Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

I guess everyone does the tests differently.

My experience has been the opposite of what you mentioned. You are in a soundproof booth, sometimes they are there with you, sometimes they are on the other side of a clear glass. I've always been able to see the person administering the test while they are giving it and I have quite a few hearing tests under my belt...

I was following CRISPR for a while but from what I read you have to do it before you lose your hearing to rewrite the faulty gene that causes hearing loss. Once you've lost your hearing it is too late.

Just as another data point, I have never been able to see the audiologist and read lips either and I have had 4 audiograms in two different states.

 

[FGG]

This has been discussed every 2 or 3 pages on this thread but I think one reason it's extremely implausible that the word score improvements were due to any kind of "learning effect" or poorly controlled trial that allowed for lip reading is that the patients would have had to be "in on it" for this to work.

What I mean is that they tested the untreated ear in each patient and did not get word score improvements in any of them (nor the placebo group). This would mean that the treated patients would have to know they got drug vs placebo and be willing to put more effort into a "learning effect" for one ear and not the other (or fake not being able to do this for the untreated ear).

I think that's almost conspiracy theory territory and I'm really not buying it.

 

[Diesel]

This has been discussed every 2 or 3 pages on this thread but I think one reason it's extremely implausible that the word score improvements were due to any kind of "learning effect" or poorly controlled trial that allowed for lip reading is that the patients would have had to be "in on it" for this to work.

What I mean is that they tested the untreated ear in each patient and did not get word score improvements in any of them (nor the placebo group). This would mean that the treated patients would have to know they got drug vs placebo and be willing to put more effort into a "learning effect" for one ear and not the other (or fake not being able to do this for the untreated ear).

I think that's almost conspiracy theory territory and I'm really not buying it.

Thanks for reminding readers about the untreated ear tests! I always forget about that part of the test! It would be helpful if Frequency Therapeutics re-iterated this in their Investor Presentation.

 

[all to gain]

Ever time I read this thread I go from real high to real lows.

Today, I'm feeling that I might as well start learning sign language so I'm prepared for my future.

 

[tommyd87]

Word score tests are performed in the sound-proof booth. They're a randomized, 25 or 50 word set of pre-recorded prompts. They're played through headphones at roughly 50 dB. The patient is supposed to repeat what words they've heard.

Typically it's a voice saying, "Say the word 'crash'" for example.

There's no way to read lips, because there isn't a person telling you what to repeat. You're in the sound booth with no visual cues.

It's normal for patients to be +/- 3 words (a 6-word spread) if they retake the test on a regular basis. So, over the course of a year, you could have scores of 20, 23, 26, and 24, and that would be normal.

Patients that did not receive FX-322 in the Phase 1/2 stayed within this normal range across the 90-day testing window. Those with more to gain (the group of 5) saw their scores improve significantly higher than the normal 6-word variance.

Since the p-value on the word score chart in the frequency presentation is 0.010 for word score, we know that the others who received FX-322 also saw an improvement, although not statistically significant. Likely do to a ceiling effect.

My guess is that they saw 10-20% improvements on average in word score consistently within the +/- 3 range. This would help explain why the p-value is showing significance, and further reinforcing that it was FX-322 providing the benefit and nothing else.

For example: A mild patient may have been at 40 words at the start of the trial (+/- 3 giving them a range of 37-43 words). At the end of the trial they probably consistently scored 45 words (42-48 correct word range). These types of results will drive that p-value down, but not be very "groundbreaking" from a clinical or investor standpoint.

There are also mild hearing loss patients who are able to get an almost full score on word recognition tests, therefore they completely negate the benefit of these tests to show whether they got a benefit or not from FX-322. The word recognition improvement is significant simply because it is impossible to improve in any way other than actually attaining the benefit from FX-322. My view is that any audiologist willing to dismiss their validity is going to need to come up with some seriously substantial reasoning to validate their contention. Clearly Frequency Therapeutics tested this because they knew that this test would give a very positive indication on how someone's hearing has improved, for example.

I also am interested in how any audiologist can believe that the word recognition tests are too varied and unreliable, especially when the proper tests tend to have something like 400 or so words in them and are always completely randomised. I think that simple logic dictates that if the tests are varied and randomised in nature then there tends to be a lot more accuracy and validity in them for the simple reason it is impossible to manipulate the outcome.

