Frequency Therapeutics — Hearing Loss Regeneration

[Thuan]

View attachment 40958

As you can see, an ABR was tested to measure hearing recovery on the auditory brainstem. The hair cells HAVE to be connected or else they wouldn't have achieved these results. The study you keep referring to was done independent from frequencies preclinical data by the way, as I've stated before.

You can view the preclinical data here:

https://www.sec.gov/Archives/edgar/data/1703647/000156459020012977/freq-10k_20191231.htm

Also I don't know if you read my explanation on the human clinical results, but here you go:

Now I don't know exactly what you're arguing here. Are you saying Frequency Therapeutics is lying to all their investors, the SEC, and the FDA about the preclinical data they did? Would be very illegal.

I'm not saying that they're lying. Have you even read my logic? I'm saying that their conclusion is based on the assumption that new hair cells directly relate to restored hearing. Conclusions are subjective. Why? Because they haven't tested if the new hair cells are all functionally correct. They are not lying in that new hair cells are being regrown. They are marketing NEW HAIR CELLS. And the assumption is that new hair cells equal restored hearing. However, that assumption may be flawed if the new hair cells are not functional.

Those slides are not evidence at all. The clinical trials are being conducted for phase 2, which we still have no conclusive evidence. Phase 1 is evidence that there is some, minor improvements, which is not definitively conclusive that all new hair cells are functional. In fact, it's the opposite.

 

[Thuan]

Do you have evidence that a portion of the regrown hair cells aren't functional or is your debate based on the fact that they didn't provide the specific details of what you're talking about?

Right now everything you've said is speculation and there's more evidence towards the hair cells being functional rather than not.

Some people returned to baseline in the most recent study but just remember it was only a single low dose in one ear. It was more to test safety then actual efficacy but they did have some clinically significant data come out of phase 1/2a anyway.
There's many variables that could have affected peoples results and we don't know if these people who did the trials had any acoustic trauma or taken ototoxic drugs since that could have changed things.

That single dose of FX-322 could have literally only regrown one hair cell and it was functional but obviously the patient wouldn't be able to tell the difference as it was on such a small scale. With phase 2 and 3 they obviously know it's safe so they can crank it up to high doses and see what they can really achieve.

Phase 2 will answer everyone's questions with larger doses over 4 weeks.

I don't have evidence. Hence it's my hypothesis for a possible explanation for their phase 1 results. In my opinion, it's a valid and logical hypothesis. You can disregard this if you don't want to discuss all possibilities. And the reason I brought this up is because I have not seen anywhere in their published, scientific, pre-clinical animal studies (not the slides) to disprove my hypothesis.

We know they have proven that, indeed, new hair cells are able to regenerate. But they did not prove if these new hair cells are neurologically active. To prove this, you either need to microscopically look at the neural connection (which they did not show in their animal study) or test their before/after brain activity (which they definitely did NOT do). Unlike FX, Hough's study did do brain activity scan on their research study to back up their claims.

And more importantly, I think everyone is jumping the gun on hypothesizing on concentration issue when the bigger issue is if these new hair cells are all, or mostly all, functional. It'll be moot if most of it is not.

 

[Thuan]

I'm seriously not trying to offend you but I disagree again.

I completely understand the internal logic you used to get to this argument, but I can say that it would be extremely illogical for a biotech (founded with the guidance of extremely experienced researchers and also including the same experienced people in their development time) to not include the most basic histologic testing before starting human clinical trials.

To do so would mean lighting a match to many millions of dollars and to put it bluntly Frequency Therapeutics just ain't that dumb.

To put this drug forward, they would have to have seen not only hair cells regenerated but also that neuro connections would have been made on histology. It's not expensive and it is the very most basic step.

The idea that any significant amount of hair cells are not synapsing and are "dead in space" is something that they would have seen on this histology before trials.

Of all the things to worry about going wrong, this is not one of them because it would imply a level of carelessness professionals of this level would not have done.

And to use your microphone example, yes you need full connectivity for sound but if FX-322 repairs hair cells and they are getting word score increases, it means the "part of the microphone" the drug addresses is being addressed. Just because it can't also fix separate jack compatibility issues (to stick with the analogy), doesn't mean it doesn't work.

And, yes, if your problem is just synapse and not hair cell, you will need a synapse drug.

I disagree with you on that basis. If there's no evidence shown (in a properly documented scientific paper), I'm not fully convinced. NO assumptions should be made. If I were an investor, then I'm not willing to put thousands of dollars into a company when I have these doubts, which they can easily show but did not (yet). I'm skeptical and the devil's advocate. You might think this is a non-issue, but I do not think so.

