Frequency Therapeutics — Hearing Loss Regeneration

[Mentos]

I find it odd that they are not doing any audiogram measurements. I don't think regenerating hair cells for 10 kHz and up would really affect speech perception much. Maybe it would bring some clarity to the sound, but I can't imagine it would be much.

Nonetheless, interesting results and could be promising for FX-345.

Does anyone know if FX-345 would have to go through the whole approval process even if the main compound of a drug is the same as FX-322? (Assuming FX-322 gets the approval finally.)

 

[Jurger]

Exactly. People in this thread are wondering why the results weren't that good and we have to remember this is for participants who have severe hearing loss. We also have to remember that the difference in hearing improvements had to be 3.1 dB or greater. For all we know there may have been more patients who were near a 3.1 dB improvement but unfortunately Frequency Therapeutics aren't going to say the improvements for each patient.

But if 4/25 in the severe hearing loss had a 3.1 dB improvement in hearing or greater in certain frequencies then imagine what the mild-moderately severe hearing loss patients results will look like end of next year.

This may be enough to get rid of tinnitus permanently.

There comes a point where we just have to admit the drug doesn't work that well.

When the Phase 1/2 trial hardly did anything for audiograms. "Well, word scores are more important anyway."

When the Phase 2a trial failed. "Well, people lied".

When the presbycusis trial failed. "Well, they're old".

When the new Phase 1/2 trial barely did anything. "Well, these are mild-moderate patients, not much room for improvement."

And now with the severe trial. "Well, theor hearing was very crappy to begin with."

Look, I love the taste of copium too. I've been there. But it doesn't fix our hearing issues.

 

[kiki]

There comes a point where we just have to admit the drug doesn't work that well.

When the Phase 1/2 trial hardly did anything for audiograms. "Well, word scores are more important anyway."

When the Phase 2a trial failed. "Well, people lied".

When the presbycusis trial failed. "Well, they're old".

When the new Phase 1/2 trial barely did anything. "Well, these are mild-moderate patients, not much room for improvement."

And now with the severe trial. "Well, theor hearing was very crappy to begin with."

Look, I love the taste of copium too. I've been there. But it doesn't fix our hearing issues.

No drug works for all people and all symptoms.

The important thing is to determine what works and what doesn't. And to maximize the effect and make it bigger.

Then develop new drugs for ineffective symptoms.

Hearing restoration is the development of a whole new field of medicine. It is natural that the method of clinical trial is trial and error. This is a difficult clinical trial in which the subjective reaction (hearing / not hearing) of the patient has a great influence. Now, they are trying to make it objective.

 

[Diesel]

Does anyone know if FX-345 would have to go through the whole approval process even if the main compound of a drug is the same as FX-322? (Assuming FX-322 gets the approval finally.)

It has to start from the beginning. BUT, trial design and other lessons learned from FX-322 will be applied to FX-345. So, it stands to reason that the trial path might be better controlled.

There comes a point where we just have to admit the drug doesn't work that well.

When the Phase 1/2 trial hardly did anything for audiograms. "Well, word scores are more important anyway."

When the Phase 2a trial failed. "Well, people lied".

When the presbycusis trial failed. "Well, they're old".

When the new Phase 1/2 trial barely did anything. "Well, these are mild-moderate patients, not much room for improvement."

And now with the severe trial. "Well, theor hearing was very crappy to begin with."

Look, I love the taste of copium too. I've been there. But it doesn't fix our hearing issues.

Sounds like you're kind of quoting what you wanted to read, to justify yourself publicly. I recall plenty of insightful discussion right here in this thread about the biology of the cochlea, brain, et al regarding the Phase 1/2, 2A, 111, 112, and 113 trials. Not all of it dismissed or justified what happened in the trials as an excuse to simply say the drug still "works" or "doesn't" outright. The ongoing relevant question is: What type of patient does it have the greatest effect on?

If you recall, the Presbycusis and Severe trials were added in July, 2020 to determine if patients with these etiologies should be INCLUDED in the FX-322 clinical study pipeline. Looks like they shouldn't, as they'll muddy the outcomes. This is totally normal to see companies do this for any drugs. Do some homework on cancer or MS drugs, for example. They'll do branch studies that fail, yet the drugs still hit the market.

