Frequency Therapeutics — Hearing Loss Regeneration

[Lucifer]

Yes, it was separate. From the link:

"The exploratory study, initiated late in 2019, was conducted at the Hannover Medical Centre in Hannover, Germany. Results were based on an analysis of cochlear fluid, known as perilymph, obtained intraoperatively from patients undergoing cochlear implant surgery. Each patient received a single intratympanic injection of FX-322, enabling researchers to directly measure the level of FX-322 in perilymph, which is not otherwise feasible in inner-ear studies because accessing the cochlea involves an invasive surgical procedure.

"When we consider these new findings, together with the hearing signal observed in our earlier Phase 1/2 study, we believe we have developed the first known evidence of a pharmacokinetic/pharmacodynamic effect of a potential hearing restoration therapeutic. Through this study we have gained critical insight into the delivery properties of FX-322 and clinical confirmation that it reached the site of action in all study patients," said Carl LeBel, Ph.D., Frequency's Chief Development Officer."

"Reached the site of action in all study patients". This is great news then. Can't wait to get injected with FX-322.

 

[BBakkers]

This sounds like dosage is not increased in the 2a trial. Wasn't this planned? Seems like Hannover is a nice city. You can get Lenire and FX-322

Hannover is now even more nice. But you are from you Germany so you must know . Skipping the Lenire treatment though. Too much vague improvement reviews, people experiencing worsening and just a vague treatment in general. I say: "put that needle in too my ear" .

 

[d'Wooluf]

Didn't they already know all that because of the word score improvements in phase 1b? How did that happen if the drug didn't reach the 'site of action'?

Sounds to me that high frequency hearing loss is now the official target.

"Both agents that make up FX-322 were also predicted to achieve therapeutically active drug levels in the high frequency range of the cochlea, based on computer models."

 

[Diesel]

Can someone translate this for me from the press release today in more simple terms?

"When we consider these new findings, together with the hearing signal observed in our earlier Phase 1/2 study, we believe we have developed the first known evidence of a pharmacokinetic/pharmacodynamic effect of a potential hearing restoration therapeutic."

Are they basically just saying the drugs are doing what that are saying they are doing? Concentrating in the cochlea, and making hair cells that send signals?

 

[Daniel Lion]

Yes, it was separate. From the link:

"The exploratory study, initiated late in 2019, was conducted at the Hannover Medical Centre in Hannover, Germany. Results were based on an analysis of cochlear fluid, known as perilymph, obtained intraoperatively from patients undergoing cochlear implant surgery. Each patient received a single intratympanic injection of FX-322, enabling researchers to directly measure the level of FX-322 in perilymph, which is not otherwise feasible in inner-ear studies because accessing the cochlea involves an invasive surgical procedure.

"When we consider these new findings, together with the hearing signal observed in our earlier Phase 1/2 study, we believe we have developed the first known evidence of a pharmacokinetic/pharmacodynamic effect of a potential hearing restoration therapeutic. Through this study we have gained critical insight into the delivery properties of FX-322 and clinical confirmation that it reached the site of action in all study patients," said Carl LeBel, Ph.D., Frequency's Chief Development Officer."

That's a Eureka moment for FX. "The first known evidence."

It's a one horse race now with Audion dropping out and other companies being further being back in trials...

May the force be with FX-322.

 

[F-u-T]

Can someone translate this for me from the press release today in more simple terms?

"When we consider these new findings, together with the hearing signal observed in our earlier Phase 1/2 study, we believe we have developed the first known evidence of a pharmacokinetic/pharmacodynamic effect of a potential hearing restoration therapeutic."

Are they basically just saying the drugs are doing what that are saying they are doing? Concentrating in the cochlea, and making hair cells that send signals?

Basically. Now they have physical proof the drug is penetrating into the Cochlea.

 

[F-u-T]

The stock market is liking this news!

 

[Bartoli]

You know it when your audiogram is normal and you hear speech well in quiet BUT find it difficult to understand speech in noisy, loud environments. The theory is majority of your haircells are there, so no problem with transmitting of signal but the signal that is transmitted goes through these synapses. Before there were perhaps 100 synapses transmitting this signal, now there's only 30 synapses transmitting that signal. There is still no problem to decipher the signal in quiet of course, because the haircells are still there. However with a noisy background and a weaker signal the problem of synapse damage becomes obvious... because you can hear but you cannot understand. Just to put it in a simplistic way.