And honestly, I do hope I am wrong. However, I'm putting this possibility out there when there's so many repetitive guesses on dosing and etc when I think this is the bigger issue out there. They already have confirmed therapeutic concentration can reach the cochlea so I think it's moot to speculate on whether we're receiving enough. The fact that the severe hearing group have some minor improvement shows it did reach the cochlea. Whether it is is concentration problem or not is a different factor, which may be true or it is something else entirely.

 

[wwtsai]

I'd like to add... and then I'll go away for a while...

Frequency Therapeutics does not claim anywhere that the hair cells being produced are actually new cells. They claim that their progenitor cell activation method takes place, and an OHC and/or IHC is created. They do claim that the cells appear to be durable over a period of a few years.

Nowhere does the firm make promissory claims to restore hearing like new. They promise a "disease modifying effect" , which in the case of hearing loss, should be interpreted as reversing damage/wear done to the cells.

This may indeed mean that the OHC/IHC that we end up getting aren't literally "as good as new" like the ones we got in utero. But, the treatment seems to restore hearing, and modify our "disease" course relative to no treatment at all.

As I have said before, expectations need to be set about FX-322. It is NOT a cure... it is a first-of-its kind treatment.

See you all next week.

Reading the Research News threads the last few days has been kind of depressing. It seems like everyone's combing through all of the information we have trying to find answers that we obviously don't have yet and/or trying to prove that this dead right from the get-go.

You can look at all the current information from a million different angles but honestly we won't be getting anything new until the next announcement or when Phase 2a results are released. It's hard to see so much positivity come out when we get information/milestones only to steadily decline into skepticism for no reason. I'll probably be staying away until Frequency Therapeutics actually releases more information.

 

[Zugzug]

That is one of my fears. The second is that we should identify all possibilities. I think the data from clinical phase 1 fits more in line with this possibility than not. The fact that there is a majority of people not improving, or statistically improving, or even if there is improvements, it is minor (just look at the audiogram metrics they posted) improvement for severe hearing loss patients. There must be an explanation why we don't see significant improvements. It could be a concentration issue or it could be an entirely different scenario.

What you brought up is a thought-provoking question. However, I do think your paranoia is a little too high. The fact that there was evidence in vitro (safe assumption), clear improvements in phase 1/2, total restoration of mice hearing in vivo, tell us that certainly these hair cells aren't regrowing and just shooting synaptic attempts all over the place. I do think it's fair to assume that the new hair cells could be different than normal hair cells that we are born with.

As a lay person following this with severe brain fog, my belief is that any lack of results are mostly due to delivery and dosage, with your theory probably accounting for a small percentage of it -- small enough to still trust the company and see this as breakthrough therapy. The phase 2a results will be very interesting.

 

[Thuan]

Let's take the worst case scenario, which is that not all new hair cells properly synapse with spiral ganglion neurons. Obviously, the in vitro findings and the stage 1/2 results are more than enough to conclude that these hair cells are at least improving function. The medicine is still revolutionary. Look at what we have so far. We have an ENT telling us to see a psychologist.

Moreover, they are up front about the fact that the delivery method needs improvements. It stands to reason that if they improve the delivery, but never improve synapsing, the results will still be revolutionary.

Is your fear that we take the drug prematurely, obtain useless healthy hair cells, only to find that in a few years, better synapsing (such as OTO-413) capabilities don't work because the body is fooled into thinking everything is okay?

Also, if you think about this logically, if you wasted all your space on faulty new hair cells, then you're permanently screwed. Carl LeBel says there is no overpopulation issue, which means at some point when you reach a population saturation, hair cells will no longer regenerate, either because of a) there's hard limit where its physically not enough space t0 expand more hair cells or b) there's a soft limit where new hair cells will not proliferate because it's too crowded.

The other option, if you did saturate your ears with faulty hair cells, is to perform self acoustic shock to kill your faulty hair cells, which will also kill your healthy ones. I'm sure this is a completely crap scenario.

But hey, if phase 2 shows good results but not promising results because it's similar to phase 1, and you want to jump in early, keep this in mind.

 

[Lucifer]

They have said the new hair cells do reform synapses with the neurons. The drug just doesn't create synapses if the hair cells are intact.

Say your hair cells are still there but they are damaged, would it still regrow synapses or would the hair cells have to be completely gone in those areas for synapses to regrow?

 

[tommyd87]

I'm seriously not trying to offend you but I disagree again.

I completely understand the internal logic you used to get to this argument, but I can say that it would be extremely illogical for a biotech (founded with the guidance of extremely experienced researchers and also including the same experienced people in their development time) to not include the most basic histologic testing before starting human clinical trials.

To do so would mean lighting a match to many millions of dollars and to put it bluntly Frequency Therapeutics just ain't that dumb.

To put this drug forward, they would have to have seen not only hair cells regenerated but also that neuro connections would have been made on histology. It's not expensive and it is the very most basic step.