If you take the time to review what Frequency Therapeutics provide, they seem to think patients with Moderate-Moderately Severe SSNHL/NIHL. Is it a cure? No it isn't. But could it restore some hearing? There's about a 27% - 40% chance it will for this cohort in a significant way. And this for a drug that barely even gets into the base of the cochlea.

 

[Tau]

Does anyone know if FX-345 would have to go through the whole approval process even if the main compound of a drug is the same as FX-322? (Assuming FX-322 gets the approval finally.)

The main compound is not the same, though, is it? It's CHIR99021 in FX-322 vs (possibly modified) LY2090314 in FX-345.

 

[Koz]

There comes a point where we just have to admit the drug doesn't work that well.

When the Phase 1/2 trial hardly did anything for audiograms. "Well, word scores are more important anyway."

When the Phase 2a trial failed. "Well, people lied".

When the presbycusis trial failed. "Well, they're old".

When the new Phase 1/2 trial barely did anything. "Well, these are mild-moderate patients, not much room for improvement."

And now with the severe trial. "Well, theor hearing was very crappy to begin with."

Look, I love the taste of copium too. I've been there. But it doesn't fix our hearing issues.

The stock price reflects everything you need to know. Frequency Therapeutics to date has been nothing but promises dwindled and watered down again and again - they have been transparent I'll give them that but it's this very transparency (mostly redacting their expectations) when other drugs/biotechs in this field have sucked at this is why it has some sufferers still supporting them.

I sometimes wonder if the people with mild hearing loss or mild tinnitus or ones with no visible loss on the audiogram really underestimate how much a severe loss on the audiogram is impactful and for a drug that's testing based on word scores so far to be defended so staunchly, please give me a break. You're clutching at straws here. For a drug that has had excellent ex-vivo results to suck donkey dick in-vivo under different circumstances to date isn't promising, no matter how optimistic and reasonable the latest "yeah but..." is.

The best part was all the scientists on here who wrote essays and walls of texts in the previous stages only for the thing to constantly bring poor to very average results in actual trials. You can discuss all you want but until they come with impressive Phase 2 clinical results be it from this or FX-345 then keep your sanity by keeping your expectations low and look after yourself in the best way you can. Reading tinnitus message board scientists getting your hopes up falsely ain't it. Enough potential drugs have come and go for this to be common knowledge by now.

 

[d'Wooluf]

It's hard to let go of though, isn't it. Like here I still am on page 636.

 

[kiki]

The stock price reflects everything you need to know. Frequency Therapeutics to date has been nothing but promises dwindled and watered down again and again - they have been transparent I'll give them that but it's this very transparency (mostly redacting their expectations) when other drugs/biotechs in this field have sucked at this is why it has some sufferers still supporting them.

I would like to see another Phase 2b in 2022.

A single (not continuous) injection at appropriate intervals (not weekly) for mild to moderate patients.

They said they were thinking of implementing it. There is plenty of time for a year.

If consultation with the FDA is difficult, they can be optional, such as FX-322-111.

 

[Lucifer]

I would like to see another Phase 2b in 2022.

A single (not continuous) injection at appropriate intervals (not weekly) for mild to moderate patients.

They said they were thinking of implementing it. There is plenty of time for a year.

If consultation with the FDA is difficult, they can be optional, such as FX-322-111.

As long as it doesn't hold back the current Phase 2b trial from coming out in the market then I support this but if the trial that you're suggesting causes delay I would rather they just focus on the single dose only.

 

[Joeseph Stope]

The stock price reflects everything you need to know. Frequency Therapeutics to date has been nothing but promises dwindled and watered down again and again - they have been transparent I'll give them that but it's this very transparency (mostly redacting their expectations) when other drugs/biotechs in this field have sucked at this is why it has some sufferers still supporting them.

