief.

It did make me wonder if that's what Audion meant by not having a "Eureka moment" and Frequency even said they felt their drug was better than their competitor (didn't name Audion but I felt it was implied) who depleted support cells.

I think in addition to not depleting hair cells, Frequency has a clear advantage in not trying to modify an already well defined support cell.

Just my opinion, but we will know a lot more soon as I think Audion's phase 2 ends much sooner than Frequency.

 

[Lucifer]

Frequency, without question. Audion depletes support cells for one and Frequency doesn't.

This paper also scared me about Audion:
https://www.frontiersin.org/articles/10.3389/fncel.2018.00073/full#F1

I believe the second compound they tested in this is Audion's gamma secretase inhibitor.

Reading that made me nervous enough to email Pipeline this study to ask if their drug (also a gamma secretase inhibitor like Audion but theirs effects Notch a bit differently) would do the same. Pipeline said their regenerated hair cells and synapses looked proper and were oriented correctly. Sigh of relief.

It did make me wonder if that's what Audion meant by not having a "Eureka moment" and Frequency even said they felt their drug was better than their competitor (didn't name Audion but I felt it was implied) who depleted support cells.

I think in addition to not depleting hair cells, Frequency has a clear advantage in not trying to modify an already well defined support cell.

Just my opinion, but we will know a lot more soon as I think Audion's phase 2 ends much sooner than Frequency.

Results for Audion Therapeutics will come out end of April.

Frequency Therapeutics results will come out end of September.

 

[d'Wooluf]

Way too early to tell. I'm hoping they both get there. Competition means there's some limit as to how much they can gouge for treatment. Frequency have been touting their solution and putting down the alternative since day one. That's how David Lucchino comes across to me. A car salesman. In the end, the Toyota he's been trying to sell me might be the best deal, but he's still pissing me off. Anyway, my money - if I had any - would be on Frequency, but go Audion!

Frequency even said they felt their drug was better than their competitor (didn't name Audion but I felt it was implied)

Case in point.

I think Audion's phase 2 ends much sooner than Frequency.

I think it officially ended. Now it's just making up the pretty graphs.

 

[FGG]

Results for Audion Therapeutics will come out end of April.

Frequency Therapeutics results will come out end of September.

The estimated complete date for the FX-322 clinical study is Sept 30th but they still have to "put together the pretty graphs", too. They have said by the end of 2020, though.

 

[patorjk]

If Audion Therapeutics were to release their drug first before Frequency Therapeutics, which one would you take?

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).

 

[Lucifer]

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).

I'm wondering the same as well. Audion seems to be ahead but people are focusing more on FX-322.

With the competition between these companies hopefully the prices will not be that high but I have a feeling it will be at least $10K for treatment.

 

[davidmp]

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).

Their trial is still ongoing:

https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-004544-10/GR

 

[brokensoul]

Just listened to the webcast presentation and Q&A session.

Everyone, listen to it, it's well worth your time.

Some initial remarks:

They seem to focus now on restoring hearing only in the higher frequencies. 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). Setting low targets they're sure they can meet or do they have doubts?

I'm wondering about the question about expecting better results after multidosing? The person who asked the question referred to their tests with restoring hearing in mice. Haven't they fully restored the cochlea of mice yet by using high doses? Their answer was vague. Shouldn't they already know that multidosing or a high dosage already creates additional improvement, even fully restores the cochlea in mice? Why the vague answer "we'll have to see after the second trial". I mean there's no reason they wouldn't know, right?

It's great they even mention tinnitus. We should all be very happy about that. The Q&A question about secondary targets is quite the teaser indeed, but vague at the same time as well. We don't know if they meant they saw trends in regards to tinnitus, it's just a generic sales type of answer for all secondary targets. We can't draw any conclusion whatsoever on that slick answer, aside from sounding positive.

I'm excited about Frequency Therapeutics, they are doing revolutionary work in regenerative medicine.

I can see hearing regeneration becoming a reality in the next 20 years, but hopefully for all of us, in this decade already.