The fact that of the 4 or 5 people in the inaugural trial that appeared to demonstrate substantial word recognition improvement not only did so but were also actually able to maintain this after the trial is the best indication that FX-322 is beneficial and effective. There are no plausible reasons or arguments put forward as yet which will dismiss the validity of the results and as a result I reckon that this is why there is criticism of the outcomes because this has never been achieved before.

 

[tommyd87]

Thank you for your evaluation.

That's right, I think Frequency Therapeutics wants to run straight to the market with its current specifications.

Therefore, I hope the Phase2a results are effective in the deeper low frequency range with multiple injections.

If this is demonstrated, I think it will have a great effect, for example, repeating a set of four injections at intervals of several months.

If the therapeutic effect reaches up to,it's the original goal,3500Hz
more patients will expect the effect, and more patients will need to inject that many times, so the unit price of the drug will be able to be set at a more accessible price.
They will be able to reduce the profit margin of the drug for a single injection.

I may be too optimistic.

I don't think you are being very optimistic but rather you are being very rational. Right now if it is the case that Frequency Therapeutics can get FX-322 down to 3500 Hz, then that obviously demonstrates very good treatment outcomes from its current capability and would be excellent for everyone.

I think that the straight to market move is very likely looking at what is happening right now if they can get this done utilising the current trial because it is inevitably going to be the best outcome for everyone.

I agree that the price of FX-322 will probably vary depending on the number of shots you need. If you need four shots as opposed to someone who needs three, then I can absolutely see Frequency Therapeutics charge a lower amount for the additional shot simply because it is smart business to do so and also it would be completely plausible and logical to encompass the development, manufacturing and any other overhead costs into the price of the initial dose(s).

I guess everyone does the tests differently.

My experience has been the opposite of what you mentioned. You are in a soundproof booth, sometimes they are there with you, sometimes they are on the other side of a clear glass. I've always been able to see the person administering the test while they are giving it and I have quite a few hearing tests under my belt...

I was following CRISPR for a while but from what I read you have to do it before you lose your hearing to rewrite the faulty gene that causes hearing loss. Once you've lost your hearing it is too late.

I don't know how it is in your nation, however in Australia, all actual word score recognition testing are usually done from an automatic recording, really for the whole purpose of not being able to have skewed results. I think I have seen some stuff in America too where the testing is done through the same method and it is I think the best practice.

I know that they tend to do these recorded word score recognition tests with people being evaluated for cochlear implants in order to demonstrate that the testing is legitimate.

I don't know much about CRISPR but I would have thought that this gene would have only played a role in some cases.

This has been discussed every 2 or 3 pages on this thread but I think one reason it's extremely implausible that the word score improvements were due to any kind of "learning effect" or poorly controlled trial that allowed for lip reading is that the patients would have had to be "in on it" for this to work.

What I mean is that they tested the untreated ear in each patient and did not get word score improvements in any of them (nor the placebo group). This would mean that the treated patients would have to know they got drug vs placebo and be willing to put more effort into a "learning effect" for one ear and not the other (or fake not being able to do this for the untreated ear).

I think that's almost conspiracy theory territory and I'm really not buying it.

This is absolutely accurate. At this stage something tells me that the types of people who were very quick to dismiss the widespread word recognition score increases (even in those were not statistically significant) may have ulterior motives in their assessments. This is probably one of the most unmanipulatable tests that can be taken because it is incredibly difficult to learn and/or be able to guess the answers to it.

There is good evidence that FX-322 was beneficial because basically, as you have pointed out, no one actually had any idea whether they got the drug or the placebo. This is why I think that there has been no one who has been able to criticise FX-322 and also provide plausible reasoning as to why the benefit can be faked or is not real because this is not subjective.

 

[Pete88]

Ever time I read this thread I go from real high to real lows.

Today, I'm feeling that I might as well start learning sign language so I'm prepared for my future.

There is no valid reason to not be optimistic about FX-322. So far, no one has put forward a valid, backed up theory as to why it won't at least improve high frequency hearing a little bit. All the negativity can be debunked by basic high school science.

This drug would not have the financial backing of several organizations equaling to several hundred million dollars if it wasn't a strong product.