I find that I do have difficulties understanding in noisy environments. Yet my speech in noise test was okay. I have hyperacusis too and I don't know how to describe it, but when I need to listen to someone talk in a noisy environment, it's like I experience some kind of auditory ADHD (for want of a better term) and I can't focus on the conversation. It all seems to come in at once, without a filter, it gets overwhelming and I just want to run for cover. I don't know if that's auditory processing disorder, hyperacusis or synapse damage or something else...
Does someone know?

Other moderately loud noises are mostly ok, but I can't stand five minutes in a reverberant room with more than a couple of people talking. I'm not equally bothered by all sounds, frequency seems to matter too. Higher frequencies being the worst.

 

[Paulmanlike]

I know this is Frequency's thread, but why is there speculation about Audion being 'out of the game' now and spoke like this is a fact? People almost seem excited about that, but to patients, competition is excellent for pricing of the drugs and also having more chance of success? Also, Audion showed positive results and people were moaning this wasn't good enough, however that's something.

I agree Frequency's approach seems the best to us laymen but what I know from biotechs is that they are highly speculative risky investments that can go tits up, very quickly.

Anyway, I wish ALL of them success.

I also think that if they are successful, it is still yet to be proved it will have any effect on the nightmare that is tinnitus! Remember, it is first and foremost a drug for hearing loss - if it helps tinnitus it's a bonus.

 

[dan]

@FGG

Hi, not sure if you read my question.

So how does the drug know which type and location of hair cells to repopulate... how does this work?

Does it fill in dead hair cell patches or will it grow hair cells all across the spectrum?

Does it target the specific frequencies that we need to get back, or will it grow "one great bush" across the frequencies? Like say your hair cells at 8kHz are intact - will it then make more of them still?

 

[FGG]

@FGG

Hi, not sure if you read my question.

So how does the drug know which type and location of hair cells to repopulate... how does this work?

Does it fill in dead hair cell patches or will it grow hair cells all across the spectrum?

Does it target the specific frequencies that we need to get back, or will it grow "one great bush" across the frequencies? Like say your hair cells at 8kHz are intact - will it then make more of them still?

I think this will likely work like regeneration in other parts of the body (e.g. Skin, intestine). Cells signal to other cells when things get crowded (otherwise you'd get an overgrowth of tissue after every injury). Since FX-322 uses the same progenitor cell activators the intestine uses in the mucosal layer, I don't believe this will be a problem. I think it will be more akin to filling in the gaps.

 

[Lucifer]

I know this is Frequency's thread, but why is there speculation about Audion being 'out of the game' now and spoke like this is a fact? People almost seem excited about that, but to patients, competition is excellent for pricing of the drugs and also having more chance of success? Also, Audion showed positive results and people were moaning this wasn't good enough, however that's something.

I agree Frequency's approach seems the best to us laymen but what I know from biotechs is that they are highly speculative risky investments that can go tits up, very quickly.

Anyway, I wish ALL of them success.

I also think that if they are successful, it is still yet to be proved it will have any effect on the nightmare that is tinnitus! Remember, it is first and foremost a drug for hearing loss - if it helps tinnitus it's a bonus.

I still think the results that Audion Therapeutics got in Phase 2 should allow them to continue and move on to Phase 3 even though there were minimal improvements.

If it doesn't do much with hearing loss maybe it might do more at getting rid of our tinnitus.

 

[Diesel]

@FGG

Hi, not sure if you read my question.

So how does the drug know which type and location of hair cells to repopulate... how does this work?

Does it fill in dead hair cell patches or will it grow hair cells all across the spectrum?

Does it target the specific frequencies that we need to get back, or will it grow "one great bush" across the frequencies? Like say your hair cells at 8kHz are intact - will it then make more of them still?

This pretty much explains the PCA approach:


Also, their May 2020 Presentation is useful in understanding:
https://investors.frequencytx.com/events-and-presentations

 

[d'Wooluf]

why is there speculation about Audion being 'out of the game' now and spoke like this is a fact?

No idea. And I agree with you about the need for more than one horse in the race.

