Frequency Therapeutics — Hearing Loss Regeneration

[Bambam0]

To me, it's better to learn this lesson early in development.

This is it.

 

[Tezcatlipoca]

I can tell you that person is no longer tinnitus free.

How do you know?

 

[Diesel]

They are pioneering this stuff. I just find it really hard to believe that we have come this far and we are still learning things. They are a publicly traded company now, not a research firm. The expectations are a lot higher now.

The IPO was about financing the future plans for the business at that time. Being publicly traded means the bar is higher in terms of transparency and practice, but they are no more immune from failure than any other traded firm.

 

[Lucifer]

I can tell you that person is no longer tinnitus free.

How come his tinnitus returned? Has this got anything to do with receiving the COVID-19 vaccine? Did it cause his tinnitus to come back?

 

[Gb3]

How come his tinnitus returned? Has this got anything to do with receiving the COVID-19 vaccine? Did it cause his tinnitus to come back?

I don't know. They didn't say anything about the COVID-19 vaccine.

 

[Lucifer]

I don't know. They didn't say anything about the COVID-19 vaccine.

Let us know when you find out more on why his tinnitus came back. It could just be a temporary spike or he exposed himself to loud noise which caused it to come back.

 

[Gb3]

Let us know when you find out more on why his tinnitus came back. It could just be a temporary spike or he exposed himself to loud noise which caused it to come back.

Their tinnitus is from sudden hearing loss. Not noise.

 

[Trevor_phillips]

Their tinnitus is from sudden hearing loss. Not noise.

I think this is because the untreated hair cells continued to accumulate continuous damage (if his tinnitus is different than the previous one) or the regrown hair cells are just not sustainable, and if this is the case, FX-322 is useless. Everybody wants regrown hair cells that can last for life.

 

[kiki]

To me, it's better to learn this lesson early in development: that weekly doses don't go as expected in living human cochlea with this really new type of regeneration compound. As opposed to once the drug is in Phase 3 or a product, and its approval gets retracted because patient's hearing starts getting fucked up by doctors overdosing them. This is a good example of a fast-fail; especially since they chose the reliable/safe route of going with a single dose.

Exactly.

Either way, they had to do multiple doses to find out how often they had to be spaced.

 

[Keith Handy]

Everybody wants regrown hair cells that can last for life.

Or at least for the normal lifespan of a hair cell.

 

[OptimusPrimed]

Frequency Therapeutics, Pipeline Therapeutics, Sound Pharmaceuticals and Otonomy are all doomed to fail? I doubt it.

These aren't the only groups working on a fix for this issue.

 

[Guywithapug]

Anyone else still confident enough in Frequency Therapeutics to invest at roughly $10?

Everything will hinge upon the severe and age related results...

 

[GlennS]

I would have preferred the opposite to be honest, but it isn't about what I want. We are trying to cure deafness. We are trying to cure tinnitus. That is the whole point. Deaf people can't hear and it shows up on their audiogram. They just want to hear birds again. There are 466 million people worldwide with hearing loss. This is why they created FX-322 in hopes of helping people with hearing loss and it has been hypothesized that this could also help with tinnitus. It was never created to help them understand words better, even though we now know this is a great side effect...

Hence my objection to this spin that we should pay attention to modest improvements in WR scores and disregard unchanged audiograms.

 

[Zugzug]

I would have preferred the opposite to be honest, but it isn't about what I want. We are trying to cure deafness. We are trying to cure tinnitus. That is the whole point. Deaf people can't hear and it shows up on their audiogram. They just want to hear birds again. There are 466 million people worldwide with hearing loss. This is why they created FX-322 in hopes of helping people with hearing loss and it has been hypothesized that this could also help with tinnitus. It was never created to help them understand words better, even though we now know this is a great side effect...

I've played this grass is greener game with myself too. Severe word processing problems would SUCK. I would so much rather comprehend speech than hear some dumb high pitched bird that I've grown to hate from hyperacusis.