The idea that any significant amount of hair cells are not synapsing and are "dead in space" is something that they would have seen on this histology before trials.

Of all the things to worry about going wrong, this is not one of them because it would imply a level of carelessness professionals of this level would not have done.

And to use your microphone example, yes you need full connectivity for sound but if FX-322 repairs hair cells and they are getting word score increases, it means the "part of the microphone" the drug addresses is being addressed. Just because it can't also fix separate jack compatibility issues (to stick with the analogy), doesn't mean it doesn't work.

And, yes, if your problem is just synapse and not hair cell, you will need a synapse drug.

There tends to be no way that some of the largest investment bodies in America would invest in something shady or something which wasn't looking like it is going to be effective. Essentially they took the decision to invest on the basis that there would be positive outcomes from FX-322 because this then means that they can yield a financial benefit/return.

I also agree about the microphone analogy becoming redundant because FX-322 is not about completely connecting things up again as a few assume it was. We know that FX-322 is a hair cell regrowth medicine and it regrows hair cells. Currently it does not appear to deal with synapse regrowth. Therefore if you need synapse regrowth then you will additionally need a synapse treatment. There haven't been any statements made by Frequency Therapeutics claiming that they treat things other than hair cells.

Consequently if FX-322 grows hair cells and can regrow them well then FX-322 is fulfilling its purpose.

I'm pretty positive that there are many people who actually agree at the moment that they will need both a synapse and a hair cell medicine to resolve their issues.

 

[Killer]

I'm not saying that they're lying. Have you even read my logic? I'm saying that their conclusion is based on the assumption that new hair cells directly relate to restored hearing. Conclusions are subjective. Why? Because they haven't tested if the new hair cells are all functionally correct. They are not lying in that new hair cells are being regrown. They are marketing NEW HAIR CELLS. And the assumption is that new hair cells equal restored hearing. However, that assumption may be flawed if the new hair cells are not functional.

Those slides are not evidence at all. The clinical trials are being conducted for phase 2, which we still have no conclusive evidence. Phase 1 is evidence that there is some, minor improvements, which is not definitively conclusive that all new hair cells are functional. In fact, it's the opposite.

Those aren't just "marketing slides", it's the actual preclinical data submitted to the FDA so that they may proceed to human clinical trials. That's clear evidence that the hair cells are connected to the auditory nerve, tested using an ABR. These conclusions, unlike yours, are based on factual data that was submitted to the FDA. If they were fabricated, you better start a lawsuit because that's illegal.

By the way, if you want to learn on how the hair cells make these connections to the auditory nerve, read the respond from Dr. McLean below. By the way, Will McLean studied inner ear biology and regeneration for over a decade, and has published and co-authored tons of papers regarding this specific field:

I have been in contact with Dr. McLean two weeks ago. He is the co-founder and vice president of Frequency Therapeutics. He seemed pretty confident about the work they're doing. I won't quote him here word for word, I will just give you the gist of it.

• Regenerating hair cells may be helpful in patients suffering from tinnitus accompanied by hearing loss.

• Tinnitus accompanied by hearing loss may be the result of the brain filling in input for a signal that is lost (eg. missing hair cells and/or neurons in a certain cochlear region).

• Research has found that providing more input can dampen tinnitus.

• They are still on track for the clinical trial start date mentioned in the articles.

• The progenitor cells are a subset of supporting cells that express a gene called Lgr5.

• The hair cells they make in a dish show that they have all the characteristics to function properly. They have long bundles, function electrically, and make the synapse components to connect to hair cells.

• They can make and restore both inner and outer hair cells.

• In development it is the hair cells and supporting cells that release the proteins to attract neurons (NT3, BDNF). Their research shows that regenerated hair cells make the synapse components to communicate with neurons, even if neurons are not present.

• They suspect that there will be several approaches that may be tailored to the cause of a person's hearing loss.

• Their work suggests that starting the regeneration process allows supporting cells and hair cells to restart the synapse formation process. If a person has all of their hair cells, this may not be the best option.

• Their analysis of donated cochleas from patients suggest that hair cells are the primary drivers of hearing loss.

• They are actively exploring the direct role of drugs on neurons.

• They acknowledge that there isn't yet a good system to diagnose "synapse only" conditions in the clinic.

Also, you come to the conclusion that the Phase 1 data is a minor improvement in hearing ability, and that no assumptions can be made on whether the hair cells created by FX-322 are functional. So please explain the following in clear terms:

The data provided by Frequency Therapeutics' phase 1 trial showed clinically meaningful results in word score recognition, which CANNOT be attributed to a placebo affect. You assumption is that random hair cells were made, but not connected to the auditory nerve, therefore non functional. How would there be ANY clinically meaningful results if NOTHING is connected to the auditory nerve? Can you give a hypothesis on how that happens? Because as the science shows, you need both synapses and hair cells to have your hearing functionality back, can you link a study that explains this phenomenon?