I sometimes wonder if the people with mild hearing loss or mild tinnitus or ones with no visible loss on the audiogram really underestimate how much a severe loss on the audiogram is impactful and for a drug that's testing based on word scores so far to be defended so staunchly, please give me a break. You're clutching at straws here. For a drug that has had excellent ex-vivo results to suck donkey dick in-vivo under different circumstances to date isn't promising, no matter how optimistic and reasonable the latest "yeah but..." is.

The best part was all the scientists on here who wrote essays and walls of texts in the previous stages only for the thing to constantly bring poor to very average results in actual trials. You can discuss all you want but until they come with impressive Phase 2 clinical results be it from this or FX-345 then keep your sanity by keeping your expectations low and look after yourself in the best way you can. Reading tinnitus message board scientists getting your hopes up falsely ain't it. Enough potential drugs have come and go for this to be common knowledge by now.

Maybe you are a bit too pessimistic, or perhaps a bit too realistic. AFAIK the heart of the rowl is to imitate nature. We know that birds and fishes can regenerate damaged hearing. Some mammals... or lizards can regenerate things like tails. The hope is that modern bio-pharma can trigger the body to somehow imitate nature -- in humans that is.

In technology and in most things, nothing ever works 100% on the first go. You have to keep going back to the drawing board and tweaking it. Just like a software program. It very rarely works tip top on the first attempt.

Even if they do come to a dead-end somewhere down the line, great things are achievable. That University... Gallaudet or some such name is a University devoted to those who are deaf/hard of hearing. That was something revolutionary when the concept first came up.

So we wait and wait for the outcome of these trials. Mind you, I wouldn't bet the farm on it but I'll certainly be cheering them on. They are fighting on our side. So many other medical/bio-pharma outfits are invested in cosmetics or nose jobs or bottom lifts.

That's where the big money is, I guess.

 

[kiki]

As long as it doesn't hold back the current Phase 2b trial from coming out in the market then I support this but if the trial that you're suggesting causes delay I would rather they just focus on the single dose only.

I have the same idea.

And if that premise is possible, I want them to do it and succeed.

I would like to see that there is no depletion of sustentacular cells, which is an advantage of FX-322, and the effect is cumulative with each injection.

Multiple injections in a very short period of time, in the sense of pushing the molecule into the cochlea, was meaningless and rather harmful.

I have tinnitus and mild hearing loss above 4 kHz.

If both are successful, there is a lot of hope for the FX-345, which seems to have similar advantages.

Especially for mild hearing loss.

 

[Chad Lawton]

You're clutching at straws here. For a drug that has had excellent ex-vivo results to suck donkey dick in-vivo under different circumstances to date isn't promising, no matter how optimistic and reasonable the latest "yeah but..." is.

Being able to soak cochlear progenitor cells in FX-322 for hours on end in a petri dish is a long ways away from the current administration method of having it barely touch the first 10% of the cochlea. The fact we are seeing a 33% to 40% rate on average in moderate to moderately severe patients while barely penetrating the cochlea with a first generation hearing loss therapeutic is a scientific breakthrough... and they are already working on a gen 2 version.

As for the people who don't consider FX-322's current results promising; they would be the same type of people that would be disappointed that the Wright brother's glider couldn't do a trans-Atlantic flight on day 1.

 

[Artem]

Mass Eye and Ear is working on stem cells to reverse blindness right now.

Please give me a link.

 

[NYCGuy]

Please give me a link.

Reversing blindness with stem cells

 

[Gb3]

Please give me a link.

CRISPR Gene Therapy Update: Seeing a Sunset

 

[Artem]

Reversing blindness with stem cells

I am very glad that the Massachusetts Eye and Ear Institute continues their active work. I always watch the news about them with hope.

I really hope that Mass Eye and Ear is not a scam after all.

 

[GlennS]

It's not all or nothing, it's not now or never

It is... if they run out of money.

 

[Koz]

Being able to soak cochlear progenitor cells in FX-322 for hours on end in a petri dish is a long ways away from the current administration method of having it barely touch the first 10% of the cochlea. The fact we are seeing a 33% to 40% rate on average in moderate to moderately severe patients while barely penetrating the cochlea with a first generation hearing loss therapeutic is a scientific breakthrough... and they are already working on a gen 2 version.

