Frequency Therapeutics — Hearing Loss Regeneration

[Thuan]

Okay, so the whole point I want to bring this up is because:

1) I want to provide an plausible explanation why the majority of the patients did not improve.

2) It would be silly to jump into early, and if possible, compassionate treatments because those new hair cells maybe dysfunctional. You'll just be using up your available space and progenitor cells on dysfunctional hair cells. Then if new treatment comes out you're screwed because there is a population saturation where new hair cells will not grow.

 

[FGG]

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.

For a quick and dirty illustration:
View attachment 40955

I'm not blindly taking his words for it if it doesn't show in the research paper. Like you said, if would be easy to confirm this so it would be trivial to include this in the research paper but they did not include this in the research paper. Please quote me the exact section that shows this in the research paper. I'm very happy to be proven wrong because I want this to work too.

Edit: The thing is a lot of people are just focusing on the fact that all we need is new hair cells. There's also the aspect if these hair cells are formed correctly because these are delicate structures in terms of mechanical transductions of signals to the spiral ganglions and to the correct connection from the spiral ganglion to the nerve.

Edit 2: Btw, they did an immunohistochemistry (showing the presence of protein structures), not a histology exam of microscopically looking at the spiral ganglion.

They definitely did histopath and not just histo staining. That's research 101.

No one would found a biotech company without doing that unless you believe they are full on frauds. And Carl LeBel wouldn't claim they were restored without the histology.

All the structures in your diagrams are visible on histology. They would know if the appropriate connections were made.

 

[Thuan]

The Cell study was in vitro. You can't test hearing function on cells in a lab.

Exactly, you cannot test that and so, they did not conclusively provide evidence of it directly restoring auditory function.

And it's way too obvious of a thing to have checked before starting trials. There is no way they didn't do full histopathology.

Assuming and guessing that Frequency Therapeutics should have or could have is quite hopeful. Companies aren't perfect and there's many examples of failed companies, especially in the auditory field.

 

[FGG]

Exactly, you cannot test that and so, they did not conclusively provide evidence of it directly restoring auditory function.

Assuming and guessing that Frequency Therapeutics should have or could have is quite hopeful. Companies aren't perfect and there's many examples of failed companies, especially in the auditory field.

I feel that it's a completely safe assumption though because even a medical student would know to do that.

 

[Thuan]

They definitely did histopath and not just histo staining. That's research 101.

Like I said, personally, I need hard evidence. All these he says, she says, could have done, should have done, and etc are just that.

Edit: What is definitively enough evidence for me is that they should have done similar case study on measuring the animal's brain activity for baseline, induce hair cell loss, measure them again to confirm changes in auditory signals in the brain, intratympanically apply the drugs, wait for a month or more, and measure the brain activity again to compare against healthy baseline, and then do a full surgical examination of the cochlea. This would provide evidence for both structural changes for the cochlea and its impact for restoring healthy CNS activity.

 

[Diesel]

Okay, so the whole point I want to bring this up is because:

1) I want to provide an plausible explanation why the majority of the patients did not improve.

2) It would be silly to jump into early, and if possible, compassionate treatments because those new hair cells maybe dysfunctional. You'll just be using up your available space and progenitor cells on dysfunctional hair cells. Then if new treatment comes out you're screwed because there is a population saturation where new hair cells will not grow.

1) All recipients of FX-322 in the Phase 1/2 did respond positively to the drug with some level of improvement. Carl LeBel and Chris Loose have said this on numerous interviews/discussions; @FGG referenced the JP discussion earlier in 2020, where this was mentioned. It's true that it wasn't statistically significant across the board, partially due to a ceiling effect, but there was a measurable improvement.

2) If the new cells produced by the FX-322 injection are dysfunctional, how was the benefit retained for up to 2 years for 4/5 of those that saw significant improvement? Wouldn't the dysfunctional cells not provide a benefit? Or wear out from daily wear-tear over the course of months?

 

[Thuan]

I feel that it's a completely safe assumption though because even a medical student would know to do that.

Yes, thank you for pointing out I'm not a medical student. I am not. Then are you implying the PR slides are geared towards investors that have medical student knowledge? As PR, would you not try to be convincing as possible to include all relevant data? That's a great assumption there and assumptions are especially dangerous for investors.

It still stands that they did not provide evidence for the point I'm trying to make. I'm not trying to be offensive. (I am not sure if you are purposely trying to be seemingly offensive using the "medical student" knowledge to argue your point).