 

[MrCrybaby]

View attachment 44694

Hence my objection to this spin that we should pay attention to modest improvements in WR scores and disregard unchanged audiograms.

I would counter with the fact that, while the original intent of the drug was to elevate audiogram and completely reverse hearing loss, increasing word scores is a big deal and can make a huge difference in quality of life for hearing loss patients. I don't expect this drug to save me but I do think it has the potential to improve people's lives in a meaningful and important way.

 

[Diesel]

View attachment 44694

Hence my objection to this spin that we should pay attention to modest improvements in WR scores and disregard unchanged audiograms.

So are you saying that it's more useful for someone to understand 11 beeps than complete words?

 

[GlennS]

So are you saying that it's more useful for someone to understand 11 beeps than complete words?

I simply don't buy the idea that your word recognition can improve without a corresponding improvement in the audiogram. If the audiogram doesn't improve then the WR improvement is an illusion, i.e. a function of some lucky guesses during testing.

Why do I feel this way? Well, it's common sense. If high frequency content in the consonants is the key to WR, then if your audiogram shows no improvement in high frequency hearing, then it's unlikely that your hearing has actually improved in any shape or form.

To me, this feels patently obvious. All of this getting lost in the weeds with IHC and OHC is bargaining, IMHO.

 

[Trevor_phillips]

I simply don't buy the idea that your word recognition can improve without a corresponding improvement in the audiogram. If the audiogram doesn't improve then the WR improvement is an illusion, i.e. a function of some lucky guesses during testing.

Why do I feel this way? Well, it's common sense. If high frequency content in the consonants is the key to WR, then if your audiogram shows no improvement in high frequency hearing, then it's unlikely that your hearing has actually improved in any shape or form.

To me, this feels patently obvious. All of this getting lost in the weeds with IHC and OHC is bargaining, IMHO.

I do agree. This is why I'm looking to synaptogenesis drug like OTO-413 or PIPE-505 which have verified proofs. The recent results showed that FX-322 is a scam.

The 10 dB improvements at 8 kHz and 6 kHz aren't reliable, audiograms can vary a lot. Furthermore, like @GlennS said above, it's impossible to improve WR without a little improvement in the audiogram. OHCs AND IHCs are inter-connected, if these people have major IHCs damage, then they have probably more OHCs damage, since they function in a mechanical way and are more susceptible to get destroyed.

I'm not gonna pay for something which is not able to regenerate hair cells in a sustainable way (or even regenerate hair cells at all ?). OTO-6XX will outperform FX-322 since the gel is long lasting and targets the whole cochlea.

I have no doubt about this. However, I pray for everyone to stay safe, something bright is going to happen about hair cell and synapses regeneration but not until the end of the decade at least.

 

[Diesel]

Please provide evidence to support the following statements:

OTO-6XX will outperform FX-322 since the gel is long lasting and targets the whole cochlea.

it's impossible to improve WR without a little improvement in the audiogram.

 

[Diesel]

If high frequency content in the consonants is the key to WR, then if your audiogram shows no improvement in high frequency hearing, then it's unlikely that your hearing has actually improved in any shape or form.

Participants with a 10 dB or greater improvement on the audiogram at 8 kHz (A high frequency on the standard audiogram) also saw sustained word score improvements. So, you're right, there probably is a correlation between high frequency improvements on the audiogram and word score. And, it that appears to be proven by a single injection of FX-322.

Disclosure: No evidence has been produced yet in the Extended-High Frequency range (8 kHz - 16 kHz).

 

[RB2014]

I've played this grass is greener game with myself too. Severe word processing problems would SUCK. I would so much rather comprehend speech than hear some dumb high pitched bird that I've grown to hate from hyperacusis.

So are you saying that it's more useful for someone to understand 11 beeps than complete words?