This is fair but considering your competition (Otonomy) has trademarked a specific delivery and gel formulation you'd think they'd know this is a problem and performance indicator they needed to tackle before even starting their Phase 2's that have all brought very very minor results. I hope I am wrong in all of this and something comes of it for your sake, my sake and everyone's sake on here but when you look at how their trials so far have been a mess and underwhelming then surely you can understand the scepticism?

As for the people who don't consider FX-322's current results promising; they would be the same type of people that would be disappointed that the Wright brother's glider couldn't do a trans-Atlantic flight on day 1.

Not really, just seen enough drugs come and go that people put their hopes behind for over a decade.

 

[Chad Lawton]

you'd think they'd know this is a problem and performance indicator they needed to tackle before even starting their Phase 2's that have all brought very very minor results.

And they have been aware of this problem, hence why they are already filing an IND for FX-345 in less than 6 months from now. That pre-clinical data for FX-345 has been years in the making.

Their trials have not been "a mess"; they have completed 5 trials thus far and they only botched 1 of them. They were told by the FDA that they would need to explore all the different etiologies and severities of hearing loss in order to gain as broad a label as possible for FX-322 and that is why they have conducted so many small trials. Don't blame the company, blame the FDA if you think the way they are currently running trials is a mess. Sure, I'll give you that the company screwed up their first Phase 2 trial but to say their trials are a mess overall is not an accurate claim. Also, if you watched R&D day, it appears the company has done a good job of learning from their mistakes and has taken a number of corrective actions to prevent it from happening again.

You may consider it very very minor results but I think it's safe to say it was life changing results for subjects 1,3 & 4 from their Phase 1/2 study.

Hearing regeneration has never been done before in history and the field is finally seeing some of its first results but it blows my mind how many people don't care or are unimpressed because FX-322 won't restore them back to perfect hearing.

Say FX-322 gets approved by the FDA, will all the naysayers that find it unimpressive not bother getting it?

 

[kiki]

This is fair but considering your competition (Otonomy) has trademarked a specific delivery and gel formulation you'd think they'd know this is a problem and performance indicator they needed to tackle before even starting their Phase 2's that have all brought very very minor results.

Is it registered as a trademark?

They say it reaches the entire cochlea, but is there any objective evidence?

Did you confirm the effect of the medicine up to 500 Hz?

 

[kiki]

And they have been aware of this problem, hence why they are already filing an IND for FX-345 in less than 6 months from now. That pre-clinical data for FX-345 has been years in the making.

They (Frequency Therapeutics) said they would reach up to 4 kHz until the Phase 1/2 results were revealed.

4 kHz was their immediate goal.

It turned out that it did not reach 4 kHz in Phase 1/2, and I think that they were immediately working on improving the gel as an improvement measure.

At the same time, I think they tried short-term continuous injections as the next best option.

 

[EkkoMusic]

Say FX-322 gets approved by the FDA, will all the naysayers that find it unimpressive not bother getting it?

Really great point and thanks for attaching that data chart.

The one thing that's keeping me (and I guess others) suspicious though: What do we know about how word test results can fluctuate test to test? We already know about the test/retest margin of error for PTA (of which their reported 10-15dB is already pretty close to that…)

Of everyone in the trial, there had to be patients who just had a 'bad day' with their hearing on the baseline right (unless those values are all averages and just not single tests???)

Sorry if I'm coming across skeptical, this is just something I feel I need to understand better!

 

[Chad Lawton]

Sorry if I'm coming across skeptical, this is just something I feel I need to understand better!

It's okay to be skeptical and it's fair to ask reasonable questions. It's a whole other thing to come out and say that the company is trying to scam investors, they rushed things, the drug is dead, etc. which are just a few of the things that have been said about the company across different social media.

The company has said that based on the historical medical literature, we shouldn't see more than 2.5% of non treated ears improve to a statistically significant degree for word recognition scores. The results they have seen across their single dose studies have been pretty in line with that.