 

[Daniel Lion]

I know this is Frequency's thread, but why is there speculation about Audion being 'out of the game' now and spoke like this is a fact? People almost seem excited about that, but to patients, competition is excellent for pricing of the drugs and also having more chance of success? Also, Audion showed positive results and people were moaning this wasn't good enough, however that's something.

I agree Frequency's approach seems the best to us laymen but what I know from biotechs is that they are highly speculative risky investments that can go tits up, very quickly.

Anyway, I wish ALL of them success.

I also think that if they are successful, it is still yet to be proved it will have any effect on the nightmare that is tinnitus! Remember, it is first and foremost a drug for hearing loss - if it helps tinnitus it's a bonus.

Hi Paulmanlike,

Read the Audion thread's last page again.

Nobody was happy, we were gutted.

Why do people think the project is dead? Two reasons. First, it says the project has been completed on the Regain site and Audion didn't mention how they would proceed. Second, this happened a few months ago; the Dutch CEO said publicly they haven't had their Eureka moment. Lucchino from Frequency Therapeutics can be quoted from Business Wire a few days ago they have met safety, delivery efficacy and drug efficacy, 3 crucial tests. Sure sounded like a Eureka moment.

Nobody is happy about Audion (hope we are wrong about their status) and a drug for hearing loss to use your words, "first and foremost" will help lots of us and you with noise induced tinnitus, that's why the big shots at Frequency Therapeutics included tinnitus in their next testing.

Everybody here is cheering for regeneration companies, we wish there were more. Not for pricing, but just to get the regenerative ball rolling and successful on all fronts of cochlear repair, and then we can worry about pricing.

 

[Koz]

Just catching up with this thread. Two things:

Firstly - so at this stage is FX-322 only for the high frequencies of sensorineural hearing loss in its current formulation and delivery method? But their aim is to cover the full range with an improved formulation and delivery method down the line? Am I getting this correct?

It's not even that simple at all, you would have to have synaptopathy at a variety of important speech frequencies (and not above) for you to even notice that effect.

Secondly - @FGG - are you saying that @sssing is wrong with regards to his explanation of synaptic damage vs. hair cell damage? My hearing loss is moderate severe to severe across all frequencies on an audiogram (125 Hz - 8 kHz). I thought synaptic damage was basically what's called "hidden hearing loss" in that the audiogram is normal because the hair cells are there but the synapses are damaged hence they struggle in a noisy environment. Correct me if I am wrong please?

I am just keen to know whether my hearing loss is hair cell damage, synapse damage or both. I quite like @AtlasFainted's plan either way of going for a hair cell and then synapse treatment when that comes if needs be.

 

[FGG]

Just catching up with this thread. Two things:

Firstly - so at this stage is FX-322 only for the high frequencies of sensorineural hearing loss in its current formulation and delivery method? But their aim is to cover the full range with an improved formulation and delivery method down the line? Am I getting this correct?


Secondly - @FGG - are you saying that @sssing is wrong with regards to his explanation of synaptic damage vs. hair cell damage? My hearing loss is moderate severe to severe across all frequencies on an audiogram (125 Hz - 8 kHz). I thought synaptic damage was basically what's called "hidden hearing loss" in that the audiogram is normal because the hair cells are there but the synapses are damaged hence they struggle in a noisy environment. Correct me if I am wrong please?

I am just keen to know whether my hearing loss is hair cell damage, synapse damage or both. I quite like @AtlasFainted's plan either way of going for a hair cell and then synapse treatment when that comes if needs be.

No, basically if you struggle with speech in a noisy environment, you have synaptopathy. But if you don't, it doesn't mean you don't. The damaged synapses could just be confined to one area (e.g.. High frequency) and wouldn't effect speech as much.

Basically the speech in noise test is probably more specific than sensitive imo.

 

[Koz]

No, basically if you struggle with speech in a noisy environment, you have synaptopathy. But if you don't, it doesn't mean you don't. The damaged synapses could just be confined to one area (e.g.. High frequency) and wouldn't effect speech as much.

Basically the speech in noise test is probably more specific than sensitive imo.

I do struggle with speech in a noisy environment in my bad ear that's diagnosed with sensorineural hearing loss, but I also most likely have hair cell loss because the loss does actually show on the audiogram in all ranges, all of the frequencies are at moderate severe to severe (dB) levels of loss.