This is a genuine concern that I have and I'm trying to have a constructive dialogue. It's quite pointless to continue the line of reasoning of "should have, could have, would have done" or "he says, she says".

 

[Kendra]

Would a combination of FX-322 and Hough Ear Institute's pill be a good combo then if the pill does in fact restore synapses? It's a shame more companies don't work together to tackle health issues when it could possibly bring relief so much quicker.

 

[Thuan]

1) All recipients of FX-322 in the Phase 1/2 did respond positively to the drug with some level of improvement. Carl LeBel and Chris Loose have said this on numerous interviews/discussions; @FGG referenced the JP discussion earlier in 2020, where this was mentioned. It's true that it wasn't statistically significant across the board, partially due to a ceiling effect, but there was a measurable improvement.

2) If the new cells produced by the FX-322 injection are dysfunctional, how was the benefit retained for up to 2 years for 4/5 of those that saw significant improvement? Wouldn't the dysfunctional cells not provide a benefit? Or wear out from daily wear-tear over the course of months?

I'm saying not all of them are dysfunctional. Some of them are connected correctly by chance. Because we don't know if there's any molecular marker that directs where the synapses grow to the correct place. It's not lego blocks that fits perfectly. The cell needs direction on where it should grow the synapse. And neurons are not mobile. Once it's grown in a certain place, it stays there (correctly or incorrectly).

 

[Pete88]

Yes, thank you for pointing out I'm not a medical student. I am not. Then are you implying the PR slides are geared towards investors that have medical student knowledge? As PR, would you not try to be convincing as possible to include all relevant data? That's a great assumption there and assumptions are especially dangerous for investors.

It still stands that they did not provide evidence for the point I'm trying to make. I'm not trying to be offensive. (I am not sure if you are purposely trying to be seemingly offensive using the "medical student" knowledge to argue your point).

This is a genuine concern that I have and I'm trying to have a constructive dialogue. It's quite pointless to continue the line of reasoning of "should have, could have, would have done" or "he says, she says".

I honestly do not think the "medical student" comment was intended as a jab or an offense. My impression is that she is saying that a team of medical researchers would not make the error that you are suggesting may have happened.

Basically, she was saying that such a basic step would not be overlooked by a team of professionals, since even the most junior and basic level in that field, i.e. a medical student, would know better.

 

[FGG]

Yes, thank you for pointing out I'm not a medical student. I am not. Then are you implying the PR slides are geared towards investors that have medical student knowledge? As PR, would you not try to be convincing as possible to include all relevant data? That's a great assumption there and assumptions are especially dangerous for investors.

It still stands that they did not provide evidence for the point I'm trying to make. I'm not trying to be offensive. (I am not sure if you are purposely trying to be seemingly offensive using the "medical student" knowledge to argue your point).

This is a genuine concern that I have and I'm trying to have a constructive dialogue. It's quite pointless to continue the line of reasoning of "should have, could have, would have done" or "he says, she says".

Their presentations are largely geared toward biotech investors and their largest share holders are biotech specialist firms.

And I wasn't trying to point out that you aren't a medical student but rather point out that Frequency Therapeutics wouldn't miss something that even a medical student would think to do.

 

[kiki]

That is my point, which they obviously of course can not test auditory function based on their experimental procedures. Scientifically, if there isn't hard evidence to establish renewed cochlear hair cells are fully functional, i.e. that the synaptic structures connect or connect correctly back to the cochlear nerve, then it's an assumption to say that renewed hair cells mean restoration of frequencies.

I've been a month away from Tinnitus Talk and the FX-322 hype and it's given a clear head to think about their animal studies.

We know that from the cochlear implant patients have confirmed therapeutic concentration of the delivered drug to the cochlea. So it isn't a matter of patients not receiving a good concentration of the drugs. So theoretically, most of the mild and moderate hearing loss group, who has hair cell damage damage, should improve as much as the severe hearing loss group.

But obviously the severe hearing loss group showed statistically minor improvements while mild and moderate showed no improvements. And I'm thinking why this is occuring when they have established concentrated drug delivery in the cochlear implant patients, and what I realized is that in their original animal studies we are assuming that new hair cells are neurological and fully functional. And this assumption was not proven with their animal studies. That study only proved the presence of a lot of new hair cell growth. The question is, does that directly correlate with auditory function in the brain?