 

[kiki]

I wonder why the progenitor cells regrow hair cells but cannot regrow synapses if there is no loss of hair cells? I wonder if it's possible to mix both OTO-413 and FX-322 together and inject it all at once? Would it regrow both hair cells and synapses even if there was no loss of hair cells?

If both succeed, I hope it can be done.

It would be nice if FX-322 and OTO-413 could be mixed and injected together, instead of injecting one after another. I think the two drugs can complement each other and have a better effect. Who will try it?

 

[FGG]

Say your hair cells are still there but they are damaged, would it still regrow synapses or would the hair cells have to be completely gone in those areas for synapses to regrow?

When FX-322 regrows hair cells, the new hair cells form new synapses. If just synapses are damaged, a synaptopathy drug is needed.

 

[Thuan]

Those aren't just "marketing slides", it's the actual preclinical data submitted to the FDA so that they may proceed to human clinical trials. That's clear evidence that the hair cells are connected to the auditory nerve, tested using an ABR. These conclusions, unlike yours, are based on factual data that was submitted to the FDA. If they were fabricated, you better start a lawsuit because that's illegal.

By the way, if you want to learn on how the hair cells make these connections to the auditory nerve, read the respond from Dr. McLean below. By the way, Will McLean studied inner ear biology and regeneration for over a decade, and has published and co-authored tons of papers regarding this specific field:

Also, you come to the conclusion that the Phase 1 data is a minor improvement in hearing ability, and that no assumptions can be made on whether the hair cells created by FX-322 are functional. So please explain the following in clear terms:

The data provided by Frequency Therapeutics' phase 1 trial showed clinically meaningful results in word score recognition, which CANNOT be attributed to a placebo affect. You assumption is that random hair cells were made, but not connected to the auditory nerve, therefore non functional. How would there be ANY clinically meaningful results if NOTHING is connected to the auditory nerve? Can you give a hypothesis on how that happens? Because as the science shows, you need both synapses and hair cells to have your hearing functionality back, can you link a study that explains this phenomenon?

Yeah, the fact that they did not have significant improvements may show a possibility that not all hair cells are functional. You and I disagree on the term significant. You interpret 10 dB improvement as significant (it certainly is an improvement) but they still nonetheless rely heavily on hearing aids because their hearing threshold has improved at most from 70 dB to 60 dB..., which still indicate much hearing loss. In this line of reasoning, I consider this as minor improvement.

I am not saying that NOTHING is functional. Please reread my previous posts. Like I said, I am hypothesizing that not ALL, or a significant portion of it, may be non-functional. There obviously is some connected new hair cells but to claim that all the newly grown hair cells is fully functional does not support this. Again, seems like you keep glancing over the emphasis, that NOT ALL, newly regenerated hair cells are functional.

And so I'm correlating, in what I considered as, minor improvements in severe hearing loss is due to some small subset of newly regenerated hair cells are connected correctly, and the majority of it is not.

Again, I am hypothesizing that NOT ALL, and most likely many, are not connected correctly.

 

[Thuan]

What you brought up is a thought-provoking question. However, I do think your paranoia is a little too high. The fact that there was evidence in vitro (safe assumption), clear improvements in phase 1/2, total restoration of mice hearing in vivo, tell us that certainly these hair cells aren't regrowing and just shooting synaptic attempts all over the place. I do think it's fair to assume that the new hair cells could be different than normal hair cells that we are born with.

As a lay person following this with severe brain fog, my belief is that any lack of results are mostly due to delivery and dosage, with your theory probably accounting for a small percentage of it -- small enough to still trust the company and see this as breakthrough therapy. The phase 2a results will be very interesting.

Again, like @FGG stated, the in vitro study can not confirm if these hair cells are functional. They tell us the new hair cells are proliferating from new progenitor cells, but (as @FGG says in the in vitro tests) can not confirm. They need to confirm it in a histology exam (and I think they also need to confirm in brain activity scan) to conclude this. It is expected of them as professionals to do such histology exam, as she claims. But until they show those results, it's not convincing to me because it's really trivial to include this, not to mention makes their research paper that much more convincing. But the fact remains that they did not include this in their research paper.

I think it's completely fair to assume that the synaptic connection has no direction. How will the new hair cells know where the synaptic connection is? Do they have eyes? No. They need molecular signals to guide them there. We just don't know if there is such signals to guide them there. Assuming that these cells can magically guide themselves there is naïve. This is different in natal development when developing into a baby. In those conditions, there are molecular markers to guide every piece of development. We are no longer in such conditions. Frequency Therapeutics' formulation prove that their formulation can simulate these conditions to induce proliferation. But they did not prove if these conditions can also guide to the correct synaptic connections.