At this point we will have to wait and see what the additional trials tell us. My only point was that FX-322 was created to cure hearing loss... not increase word recognition scores. Debating on which one is more important is not going to help any of us. If the additional increased word scores hold true for subsequent trials, then this is an unexpected win for them and hopefully they can build off that. At the end of the day, as everyone has pointed out, there are still many things they don't understand about the human ear and hopefully with additional testing they can figure out how to make FX-322 more effective.

 

[Tezcatlipoca]

I love how a 1920s test is somehow the gold standard of hearing, and real life changes are "illusions."

 

[RB2014]

Participants with a 10 dB or greater improvement on the audiogram at 8 kHz (A high frequency on the standard audiogram) also saw sustained word score improvements. So, you're right, there probably is a correlation between high frequency improvements on the audiogram and word score. And, it that appears to be proven by a single injection of FX-322.

Disclosure: No evidence has been produced yet in the Extended-High Frequency range (8 kHz - 16 kHz).

View attachment 44702

And... From what we think... There should have been improvements in the 8 kHz to 16 kHz range as well, since FX-322 would have hit those areas first, which would have only helped with the word scores.

Word scores also dropped in the 1 to 2 year time period... I wonder if any improvements in the 8 kHz to 16 kHz range didn't stand the test of time as people seem to lose those frequencies faster for some reason.

 

[Diesel]

At this point we will have to wait and see what the additional trials tell us. My only point was that FX-322 was created to cure hearing loss... not increase word recognition scores. Debating on which one is more important is not going to help any of us. If the additional increased word scores hold true for subsequent trials, then this is an unexpected win for them and hopefully they can build off that. At the end of the day, as everyone has pointed out, there are still many things they don't understand about the human ear and hopefully with additional testing they can figure out how to make FX-322 more effective.

To be honest, you're treading on unrealistic expectations territory with this comment.

How do we define any drug as a bonafide CURE for hearing loss, and associated symptoms (tinnitus, hyperacusis, distortions, et al)? FX-322 cannot simply be a CURE for hearing loss by itself, because it's been known from very early on (as early as 2018) that it cannot repair areas of the cochlea where the synaptopathy is present with otherwise healthy hair cells. So, in any individual, where hearing loss is likely a mixed pathology (dead cells + synaptopathy), it may only be able to resolve part of the underlying condition leading to hearing loss. Therefore, FX-322 ALONE can never be a full hearing loss cure. It can only partially treat a specific underlying issue.

To get even more philosophical on you, how do we define a CURE for hearing loss? Is one cured when their hearing is fully restored back to the day they shot out of mom's uterus? Or just when they're able to ACE the three standard hearing loss tests (Audiogram, WR, WIN)? Or does the CURE mean that they no longer experience tinnitus at all? Is that possible? Some have provided old research that shows that people with "normal" hearing still experience tinnitus when things get uber quiet. So, what's the cure benchmark there? How about hyperacusis? Or, is the CURE when someone's quality of life gets above a certain "normal" threshold?

This is why Frequency Therapeutics uses the term, "Disease Modifying Effect"... FX-322 is a treatment for those with SNHL/NIHL where hair cell death/damage has occurred. It has been demonstrated in vitro that FX-322 is restoring lost hearing by replacing those poorly performing/missing cells. This is also believed to be happening in vivo, and has been observed by those clinical measurement improvements. Even though the patient saw a benefit from specific hair cells being restore anew, neighboring hair cells and those untouched by FX-322 may still be at their aged/worn state, or have some form of synaptopathy. Therefore, FX-322 can only modify their hearing loss disease so much, but not likely to a NEW state. It's also been shown that the progression of hearing loss in those that received FX-322 still realized ongoing deterioration in their hearing after initial restoration. This is what should be expected when the progression of a disease is modified by drug intervention. A patient gets X% better, rolling back their progression a few years, but eventually they return the original baseline without regular intervention. A perfect example is the long-term study on those Phase 1/2 patients.