I don't actually know if my damage is synaptic or hair cell or both. Seeing as I have moderate severe to severe hearing loss, I would safely say hair cell loss is a definite. I don't think it makes a difference knowing now or pursuing knowing, as there is no cure for either, I will probably get to the bottom of it when these drugs (at least one of them) are out on the market after they hopefully pass clinical trials.

All I know is my MRIs have come back normal, my middle ear function has come back normal (tympanogram) and that my hearing loss is strictly sensorineural which will have been because of loud noise.

So, lastly, am I getting this bit correct - at this stage is FX-322 only for the high frequencies of sensorineural hearing loss in its current formulation and delivery method? But their aim is to cover the full range with an improved formulation and delivery method down the line?

 

[Lucifer]

I really hope my issues are due to damaged hair cells. If it's synapses I would have to wait longer to get cured.

 

[FGG]

I do struggle with speech in a noisy environment in my bad ear that's diagnosed with sensorineural hearing loss, but I also most likely have hair cell loss because the loss does actually show on the audiogram in all ranges, all of the frequencies are at moderate severe to severe (dB) levels of loss.

I don't actually know if my damage is synaptic or hair cell or both. Seeing as I have moderate severe to severe hearing loss, I would safely say hair cell loss is a definite. I don't think it makes a difference knowing now or pursuing knowing, as there is no cure for either, I will probably get to the bottom of it when these drugs (at least one of them) are out on the market after they hopefully pass clinical trials.

All I know is my MRIs have come back normal, my middle ear function has come back normal (tympanogram) and that my hearing loss is strictly sensorineural which will have been because of loud noise.

I had written that backwards btw, but I wasn't able to edit. The test is more sensitive with a positive result than specific with a negative. It sounds like you probably have mixed losses but if you also have damaged IHCs in places with synapse loss, then you can fix the synaptopathy in those places when you re-grow a new one with FX-322. If not, you would need a synapse drug.

 

[InfiniteLoop]

I really hope my issues are due to damaged hair cells. If it's synapses I would have to wait longer to get cured.

I thought that after the damaged hair cells go, the dorsal cochlear nucleus associated neurons disappear next. It takes about a month or two after initial hair cell damage. Acute tinnitus will be cured before chronic tinnitus get "solved". Unfortunately, it will not be in my lifetime.

 

[d'Wooluf]

No, basically if you struggle with speech in a noisy environment, you have synaptopathy.

I don't think you can say that unequivocally. A moderately severe to severe loss would probably be sufficient in itself for hearing difficulties in noise.

So, lastly, am I getting this bit correct - at this stage is FX-322 only for the high frequencies of sensorineural hearing loss in its current formulation and delivery method? But their aim is to cover the full range with an improved formulation and delivery method down the line?

My reading between the lines of what we're hearing from Frequency Therapeutics is that improving high frequency hearing loss is what Frequency Therapeutics are about now. Others have hinted at FX-322 Mark II. I don't know if that follows from something that has be communicated by Frequency Therapeutics. I don't remember reading anything to that effect. Maybe I missed it.

 

[Sevv]

I really hope my issues are due to damaged hair cells. If it's synapses I would have to wait longer to get cured.

In all likeliness, you have certainly some damaged hair cells. So even if it's not your main problem, alleviating that should at least reduce your tinnitus to some degree...
The lower the tinnitus, the more normal your life. Not perfectly normal, but a lot better.

 

[sssing]

I thought that after the damaged hair cells go, the dorsal cochlear nucleus associated neurons disappear next. It takes about a month or two after initial hair cell damage. Acute tinnitus will be cured before chronic tinnitus get "solved". Unfortunately, it will not be in my lifetime.

Sorry but I think the neurons(at least the spiral ganglion neurons I am sure) do not disappear soon with hair cell loss because if they do, then cochlear implants would not be able to work. Cochlear implants have worked on people who have acquired hearing loss and some for years. They depend on these neurons to establish the hearing signal. It definitely cannot be DIRECTLY sending electrical signals to the central auditory nerve because the electrode array is implanted into the cochlear so it must go through the spiral ganglion neurons. These neurons survive even when their corresponding hair cell is 'dead' because they receive blood supply from the other arteries in the cochlear, not the hair cell.