Another thing to keep in mind is that the placebo arm of the botched Phase 2a consisted of only 21 patients which is only 1/3 the size of the drug recipient group which had 69 patients in it. Out of the 21 placebo subjects, 10 saw an improvement and out of the 69 FX-322 dosed subjects, 30 saw an improvement. This is where we get the statement "it showed no benefit over placebo" as nearly 50% of both groups saw a response. So all it took was 10 people to ruin the 90 person study.

Sure, maybe one or two of them had a bad hearing day but its unlikely that a bad hearing day would be enough to show statistically significant improvements later on down the road. No, the values they entered the study with were not averages, they were results from a one time test and that is one of the mistakes the company has openly admitted to making. The new Phase 2 requires subjects test 3 times over a 1 month period for more baseline consistency. The company also admits to making the mistake of telling subjects they would need WR deficits in order to gain admission to the study, so what did some subjects do? They pretended to hear less words on the WR test for entry. The company is now using multiple WR hearing tests in the new Phase 2 and they are not telling the subjects what criteria they need or are looking for on those tests. It will also be much harder for subjects to lie 3 times across multiple WR tests and be consistent about it.

 

[Artem]

Аnother thing to keep in mind is that the placebo arm of the botched Phase 2a consisted of only 21 patients which is only 1/3 the size of the drug recipient group which had 69 patients in it. Out of the 21 placebo subjects, 10 saw an improvement and out of the 69 FX-322 dosed subjects, 30 saw an improvement. This is where we get the statement "it showed no benefit over placebo" as nearly 50% of both groups saw a response. So all it took was 10 people to ruin the 90 person study.

Sure, maybe one or two of them had a bad hearing day but its unlikely that a bad hearing day would be enough to show statistically significant improvements later on down the road. No, the values they entered the study with were not averages, they were results from a one time test and that is one of the mistakes the company has openly admitted to making. The new Phase 2 requires subjects test 3 times over a 1 month period for more baseline consistency. The company also admits to making the mistake of telling subjects they would need WR deficits in order to gain admission to the study, so what did some subjects do? They pretended to hear less words on the WR test for entry. The company is now using multiple WR hearing tests in the new Phase 2 and they are not telling the subjects what criteria they need or are looking for on those tests. It will also be much harder for subjects to lie 3 times across multiple WR tests and be consistent about it.

Hello, Chad Lawton! Why isn't the audiogram measured? After all, this is indisputable and clear. Purpose of the drug is to improve speech intelligibility in noise? Is this goal too narrow for a company that markets itself as developing a remedy for hearing loss?

Best regards,
Artem

 

[Gb3]

I was extremely excited about Frequency Therapeutics at first because of the anecdotal reports regarding tinnitus but there hasn't been any mention of it since their Phase 1 trials.

 

[Chad Lawton]

Hello, Chad Lawton! Why isn't the audiogram measured? After all, this is indisputable and clear. Purpose of the drug is to improve speech intelligibility in noise? Is this goal too narrow for a company that markets itself as developing a remedy for hearing loss?

Best regards,
Artem

According to ClinicalTrials.gov, audiograms are being measured in the new Phase 2 trial, they just aren't being used as a primary outcome.

Imagine having to build a plane while you're flying it. That is what the company is doing right now as hearing regeneration has never been done before. The initial expected outcome of the audiology community was that there were going to be improvements in audiograms when regenerating extended high frequency cochlear hair cells but instead we are seeing improvements in speech perception first. Side note, audiograms are no more indisputable than word recognition tests. Its just as easy to pretend you don't hear a beep as it is to pretend you don't understand a word.

I know many around here consider audiograms to be the divine trinity or the holy grail of hearing measurement but as hearing regeneration science advances, we are learning more and more about the intricacies of the inner ear and hearing. Now we know that the health of the cochlea can determine both loudness of sounds & clarity of sounds and there is a lot of time being spent now on learning how the two are related and what anatomic parts of the cochlea are responsible for each.