As for measuring hearing loss:

Audiogram, Word Recognition, Word in Noise are the three COMMON assessments used in clinical practice to determine a patient's level or hearing loss. These three are generally accepted as the "standard" for hearing treatment practice across the United States. Even researchers and clinicians agree these tests are imperfect, not sensitive enough for specific conditions, and do not provide a complete picture of a patient's hearing condition. Yet, FX-322 has shown improvement, although not consistent, on all three tests.

 

[Trevor_phillips]

Please provide evidence to support the following statements:

If I take the example of a teacher explaining a lesson to his students in a large auditorium, assuming that all students have excellent hearing, the teacher will still need a microphone to properly interact with the whole room.

This is what I want to explain. A minimum amount of amplification is fundamental even if the mechanical-electrical transduction triggered by the inner hair cells is very good. Students basically won't understand anything even if they have inner ear hair cells in good health.

So, based on the fact that hearing loss is mostly about destroyed outer hair cells and inner hair cells as well, one cannot be able to figure out something without an minimal improvement at sound amplification. In addition to, it is known that outer hair cells have the role of filter, they allow (with synapses) to indirectly understand speech in noisy environments.

This is the reason why hearing aids are limited in noisy environment, because OHCs are damaged and they perceive upcoming sounds as an hubbub, despite good inner hair cells condition.

For OTO-6XX, it is known that Otonomy is using a gel (for instance like the one used in OTO-413/OTO-313) that can be long lasting, so the effect could be very sustainable and could reach the cochlea from the apex to the base.

For the rest, I'm basing my speech on the currents pre-clinical tests that they're doing currently (they said indirectly that they're pleased with what they're seeing) and the picture reconstruction, with hair cells marked in green. We don't have any picture of FX-322 regrowing hair cells and the one used by Frequency Therapeutics is from Novartis.

 

[Kleiner]

Just my opinion:

FX-322 in the upcoming results must show clinically significant results in WR and extended audiogram tests, even if they are minimal, they must prove that the drug works.

WR tests measure IHC but also OHC, the two are inseparable.

The theory that FX-322 already repairs IHCs and then OHCs is limited, some patients have damaged OHCs and almost no IHC damage.

The only explanation would be that OHCs cannot grow back unlike IHCs, but it will take clear results on WR tests to prove it.

Their biggest mistake is not adding objective tests like OHC emissions

With the two studies of Phase 1b and Phase 2a, I think we will have enough evidence to declare the FX-322 as working or not.

We don't have enough information to form a solid opinion, positive or negative.

 

[Street Novelist]

If I take the example of a teacher explaining a lesson to his students in a large auditorium, assuming that all students have excellent hearing, the teacher will still need a microphone to properly interact with the whole room.

This is what I want to explain. A minimum amount of amplification is fundamental even if the mechanical-electrical transduction triggered by the inner hair cells is very good. Students basically won't understand anything even if they have inner ear hair cells in good health.

So, based on the fact that hearing loss is mostly about destroyed outer hair cells and inner hair cells as well, one cannot be able to figure out something without an minimal improvement at sound amplification. In addition to, it is known that outer hair cells have the role of filter, they allow (with synapses) to indirectly understand speech in noisy environments.

This is the reason why hearing aids are limited in noisy environment, because OHCs are damaged and they perceive upcoming sounds as an hubbub, despite good inner hair cells condition.

For OTO-6XX, it is known that Otonomy is using a gel (for instance like the one used in OTO-413/OTO-313) that can be long lasting, so the effect could be very sustainable and could reach the cochlea from the apex to the base.

For the rest, I'm basing my speech on the currents pre-clinical tests that they're doing currently (they said indirectly that they're pleased with what they're seeing) and the picture reconstruction, with hair cells marked in green. We don't have any picture of FX-322 regrowing hair cells and the one used by Frequency Therapeutics is from Novartis.