@FGG when you said "Podcast, Carl LeBel confirmed that these hair cells form synapses", can you please cite exactly, in their preclinical studies which I have linked above, where they proved these synaptic structures are connected to the cochlear nerve? They showed that the synaptic markers are there with the new hair cells, but where exactly, as in their experimental procedures, that support these synaptic structures lead back to the cochlear nerve?

It's a great discovery to be able to induce regrowth on a once believed impossible situation. Now the question is, are these regenerated cochlear hair cells fully and neurological functional. I think the clinical phase 2 trials will confirm this.

dB is a logarithmic function. The number of regenerated hair cells will probably differ depending on whether the hearing loss level improves from 60 dB to 50 dB and from 40 dB to 30 dB. Therefore, I think that the more severe the hearing loss, the greater the improvement effect.

I think the more severe the hearing loss, the greater the improvement in dB when the same number of hair cells are regenerated.

 

[weab00]

Would a combination of FX-322 and Hough Ear Institute's pill be a good combo then if the pill does in fact restore synapses? It's a shame more companies don't work together to tackle health issues when it could possibly bring relief so much quicker.

Otonomy is far more promising than Hough Ear Institute.

 

[Diesel]

Yes, thank you for pointing out I'm not a medical student. I am not. Then are you implying the PR slides are geared towards investors that have medical student knowledge? As PR, would you not try to be convincing as possible to include all relevant data? That's a great assumption there and assumptions are especially dangerous for investors.

It still stands that they did not provide evidence for the point I'm trying to make. I'm not trying to be offensive. (I am not sure if you are purposely trying to be seemingly offensive using the "medical student" knowledge to argue your point).

This is a genuine concern that I have and I'm trying to have a constructive dialogue. It's quite pointless to continue the line of reasoning of "should have, could have, would have done" or "he says, she says".

There's no need to get into the level of detail you're seeking in an investor deck. The average investor (institutional or retail) wants to know how this new drug is going to make them maximum returns. Usually, there isn't as much focus in that much detail on how the sausage is made.

They want to sees proof/evidence that supports the end-product actually provides a benefit. That benefit is restored hearing. This is why they spend half the deck on the Phase 1/2 results and the "long term study."

Then, an investor wants to know how big the market is to consume that product. Finally, the strategic direction of the product / company is creates an acceptable risk/return relationship. Frequency Therapeutics does this by describing the Phase 2A, and MS pipeline, among other places where progenitors exist.

 

[Thuan]

There's no need to get into the level of detail you're seeking in an investor deck. The average investor (institutional or retail) wants to know how this new drug is going to make them maximum returns. Usually, there isn't as much focus in that much detail on how the sausage is made.

They want to sees proof/evidence that supports the end-product actually provides a benefit. That benefit is restored hearing. This is why they spend half the deck on the Phase 1/2 results and the "long term study."

Then, an investor wants to know how big the market is to consume that product. Finally, the strategic direction of the product / company is creates an acceptable risk/return relationship. Frequency Therapeutics does this by describing the Phase 2A, and MS pipeline, among other places where progenitors exist.

I think that's contradictory logic. As an investor, I would want hard proof and the least amount of ambiguities (i.e. show me proof from your preclinical studies confirmed functional hair cells, not just regenerating lots of hair cells). If they're spending thousands or millions into a company, it would be very risky to assume that they did X and Y based on faith because well, he or she says so. Now, I'm not saying Frequency Therapeutics is purposely misleading but what I am saying is that there is a lack of evidence to support new hair cells are fully functional. I'm just pointing out this supporting evidence is missing to definitively conclude that in the animal studies. And that this issue I'm pointing out could be a reason why we didn't see major improvements, but minor improvement in a select few.

I guess we'll know by the end of summer.

Edit: It's depressing everyone is taking assumptions as facts from a) it's from the slides, b) he/she says so or c) it's true cause it's expected. At least for me, none of these are good enough.

Edit 2: This is not even a small ambiguity. It's a major ambiguity. Lots of new and maybe non-functional hair cells is completely is a broken product with much issues. Am I really supposed to take by faith that a company has thoroughly checked that the new cochlear hair cells are indeed functional just because professional standards expect of them? Well, if they did do confirm that, then it's trivial to include it to be MORE convincing.

 

[tommyd87]

There's no need to get into the level of detail you're seeking in an investor deck. The average investor (institutional or retail) wants to know how this new drug is going to make them maximum returns. Usually, there isn't as much focus in that much detail on how the sausage is made.