 

[FGG]

Also, if you think about this logically, if you wasted all your space on faulty new hair cells, then you're permanently screwed. Carl LeBel says there is no overpopulation issue, which means at some point when you reach a population saturation, hair cells will no longer regenerate, either because of a) there's hard limit where its physically not enough space t0 expand more hair cells or b) there's a soft limit where new hair cells will not proliferate because it's too crowded.

The other option, if you did saturate your ears with faulty hair cells, is to perform self acoustic shock to kill your faulty hair cells, which will also kill your healthy ones. I'm sure this is a completely crap scenario.

But hey, if phase 2 shows good results but not promising results because it's similar to phase 1, and you want to jump in early, keep this in mind.

Again, "saturating your cochlea" with hair cells that didn't connect would be extremely obvious on histology. You would see hair cells lacking normal synaptic connections.

I think this worry would be more of a concern if Frequency Therapeutics was started before anyone knew how hair cells worked or could visualize synapses, but neither is true.

All I can say is phase 2a results and the high frequency audiogram changes should answer this question for you.

But for now, I am going to repeat @Killer's question, which is: what alternate explanation for improved word scores do you have if hair cells are not functional in this hypothetical situation?

 

[Thuan]

When FX-322 regrows hair cells, the new hair cells form new synapses. If just synapses are damaged, a synaptopathy drug is needed.

I think you are missing an important aspect I'm trying to make. It's not just a matter of a drug plopping down a new neural cell. It's the fact that the new cell need to know where to connect to and connect correctly. There needs to be molecular signals for the cells to guide them to grow properly. That's what happens in natal development. We have different concentrated molecular markers to guide every piece of cell where to grow and how much. We don't have such molecular markers because we're way past natal development. It's much more than, "Okay, we just need a new cell." We need a drug that can actually guide them to connect correctly. It's similar to the point I'm trying to make for the new hair cells with the attached spiral ganglion.

There's a fact that neurotrophic factors can induce neurogenesis has been discovered SO LONG ago but shown little to no success in human trials. It's not to say that they didn't induce neurogenesis but that the neurogenesis did not produce expected results.

 

[Killer]

Yeah, the fact that they did not have significant improvements may show a possibility that not all hair cells are functional. You and I disagree on the term significant. You interpret 10 dB improvement as significant (it certainly is an improvement) but they still nonetheless rely heavily on hearing aids because their hearing threshold has improved at most from 70 dB to 60 dB..., which still indicate much hearing loss. In this line of reasoning, I consider this as minor improvement.

I am not saying that NOTHING is functional. Please reread my previous posts. Like I said, I am hypothesizing that not ALL, or a significant portion of it, may be non-functional. There obviously is some connected new hair cells but to claim that all the newly grown hair cells is fully functional does not support this. Again, seems like you keep glancing over the emphasis, that NOT ALL, newly regenerated hair cells are functional.

And so I'm correlating, in what I considered as, minor improvements in severe hearing loss is due to some small subset of newly regenerated hair cells are connected correctly, and the majority of it is not.

Again, I am hypothesizing that NOT ALL, and most likely many, are not connected correctly.

These are the clinically significant results I'm referring to:

These aren't "minor" for someone who could barely hear half the words, now can hear most of the words correctly, which is also tested against a placebo group.

And it is you responsibility to proven how "some" hair cells are connected, as it is the conclusion you are drawing upon. So let me rephrase here:

How does this small minority of hair cells connect to the auditory nerve? Without some catalyst, it would seem impossible for any to do so, thus no hearing improvements at all. Is there a study linked to this phenomenon that regenerating non connected hair cells shows a statically significant increase in hearing functionality, attributed to some other hypothesis? Or that non connected hair cell start some process of connecting a minority of hair cells to the auditory nerve? Why would is only be a minority of hair cells?

If you can't answer these questions, the conclusions draw by Frequency Therapeutics, and the dozens of scientists who work on this, are the most reliable thing we have, and we should be basing our ideas and conclusions on what they have accomplished and shown in their data and testing, not ignore it.

 

[Paulmanlike]

@Thuan I like the way you are questioning things, maybe this can be a question if Tinnitus Talk ever does another podcast interview with Frequency Therapeutics.

I can however see why you were called paranoid, but I could see your thought process on it.

Now here is something that I am going to consider. So a couple of years ago I went for a hearing test. I did so after a wax removal so no conductive hearing loss issues there. Anyway, I had a dip in an audiogram when I tried my best to hear it.

Wanting to reconfirm this, I went for another audiogram that came out normal.