Do we know when Otonomy is going to start clinical trials for OTO-6XX? I haven't seen anything from them.

 

[Trevor_phillips]

Do we know when Otonomy is going to start clinical trials for OTO-6XX? I haven't seen anything from them.

Absolutely nothing is known about OTO-6XX. They did say that they are going to claim any information when they'll have an update to provide about the current pre-clinical tests. I won't be surprised if this is after OTO-413 results in mid-2022. I think that OTO-6XX will move to clinical trials when Otonomy will have enough cash, after the next phases of OTO-413/OTO-313.

 

[Zugzug]

To be honest, you're treading on unrealistic expectations territory with this comment.

How do we define any drug as a bonafide CURE for hearing loss, and associated symptoms (tinnitus, hyperacusis, distortions, et al)? FX-322 cannot simply be a CURE for hearing loss by itself, because it's been known from very early on (as early as 2018) that it cannot repair areas of the cochlea where the synaptopathy is present with otherwise healthy hair cells. So, in any individual, where hearing loss is likely a mixed pathology (dead cells + synaptopathy), it may only be able to resolve part of the underlying condition leading to hearing loss. Therefore, FX-322 ALONE can never be a full hearing loss cure. It can only partially treat a specific underlying issue.

To get even more philosophical on you, how do we define a CURE for hearing loss? Is one cured when their hearing is fully restored back to the day they shot out of mom's uterus? Or just when they're able to ACE the three standard hearing loss tests (Audiogram, WR, WIN)? Or does the CURE mean that they no longer experience tinnitus at all? Is that possible? Some have provided old research that shows that people with "normal" hearing still experience tinnitus when things get uber quiet. So, what's the cure benchmark there? How about hyperacusis? Or, is the CURE when someone's quality of life gets above a certain "normal" threshold?

This is why Frequency Therapeutics uses the term, "Disease Modifying Effect"... FX-322 is a treatment for those with SNHL/NIHL where hair cell death/damage has occurred. It has been demonstrated in vitro that FX-322 is restoring lost hearing by replacing those poorly performing/missing cells. This is also believed to be happening in vivo, and has been observed by those clinical measurement improvements. Even though the patient saw a benefit from specific hair cells being restore anew, neighboring hair cells and those untouched by FX-322 may still be at their aged/worn state, or have some form of synaptopathy. Therefore, FX-322 can only modify their hearing loss disease so much, but not likely to a NEW state. It's also been shown that the progression of hearing loss in those that received FX-322 still realized ongoing deterioration in their hearing after initial restoration. This is what should be expected when the progression of a disease is modified by drug intervention. A patient gets X% better, rolling back their progression a few years, but eventually they return the original baseline without regular intervention. A perfect example is the long-term study on those Phase 1/2 patients.

View attachment 44703

As for measuring hearing loss:

Audiogram, Word Recognition, Word in Noise are the three COMMON assessments used in clinical practice to determine a patient's level or hearing loss. These three are generally accepted as the "standard" for hearing treatment practice across the United States. Even researchers and clinicians agree these tests are imperfect, not sensitive enough for specific conditions, and do not provide a complete picture of a patient's hearing condition. Yet, FX-322 has shown improvement, although not consistent, on all three tests.

Some users will shoot me dead, but I consider the current formulation of FX-322 to be like an attempt at a small cure. I think the difference between a treatment and cure is that a treatment is intended on covering up a problem.

Now of course, a great treatment can actually be better than a small cure. For example, Ebselen, as a potential treatment for inflammation and NMDA excitability, could be a great treatment. Prednisone can be a great treatment.

Growing hair cells is a cure. It doesn't cure all of hearing loss, but it's a real attempt at a cure. Most people with chronic illness know the difference.

 

[Tezcatlipoca]

Ebselen, as a potential treatment for inflammation and NMDA excitability, could be a great treatment.

I didn't realize it's also an NDMA antagonist. That's great! Its the same stuff as OTO-313