They want to sees proof/evidence that supports the end-product actually provides a benefit. That benefit is restored hearing. This is why they spend half the deck on the Phase 1/2 results and the "long term study."

Then, an investor wants to know how big the market is to consume that product. Finally, the strategic direction of the product / company is creates an acceptable risk/return relationship. Frequency Therapeutics does this by describing the Phase 2A, and MS pipeline, among other places where progenitors exist.

I absolutely agree, as the three things that are relevant to the investors are whether it is safe, whether it is going to work and how well it can work. Investors want it to be safe so it can be sold constantly with no real risk of the company getting sued or the treatment being pulled. Investors want it to work well to ensure that the treatment can consequently assist the most individuals possible and also deliver them the greatest treatment benefit too.

Good benefit and good safety means a pharmaceutical company like Frequency Therapeutics can charge a higher price for a medicine because the larger the benefit delivered, the more people are able to utilise this and do so with limited risk.

No investor cares about how these outcomes are actually achieved at all, as long as they actually get there in the end.

 

[tommyd87]

I think that's contradictory logic. As an investor, I would want hard proof and the least amount of ambiguities (i.e. show me proof from your preclinical studies confirmed functional hair cells, not just regenerating lots of hair cells). If they're spending thousands or millions into a company, it would be very risky to assume that they did X and Y based on faith because well, he or she says so. Now, I'm not saying Frequency Therapeutics is purposely misleading but what I am saying is that there is a lack of evidence to support new hair cells are fully functional. I'm just pointing out this supporting evidence is missing to definitively conclude that in the animal studies. And that this issue I'm pointing out could be a reason why we didn't see major improvements, but minor improvement in a select few.

I guess we'll know by the end of summer.

Edit: It's depressing everyone is taking assumptions as facts from a) it's from the slides, b) he/she says so or c) it's true cause it's expected. At least for me, none of these are good enough.

The thing though is that Frequency Therapeutics have demonstrated that these new hair cells are functional. From what we have seen in the trial outcomes, one can conclude that there was a hearing improvement, otherwise they wouldn't have obtained the results that they got.

The facts state that hair cells let you hear and that you either don't hear something or you hear something. The logic states if they heard more sound after being administered FX-322, then they must have had improvement in their number of hair cells.

Therefore it tends to be more likely than not that FX-322 then worked as expected.

 

[Thuan]

Again, my point is that we can not discount the fact that perhaps some, many, or most regenerated hair cells are non-functional And currently, we can not discount this because there is NO hard evidence to confirm this. As investors, you should seriously consider this. Making the assumption that new hair cells alone mean restored hearing is flawed. To restore hearing, it is more than just getting new hair cells to grow. You need functional new hair cells, where they actually connect to the cochlear nerve and that the hair cell's mechanical transduction proteins are correctly working.

 

[Thuan]

The thing though is that Frequency Therapeutics have demonstrated that these new hair cells are functional. From what we have seen in the trial outcomes, one can conclude that there was a hearing improvement, otherwise they wouldn't have obtained the results that they got.

The facts state that hair cells let you hear and that you either don't hear something or you hear something. The logic states if they heard more sound after being administered FX-322, then they must have had improvement in their number of hair cells.

Therefore it tends to be more likely than not that FX-322 then worked as expected.

They have NOT demonstrated that ALL the new hair cells are functional. Where did you get that? Please cite to support your claims. Slides are just slides. They are not research papers. Please cite a proper research paper and explain how they concluded it. [Note: conclusions are also up for debate too].

Of course I'm being technical here, since the company might not have released all their pre-clinical studies. If there are unreleased research data, then there's not much we can do. But based on the available research data that they published (scientific research papers), they did not confirm this.

On the second point, yes cochlear hair cells let you hear. But that is just ONE component of allowing you to hear. The hair cell is the mechanical aspect to capture sound waves. The other component is the actual neuronal connection that flows to the CNS. If you have just one of the two parts or you have both parts but one part is broken, then it's still not going to work as expected.

Edit: I don't know why there's so many misunderstanding on this basic logic. Say if you have a new microphone but the connector is missing or that the connector just couldn't fit into your 3.5mm jack, then obviously you there will be no signals to your receiving end. What I'm saying that is there's no evidence to support if the connection to the 3.5mm jack is properly made.