Now, I see a lot of comments about how this is immune to a placebo effect. I disagree to a point. So one theory to why I scored normal compared to a dip was maybe because I perceived my tinnitus louder that day, interfering with the results.

How would we know if these small number of trial participants with improved audiogram results on the high frequencies just coincidentally all had tinnitus and it was lower that day, so they were able to hear the tones better and the hearing loss was never there in the first place?

Now for the word scores. When you first go to the optician, you are asked to view a line. You do so and struggle and say you can't read it. But then they say try fifth one down, you squint and you can. And once you do the test for a second time, you try somewhat harder as you're used to what it was like from the first time.

Now we all want this to work, however it is premature to say "this definitely works".

 

[FGG]

I think you are missing an important aspect I'm trying to make. It's not just a matter of a drug plopping down a new neural cell. It's the fact that the new cell need to know where to connect to and connect correctly. There needs to be molecular signals for the cells to guide them to grow properly. That's what happens in natal development. We have different concentrated molecular markers to guide every piece of cell where to grow and how much. We don't have such molecular markers because we're way past natal development. It's much more than, "Okay, we just need a new cell." We need a drug that can actually guide them to connect correctly. It's similar to the point I'm trying to make for the new hair cells with the attached spiral ganglion.

There's a fact that neurotrophic factors can induce neurogenesis has been discovered SO LONG ago but shown little to no success in human trials. It's not to say that they didn't induce neurogenesis but that the neurogenesis did not produce expected results.

No, I got all of that.

Respectfully, I think you are missing my point, which is that the products of synaptogenesis are visible on histology.

They can look at the "product" of these interactions and observe if these connections are missing or not. They don't have to see the biochemical precursors to know this occurs when the neurons are visible under current imaging technology.

 

[Zugzug]

I think it's completely fair to assume that the synaptic connection has no direction. How will the new hair cells know where the synaptic connection is? Do they have eyes? No. They need molecular signals to guide them there.

See, I just don't think your theory adds up. If it was "random," there's absolutely no way we would see such obvious word score improvements. I definitely agree with you that there is a stochastic element to this process, but the whole process is not random.

 

[Thuan]

Again, "saturating your cochlea" with hair cells that didn't connect would be extremely obvious on histology. You would see hair cells lacking normal synaptic connections.

I think this worry would be more of a concern if Frequency Therapeutics was started before anyone knew how hair cells worked or could visualize synapses, but neither is true.

All I can say is phase 2a results and the high frequency audiogram changes should answer this question for you.

But for now, I am going to repeat @Killer's question, which is: what alternate explanation for improved word scores do you have if hair cells are not functional in this hypothetical situation?

I did post the alternative explanation in post #10981. I'll paste it here since there seems to be people not reading completely. Whether you agree or disagree is another matter. But it is an explanation.

From post #10981:
--
So the basis for my concern is that the new hair cells and the spiral ganglions are not connected to the receiving end of the cochlear nerve. The spiral ganglions need a signal to know the direction to grow toward the cochlear nerve. The issue is that we currently do not know if these drugs provide such signal for the ganglions to grow in the direction of the nerve. My guess is that the some cochlear hair cells are able to grow the spiral ganglions to the correct direction by random chance. And, the majority of the new hair cells are growing the spiral ganglions in the wrong direction or places.

So if it's by random chance, then by simple math, the more regenerated hair cells you have the higher the chances of renew hair cells being randomly connected correctly. We know from Carl LeBel that overpopulation is not an issue, which means there is a population saturation where new hair cells stop growth. Because the severe hearing loss group has more spaces to grow the new hair cells, then it makes sense for them to have more random correctly connected hair cells. Hence, only the severe hearing loss group had minor improvements. It's a hypothesis on why the majority did not show improvements. And I think this is a legitimate concern.
--

I think this a plausible situation.

I think this worry would be more of a concern if Frequency Therapeutics was started before anyone knew how hair cells worked or could visualize synapses, but neither is true

The limitations is logically plausible to me. The importance of such concern (whether is high/low or important to you or not) does not rule this out nor make it not true. We have different opinions on this.

 

[FGG]

See, I just don't think your theory adds up. If it was "random," there's absolutely no way we would see such obvious word score improvements. I definitely agree with you that there is a stochastic element to this process, but the whole process is not random.

It doesn't. If the new hair cells didn't synapse they wouldn't be functional and word scores wouldn't improve.

I can't think of another hypothesis for why the word scores would improve so much.

 

[Thuan]

See, I just don't think your theory adds up. If it was "random," there's absolutely no way we would see such obvious word score improvements. I definitely agree with you that there is a stochastic element to this process, but the whole process is not random.

If there's no molecular guide, then I assume it's random. If it's not random, what mechanism will cause them to correctly grow toward the nerve? I refuse to just hope it works. What is the explanation that they just magically grow correctly? Also, there can be a guide but we don't know. They didn't provide evidence to prove or disprove it. They just didn't test it.