 

[xyz]

I thought that after the damaged hair cells go, the dorsal cochlear nucleus associated neurons disappear next. It takes about a month or two after initial hair cell damage. Acute tinnitus will be cured before chronic tinnitus get "solved". Unfortunately, it will not be in my lifetime.

I would guess that with the regrown hair cells also the connection to the auditory nerve is repaired somehow, since you wouldn't get hearing improvements when regrowing some "dummy hair cells" with no relevant nerve connection. However I think, currently there is just not much data what these regeneration techniques mean for tinnitus. Audion please publish your results, you have been funded with EU tax payers money!

 

[HootOwl]

I thought that after the damaged hair cells go, the dorsal cochlear nucleus associated neurons disappear next. It takes about a month or two after initial hair cell damage. Acute tinnitus will be cured before chronic tinnitus get "solved". Unfortunately, it will not be in my lifetime.

Spiral ganglion neurons have been established to persist in high quantities even in people who have been deaf or have severe hearing loss for many many years (sometimes their whole lives). @FGG posted the case studies some time back in this thread.

Spiral ganglion loss will only be a problem if there's an underlying genetic component that contributes to their degradation overtime, but I believe Rinri is working on this kind of neuropathy problem.

I'm not aware of any SGNs in the dorsal cochlear nucleus, only the fusiform cells which are a separate entity entirely.

Edit: I've noticed some papers will refer to the afferent nerve fibers as SGNs. I don't know why they do this... it's obvious they're talking about the fibers themselves and not the cell bodies which only adds needless confusion imo. Nerve fibers can degrade extremely rapidly but we will have synaptopathy drugs for that.

 

[FGG]

I don't think you can say that unequivocally. A moderately severe to severe loss would probably be sufficient in itself for hearing difficulties in noise.

My reading between the lines of what we're hearing from Frequency Therapeutics is that improving high frequency hearing loss is what Frequency Therapeutics are about now. Others have hinted at FX-322 Mark II. I don't know if that follows from something that has be communicated by Frequency Therapeutics. I don't remember reading anything to that effect. Maybe I missed it.

At moderately severe to severe, most people have lost some IHCs, so you have effectively lost that synapse and yes they do have speech in noise issues. FX-322 could help that situation but not a true isolated synaptopathy.

And obviously if you have severe enough hearing loss in the right frequencies, you have speech difficulties period, not just in noise.

 

[serendipity1996]

I thought that after the damaged hair cells go, the dorsal cochlear nucleus associated neurons disappear next. It takes about a month or two after initial hair cell damage. Acute tinnitus will be cured before chronic tinnitus get "solved". Unfortunately, it will not be in my lifetime.

I think a lot of the evidence factually points to longevity of the nerves sometimes even decades after hair cell loss. I don't have the paper on me right now but I'll look it up.

Edit: just saw HootOwl's post - she knows more about it than I do!

 

[FGG]

I think a lot of the evidence factually points to longevity of the nerves sometimes even decades after hair cell loss. I don't have the paper on me right now but I'll look it up.

Edit: just saw HootOwl's post - she knows more about it than I do!

Exactly, the original studies were based on rodents but humans have very different SGNs it turns out.

 

[sssing]

I find that I do have difficulties understanding in noisy environments. Yet my speech in noise test was okay. I have hyperacusis too and I don't know how to describe it, but when I need to listen to someone talk in a noisy environment, it's like I experience some kind of auditory ADHD (for want of a better term) and I can't focus on the conversation. It all seems to come in at once, without a filter, it gets overwhelming and I just want to run for cover. I don't know if that's auditory processing disorder, hyperacusis or synapse damage or something else...
Does someone know?

Other moderately loud noises are mostly ok, but I can't stand five minutes in a reverberant room with more than a couple of people talking. I'm not equally bothered by all sounds, frequency seems to matter too. Higher frequencies being the worst.

Hi, I am sorry but it's likely from what you shared about your symptoms (difficulty understanding speech in noisy environments and some decrease sound tolerance) that there is some damage even though your SIN test was ok. Loss of clarity could lead to speech to seem like it comes in at once? From what I read it could be due to outer hair cell loss, because it is the outer hair cells that helps us to distinguish between similar frequencies. So FX-322 will be able to help you.