Edit 2: There's also considerations of conflict of interests. I'm sure those of you who have browsed and actually READ research papers, then you'll know many of them divulge conflict of interests because their conclusions or results can and may be biased. Hence, personally, there's a level of doubt and uncertainty just blinding taking their words for it on their press releases and PR slides.

 

[Diesel]

Edit: It's depressing everyone is taking assumptions as facts from a) it's from the slides, b) he/she says so or c) it's true cause it's expected. At least for me, none of these are good enough.

The SEC, FDA, and other regulatory entities hold publicly traded firms, including Frequency Therapeutics, accountable for releasing information/communications that are based on facts, and verified evidence, that is to the best of their knowledge. Using data from recently completed clinical trials and studies meets these conditions.

1. Here's the drug and proof showing how it works, and how we learned about it. Small molecules activating specific progenitor cells. Discovered in the intestine.
2. These progenitor cells exist in the ear. Here's proof that they exist. Here's what is known that they do in utero.
3. This drug was injected into human cochlea the lab and we observed these cells making hair cells for hearing.
4. Then this drug was injected in an FDA-sponsored clinical trial in living ears. Participant hearing improved in clinical meaningful ways. Here's data that is understandable from that FDA-sponsored trial.
5. By the way, if you want even more detail, we have research posted on our website.

This description meets the criteria from a regulatory compliance standpoint.

 

[Killer]

They have NOT demonstrated that ALL the new hair cells are functional. Where did you get that? Please cite to support your claims. Slides are just slides. They are not research papers. Please cite a proper research paper and explain how they concluded it. [Note: conclusions are also up for debate too].

Of course I'm being technical here, since the company might not have released all their pre-clinical studies. If there are unreleased research data, then there's not much we can do. But based on the available research data that they published (scientific research papers), they did not confirm this.

On the second point, yes cochlear hair cells let you hear. But that is just ONE component of allowing you to hear. The hair cell is the mechanical aspect to capture sound waves. The other component is the actual neuronal connection that flows to the CNS. If you have just one of the two parts or you have both parts but one part is broken, then it's still not going to work as expected.

Edit: I don't know why there's so many misunderstanding on this basic logic. Say if you have a new microphone but the connector is missing or that the connector just couldn't fit into your 3.5mm jack, then obviously you can't send signals. What I'm saying that is there's no evidence to support if the connection to the 3.5mm jack is properly made.

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:

Of the 23 patients, 14 has mild hearing loss, thus none of them has any clinically meaningful word recognition improvements as they were already scoring 45+ words out of 50, also called the ceiling effect. Of those, 9 had moderate to moderately severe hearing loss, 3 of which were given placebos. Of the 6 of those, 4 showed clinically significant results that can be without a reasonable doubt attributed to FX-322. Of those 4, 3 has a 10-15 decibel improvement at 8 kHz.

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.

 

[Zugzug]

They have NOT demonstrated that ALL the new hair cells are functional. Where did you get that? Please cite to support your claims. Slides are just slides. They are not research papers. Please cite a proper research paper and explain how they concluded it. [Note: conclusions are also up for debate too].

Of course I'm being technical here, since the company might not have released all their pre-clinical studies. If there are unreleased research data, then there's not much we can do. But based on the available research data that they published (scientific research papers), they did not confirm this.

On the second point, yes cochlear hair cells let you hear. But that is just ONE component of allowing you to hear. The hair cell is the mechanical aspect to capture sound waves. The other component is the actual neuronal connection that flows to the CNS. If you have just one of the two parts or you have both parts but one part is broken, then it's still not going to work as expected.

Edit: I don't know why there's so many misunderstanding on this basic logic. Say if you have a new microphone but the connector is missing or that the connector just couldn't fit into your 3.5mm jack, then obviously you there will be no signals to your receiving end. What I'm saying that is there's no evidence to support if the connection to the 3.5mm jack is properly made.

Edit 2: There's also considerations of conflict of interests. I'm sure those of you who have browsed and actually READ research papers, then you'll know many of them divulge conflict of interests because their conclusions or results can and may be biased. Hence, personally, there's a level of doubt and uncertainty just blinding taking their words for it on their press releases and PR slides.

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?

 

[tommyd87]

They have NOT demonstrated that ALL the new hair cells are functional. Where did you get that? Please cite to support your claims. Slides are just slides. They are not research papers. Please cite a proper research paper and explain how they concluded it. [Note: conclusions are also up for debate too].