 

[FGG]

@Thuan I like the way you are questioning things, maybe this can be a question if Tinnitus Talk ever does another podcast interview with Frequency Therapeutics.

I can however see why you were called paranoid, but I could see your thought process on it.

Now here is something that I am going to consider. So a couple of years ago I went for a hearing test. I did so after a wax removal so no conductive hearing loss issues there. Anyway, I had a dip in an audiogram when I tried my best to hear it.

Wanting to reconfirm this, I went for another audiogram that came out normal.

Now, I see a lot of comments about how this is immune to a placebo effect. I disagree to a point. So one theory to why I scored normal compared to a dip was maybe because I perceived my tinnitus louder that day, interfering with the results.

How would we know if these small number of trial participants with improved audiogram results on the high frequencies just coincidentally all had tinnitus and it was lower that day, so they were able to hear the tones better and the hearing loss was never there in the first place?

Now for the word scores. When you first go to the optician, you are asked to view a line. You do so and struggle and say you can't read it. But then they say try fifth one down, you squint and you can. And once you do the test for a second time, you try somewhat harder as you're used to what it was like from the first time.

Now we all want this to work, however it is premature to say "this definitely works".

It's funny you used the eye squinting analogy, because LeBel specifically talked about that in the Tinnitus Talk Podcast. He said "you can't squint your ears."

If it was due to just "trying harder" why did none of the untreated ears in the same patient improve? Why didn't the placebo group improve? Why do audiologist consider doubling word scores unheard of?

I understand skepticism but it has to take into account the data we already know.

 

[hopes]

I think FX-322 has good chances to restore at least a part of hearing loss (higher frequencies) but I'm so afraid when it comes to tinnitus. There are so many "what ifs" involved to solve this curse. I truly hope I'm too skeptical but anyways we'll know in Q2 of 2021.

 

[FGG]

I did post the alternative explanation in post #10981. I'll paste it here since there seems to be people not reading completely. Whether you agree or disagree is another matter. But it is an explanation.

From post #10981:
--
So the basis for my concern is that the new hair cells and the spiral ganglions are not connected to the receiving end of the cochlear nerve. The spiral ganglions need a signal to know the direction to grow toward the cochlear nerve. The issue is that we currently do not know if these drugs provide such signal for the ganglions to grow in the direction of the nerve. My guess is that the some cochlear hair cells are able to grow the spiral ganglions to the correct direction by random chance. And, the majority of the new hair cells are growing the spiral ganglions in the wrong direction or places.

So if it's by random chance, then by simple math, the more regenerated hair cells you have the higher the chances of renew hair cells being randomly connected correctly. We know from Carl LeBel that overpopulation is not an issue, which means there is a population saturation where new hair cells stop growth. Because the severe hearing loss group has more spaces to grow the new hair cells, then it makes sense for them to have more random correctly connected hair cells. Hence, only the severe hearing loss group had minor improvements. It's a hypothesis on why the majority did not show improvements. And I think this is a legitimate concern.
--

I think this a plausible situation.

The limitations is logically plausible to me. The importance of such concern (whether is high/low or important to you or not) does not rule this out nor make it not true. We have different opinions on this.

If the neurite outgrowth "growing in the wrong direction" were a significant problem it would have been noted on histology (direction is a visible parameter).

None of that answers the word score question, though either, unless I'm missing something. The word score improvements are not minor.

 

[Zugzug]

It doesn't. If the new hair cells didn't synapse they wouldn't be functional and word scores wouldn't improve.

I can't think of another hypothesis for why the word scores would improve so much.

I think @Thuan's main issue isn't that synapsing isn't occurring. I think the main question is the following: Say the synaptic direction attempts are totally random (like in the original diagram above). Is the probability of a random synapse occurring high enough to produce all of the results?

The answer is definitely no. There are so many low probability events that have to happen.

1) Frequency Therapeutics has to mess up histology, which is almost unthinkable.
2) The full restoration of hearing in mice has to be totally random.
3) The fact that every single phase 1/2 patient saw clear improvements means that hundreds (thousands?) or hair cells would have to grow in such a way to perfectly synapse.

In my opinion, the probability that some of the hair cells don't synapse correctly is much more plausible than it being totally random.

 

[Thuan]

I understand skepticism but it has to take into account the data we already know.

I am not throwing skepticism out there but discussing possibilities that there can be issues. I think my thought processing is logical and plausible. Identify possible issues and see if there can be solutions.

 

[Thuan]

@Thuan I like the way you are questioning things, maybe this can be a question if Tinnitus Talk ever does another podcast interview with Frequency Therapeutics.