PS: part of my previous questions were sort of answered during this webcast:
- stable hearing loss history was indeed the answer,
- they also answered they expect improvements downstream in terms of synapses,
- why only 4 people saw improvements was explained by stating they all saw improvements, but only 4 were statistically significant!!).

 

[brokensoul]

One of the issues with hair cell regeneration remains, in my opinion, is that we need to have a solution to deal with dysfunctional hair cells. By which I mean hair cells that remain present, but have lost their stereocilia for 90% for example or where the stereocilia are tangled up instead of nicely aligned. They are still in place taking up space. FX-322 will do nothing for these half working half broken hair cells, if I understand correctly. They need be completely dead and removed from the cochlea. Maybe we'll need some broken hair cell clean up drug, before we start regenerating hair cells, if we want to attain a perfectly restored cochlea?

What is your opinion on this?

Broken hair cells could be (partially) responsible for tinnitus as well maybe. At least, they must certainly have an effect on hearing ability. I wonder why nobody talks about that. A hair cell function is not binary; dead or perfect, we have all possible layers between that as well. Look at some of the scans they do of inside the cochlea. Some hair cells (stereocilia in fact) are active, but look very messed up.

It's one of the questions I would ask Frequency Therapeutics.

 

[all to gain]

I can see hearing regeneration becoming a reality in the next 20 years, but hopefully for all of us, in this decade already.

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

 

[FGG]

One of the issues with hair cell regeneration remains, in my opinion, is that we need to have a solution to deal with dysfunctional hair cells. By which I mean hair cells that remain present, but have lost their stereocilia for 90% for example or where the stereocilia are tangled up instead of nicely aligned. They are still in place taking up space. FX-322 will do nothing for these half working half broken hair cells, if I understand correctly. They need be completely dead and removed from the cochlea. Maybe we'll need some broken hair cell clean up drug, before we start regenerating hair cells, if we want to attain a perfectly restored cochlea?

What is your opinion on this?

Broken hair cells could be (partially) responsible for tinnitus as well maybe. At least, they must certainly have an effect on hearing ability. I wonder why nobody talks about that. A hair cell function is not binary; dead or perfect, we have all possible layers between that as well. Look at some of the scans they do of inside the cochlea. Some hair cells (stereocilia in fact) are active, but look very messed up.

It's one of the questions I would ask Frequency Therapeutics.

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).

 

[FGG]

Just listened to the webcast presentation and Q&A session.

Everyone, listen to it, it's well worth your time.

Some initial remarks:

They seem to focus now on restoring hearing only in the higher frequencies. 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). Setting low targets they're sure they can meet or do they have doubts?

I'm wondering about the question about expecting better results after multidosing? The person who asked the question referred to their tests with restoring hearing in mice. Haven't they fully restored the cochlea of mice yet by using high doses? Their answer was vague. Shouldn't they already know that multidosing or a high dosage already creates additional improvement, even fully restores the cochlea in mice? Why the vague answer "we'll have to see after the second trial". I mean there's no reason they wouldn't know, right?

It's great they even mention tinnitus. We should all be very happy about that. The Q&A question about secondary targets is quite the teaser indeed, but vague at the same time as well. We don't know if they meant they saw trends in regards to tinnitus, it's just a generic sales type of answer for all secondary targets. We can't draw any conclusion whatsoever on that slick answer, aside from sounding positive.

I'm excited about Frequency Therapeutics, they are doing revolutionary work in regenerative medicine.

I can see hearing regeneration becoming a reality in the next 20 years, but hopefully for all of us, in this decade already.

PS: part of my previous questions were sort of answered during this webcast:
- stable hearing loss history was indeed the answer,
- they also answered they expect improvements downstream in terms of synapses,
- why only 4 people saw improvements was explained by stating they all saw improvements, but only 4 were statistically significant!!).

They actually explained that mice ear drums don't allow for multi dosing so it's never been tested until now but they believe it will improve results. I think that was less evasive and more just trying to be as factual as possible.