Of course I'm being technical here, since the company might not have released all their pre-clinical studies. If there are unreleased research data, then there's not much we can do. But based on the available research data that they published (scientific research papers), they did not confirm this.

On the second point, yes cochlear hair cells let you hear. But that is just ONE component of allowing you to hear. The hair cell is the mechanical aspect to capture sound waves. The other component is the actual neuronal connection that flows to the CNS. If you have just one of the two parts or you have both parts but one part is broken, then it's still not going to work as expected.

Edit: I don't know why there's so many misunderstanding on this basic logic. Say if you have a new microphone but the connector is missing or that the connector just couldn't fit into your 3.5mm jack, then obviously you there will be no signals to your receiving end. What I'm saying that is there's no evidence to support if the connection to the 3.5mm jack is properly made.

If you actually read what I said, I never said and/or claimed that Frequency Therapeutics have specifically stated that all new hair cells are functional. Merely I stated that Frequency Therapeutics have demonstrated that the new hair cells regrown by FX-322 have worked to improve hearing just like how they are supposed to.

I agree that the nerve ends/synapses are also equally important in individual's ability to hear and that there probably may have been hair cells that have regrown and not functioned due to the other parts not connecting. However this has no bearing on the fact that FX-322 was able to make hair cells regrow and also function in the way which they were supposed to, therefore supporting the conclusion that FX-322 was actually effective at achieving its stated purpose.

 

[xyz]

They have NOT demonstrated that ALL the new hair cells are functional. Where did you get that? Please cite to support your claims. Slides are just slides. They are not research papers. Please cite a proper research paper and explain how they concluded it. [Note: conclusions are also up for debate too].

Of course I'm being technical here, since the company might not have released all their pre-clinical studies. If there are unreleased research data, then there's not much we can do. But based on the available research data that they published (scientific research papers), they did not confirm this.

On the second point, yes cochlear hair cells let you hear. But that is just ONE component of allowing you to hear. The hair cell is the mechanical aspect to capture sound waves. The other component is the actual neuronal connection that flows to the CNS. If you have just one of the two parts or you have both parts but one part is broken, then it's still not going to work as expected.

Edit: I don't know why there's so many misunderstanding on this basic logic. Say if you have a new microphone but the connector is missing or that the connector just couldn't fit into your 3.5mm jack, then obviously you there will be no signals to your receiving end. What I'm saying that is there's no evidence to support if the connection to the 3.5mm jack is properly made.

Edit 2: There's also considerations of conflict of interests. I'm sure those of you who have browsed and actually READ research papers, then you'll know many of them divulge conflict of interests because their conclusions or results can and may be biased. Hence, personally, there's a level of doubt and uncertainty just blinding taking their words for it on their press releases and PR slides.

Probably we will see this after the current trial finishes. If there are great hearing improvements the hair cells transmit the signal properly to the CNS otherwise its the new microphone with the broken connection.

 

[paul mclean]

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.

 

[Diesel]

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.

 

[Lucifer]

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?

 

[Thuan]

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?

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.

 

[FGG]

They have NOT demonstrated that ALL the new hair cells are functional. Where did you get that? Please cite to support your claims. Slides are just slides. They are not research papers. Please cite a proper research paper and explain how they concluded it. [Note: conclusions are also up for debate too].

Of course I'm being technical here, since the company might not have released all their pre-clinical studies. If there are unreleased research data, then there's not much we can do. But based on the available research data that they published (scientific research papers), they did not confirm this.

On the second point, yes cochlear hair cells let you hear. But that is just ONE component of allowing you to hear. The hair cell is the mechanical aspect to capture sound waves. The other component is the actual neuronal connection that flows to the CNS. If you have just one of the two parts or you have both parts but one part is broken, then it's still not going to work as expected.

Edit: I don't know why there's so many misunderstanding on this basic logic. Say if you have a new microphone but the connector is missing or that the connector just couldn't fit into your 3.5mm jack, then obviously you there will be no signals to your receiving end. What I'm saying that is there's no evidence to support if the connection to the 3.5mm jack is properly made.

Edit 2: There's also considerations of conflict of interests. I'm sure those of you who have browsed and actually READ research papers, then you'll know many of them divulge conflict of interests because their conclusions or results can and may be biased. Hence, personally, there's a level of doubt and uncertainty just blinding taking their words for it on their press releases and PR slides.

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.

 

[FGG]

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?

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.