I can however see why you were called paranoid, but I could see your thought process on it.

Now here is something that I am going to consider. So a couple of years ago I went for a hearing test. I did so after a wax removal so no conductive hearing loss issues there. Anyway, I had a dip in an audiogram when I tried my best to hear it.

Wanting to reconfirm this, I went for another audiogram that came out normal.

Now, I see a lot of comments about how this is immune to a placebo effect. I disagree to a point. So one theory to why I scored normal compared to a dip was maybe because I perceived my tinnitus louder that day, interfering with the results.

How would we know if these small number of trial participants with improved audiogram results on the high frequencies just coincidentally all had tinnitus and it was lower that day, so they were able to hear the tones better and the hearing loss was never there in the first place?

Now for the word scores. When you first go to the optician, you are asked to view a line. You do so and struggle and say you can't read it. But then they say try fifth one down, you squint and you can. And once you do the test for a second time, you try somewhat harder as you're used to what it was like from the first time.

Now we all want this to work, however it is premature to say "this definitely works".

See, the point that I was trying to make is not to say "this doesn't work" but to give a plausible explanation that's different from just a dosage issue for the phase 1 results. It's quite reasonable not to discount actual possibilities that can seriously affect the success of Frequency Therapeutics' product, both in terms of potential patients as ourselves and more importantly, for actual investors of Frequency Therapeutics. People should understand that they definitely did NOT confirm functional hair cells in their animal studies. They did confirm that it grew new hair cells. Those are not mutually exclusive. The phase 2 clinical trial is definitely going to prove this. And because I think there's such a large ambiguity on the point I'm making that investors here should clearly understand the risk I'm pointing out.

 

[FGG]

If there's no molecular guide, then I assume it's random. If it's not random, what mechanism will cause them to correctly grow toward the nerve? I refuse to just hope it works. What is the explanation that they just magically grow correctly? Also, there can be a guide but we don't know. They didn't provide evidence to prove or disprove it. They just didn't test it.

Who says there is no molecular guide? This was from @Killer's post above.

Per a conversation with Dr. McLean (a founder):

"In development it is the hair cells and supporting cells that release the proteins to attract neurons (NT3, BDNF). Their research shows that regenerated hair cells make the synapse components to communicate with neurons, even if neurons are not present."

This means the newly formed hair cells (e.g., regenerated hair cells) produce the molecular "signal" you are looking for, hence the doubling of word scores, etc.

As an aside, large quantities of BDNF are what OTO-413 is but it seems from Frequency Therapeutics' results that the quantity produced by regeneration is enough to form connections with the new hair cells.

Which actually makes me wonder if enough hair cell regeneration in the more moderate to severe cases will also confer an additional synaptopathy benefit from the extra NT3 and BDNF (which wouldn't help the mild cases as much but is still exciting).

Anyway, there is no evidence that neurite outgrowth to the cell is random or haphazard and non functional, just the opposite.

I realize you won't be happy with word scores and the assumption Frequency Therapeutics did the bare minimum and need audiogram changes but luckily we will have extended audiogram findings soon and it will hopefully allay your fears.

 

[Paulmanlike]

It's funny you used the eye squinting analogy, because LeBel specifically talked about that in the Tinnitus Talk Podcast. He said "you can't squint your ears."

If it was due to just "trying harder" why did none of the untreated ears in the same patient improve? Why didn't the placebo group improve? Why do audiologist consider doubling word scores unheard of?

I understand skepticism but it has to take into account the data we already know.

Yeah I just remembered that comment now that you mentioned it.

I'm quite positive @FGG, don't get me wrong, but I was thinking about these possibilities even with the encouraging data early on. You can understand my skepticism. It's been failure after failure when it comes to any potential solution for tinnitus. It's also a fact that most biotechs fail. The odds are against us. There's no denying that. However I am encouraged by these results, however my mind works overtime as I really want FX-322 to work.

Agreed on those points you make and that is what makes me hang on. I go from my own experience though, which is that one audiologist would have diagnosed me with mild hearing loss on a standard audiogram and the next one a couple of weeks later said I was within normal range (on a standard audiogram).

Now if this was done on a larger patient population, I would have been even more convinced (I'll have to wait for the phase 2a) but the sample is so small that I question possibilities of different scenarios.

Can we really say FX-322 definitely does something on such a small sample size?

What about the audiologists saying it's unheard of?

Has there ever been word score tests done in the same time frame as those used in the FX-322 trials, with patients knowing they were on a trial for a hearing restoration drug? What if the placebo effect just coincidentally affected those given FX-322 over the placebo? It was such a small patient population after all.

Also, I'd like to thank you @FGG and @Diesel for your continued contribution to this thread and Research News. It is both of your posts that I enjoy reading the most. Your posts are read by many and certainly appreciated.