For those so focused on audiograms and who have little interest in clarity, I pose this question to you. If you have a blown out speaker in your car or your surround sound system in your house and that speaker sounds absolutely terrible, scratchy & distorted, etc; would you be satisfied by just cranking up the speaker and listening to the distorted music louder? Would that improve the quality of the experience you get from that speaker? Or would you prefer to fix the distortion? Say you do manage to fix the distortion from that speaker; is that not considered an improvement to the sound coming from that speaker much like improving speech perception is an improvement to hearing?

 

[kiki]

Its just as easy to pretend you don't hear a beep as it is to pretend you don't understand a word.

I heard they seemed to say in the webinar that there was no improvement in EHFPTA in Phase 2.

Do you think this means "compared to a placebo"?

Do you think EXFPTA had the same problems as word recognition?

I think a cheat that doesn't hear a beep is easier than a cheat that doesn't understand a word.

 

[Artem]

According to ClinicalTrials.gov, audiograms are being measured in the new Phase 2 trial, they just aren't being used as a primary outcome.

Imagine having to build a plane while you're flying it. That is what the company is doing right now as hearing regeneration has never been done before. The initial expected outcome of the audiology community was that there were going to be improvements in audiograms when regenerating extended high frequency cochlear hair cells but instead we are seeing improvements in speech perception first. Side note, audiograms are no more indisputable than word recognition tests. Its just as easy to pretend you don't hear a beep as it is to pretend you don't understand a word.

I know many around here consider audiograms to be the divine trinity or the holy grail of hearing measurement but as hearing regeneration science advances, we are learning more and more about the intricacies of the inner ear and hearing. Now we know that the health of the cochlea can determine both loudness of sounds & clarity of sounds and there is a lot of time being spent now on learning how the two are related and what anatomic parts of the cochlea are responsible for each.

For those so focused on audiograms and who have little interest in clarity, I pose this question to you. If you have a blown out speaker in your car or your surround sound system in your house and that speaker sounds absolutely terrible, scratchy & distorted, etc; would you be satisfied by just cranking up the speaker and listening to the distorted music louder? Would that improve the quality of the experience you get from that speaker? Or would you prefer to fix the distortion? Say you do manage to fix the distortion from that speaker; is that not considered an improvement to the sound coming from that speaker much like improving speech perception is an improvement to hearing?

The audiogram can be extended (up to 16 kHz inclusive). In rare cases, a person's speech captures 8 kHz. If the drug does not reach the appropriate depth, then where do the changes in word perception come from?

To the Question of the honesty of the subjects - you can give a combination of short and long signals.

P.S. I don't quite share this analogy with a damaged audio system and an increase in volume. I think the analogy with adjusting frequencies with an equalizer is more appropriate.

Best regards,
Artem

 

[Street Novelist]

Can someone answer me this: if I am ineligible to be in their trial due to having too good word scores, does that mean I'll have to wait until it's released to the open market, or would I still be ineligible?

 

[SD7]

The audiogram can be extended (up to 16 kHz inclusive). In rare cases, a person's speech captures 8 kHz. If the drug does not reach the appropriate depth, then where do the changes in word perception come from?

To the Question of the honesty of the subjects - you can give a combination of short and long signals.

P.S. I don't quite share this analogy with a damaged audio system and an increase in volume. I think the analogy with adjusting frequencies with an equalizer is more appropriate.

Best regards,
Artem

The delivery critique is well warranted and they are working on it in the reformulation of FX-322 and the upcoming FX-345. It's not as rare as you may think, f, s and t can breach that upper bound depending on the pitch of the speaker.

You're right there are most sophisticated ways to perform audiograms, however audiograms are primarily testing the outer hair cells whereas frequency is primarily interested in regenerating the inner hair cells for clarity.

I think the aforementioned analogy is fine if you consider the difference purposes the hair cells have. Outer hair cells amplify sounds and can be tested via the audiogram whereas the inner hair cells are for clarity and can be tested via word scores or word in noise tests. @Chad Lawton is right if you had to choose between clarity and loudness you should almost always prefer an increase in clarity. Hearing aids can help with subsets of outer hair cell dysfunction however there is no equivalent for clarity.