We aren't talking about a few random scientists at the early stages of randomly testing some chemicals in a lab, making optimistic claims. We are talking about a legitimate product over half way through the process of being released for public consumption, with enthusiastic, big time financial backers.

Perhaps the pessimism is grounded in the fact that this truly is a breakthrough and as such, has never been seen before, which makes it hard to believe but there is nothing beyond blind pessimism that suggests FX-322 won't be beneficial to at least the high frequencies.

 

[FGG]

There is no valid reason to not be optimistic about FX-322. So far, no one has put forward a valid, backed up theory as to why it won't at least improve high frequency hearing a little bit. All the negativity can be debunked by basic high school science.

This drug would not have the financial backing of several organizations equaling to several hundred million dollars if it wasn't a strong product.

We aren't talking about a few random scientists at the early stages of randomly testing some chemicals in a lab, making optimistic claims. We are talking about a legitimate product over half way through the process of being released for public consumption, with enthusiastic, big time financial backers.

Perhaps the pessimism is grounded in the fact that this truly is a breakthrough and as such, has never been seen before, which makes it hard to believe but there is nothing beyond blind pessimism that suggests FX-322 won't be beneficial to at least the high frequencies.

Agree. I think the pessimism is at least partially routed in the drug being a breakthrough.

If you were on a Leber's Congenital Amaurosis forum, I'm sure there would have been Luxturna naysayers galore before the drug came out.

Same with Eteplirsen, Gilead's Hep C cure, Zenteglo, etc etc.

I think people are so used to drugs treating symptoms and not the underlying problem that it seems like science fiction that we now have the imaging technology, AI, gene sequencing (importantly including unlocking embryonic development genes that produces the structures we are now trying to regenerate), etc etc to tackle the underlying problems to disease and conditions.

 

[GBB]

Agree. I think the pessimism is at least partially routed in the drug being a breakthrough.

If you were on a Leber's Congenital Amaurosis forum, I'm sure there would have been Luxturna naysayers galore before the drug came out.

Same with Eteplirsen, Gilead's Hep C cure, Zenteglo, etc etc.

I think people are so used to drugs treating symptoms and not the underlying problem that it seems like science fiction that we now have the imaging technology, AI, gene sequencing (importantly including unlocking embryonic development genes that produces the structures we are now trying to regenerate), etc etc to tackle the underlying problems to disease and conditions.

Nobody wants to have their heart broken by their crush.

 

[tommyd87]

There is no valid reason to not be optimistic about FX-322. So far, no one has put forward a valid, backed up theory as to why it won't at least improve high frequency hearing a little bit. All the negativity can be debunked by basic high school science.

This drug would not have the financial backing of several organizations equaling to several hundred million dollars if it wasn't a strong product.

We aren't talking about a few random scientists at the early stages of randomly testing some chemicals in a lab, making optimistic claims. We are talking about a legitimate product over half way through the process of being released for public consumption, with enthusiastic, big time financial backers.

Perhaps the pessimism is grounded in the fact that this truly is a breakthrough and as such, has never been seen before, which makes it hard to believe but there is nothing beyond blind pessimism that suggests FX-322 won't be beneficial to at least the high frequencies.

Excellent post and I absolutely agree that FX-322 will be beneficial at least to the higher frequencies in its current form.

There is also a good chance that those investors may actually know some things that we don't know about FX-322's performance or have extreme confidence in the treatment.

I think that @FGG is fair in her belief that this treatment is going into new unchartered territory and I think that we are not only seeing people concerned with the unknown but also we are seeing people either not believing this can happen or not thinking that this will happen.

I have a feeling that once we see FX-322 get approved and also shown to work we will see that a large amount of the fear in the effectiveness of FX-322 is gone then. We will also see that those trying to downplay this treatment will be silent and not able to try to convince us that there is no way for something like this to work.

 

[serendipity1996]

Agree. I think the pessimism is at least partially routed in the drug being a breakthrough.

If you were on a Leber's Congenital Amaurosis forum, I'm sure there would have been Luxturna naysayers galore before the drug came out.

Same with Eteplirsen, Gilead's Hep C cure, Zenteglo, etc etc.

I think people are so used to drugs treating symptoms and not the underlying problem that it seems like science fiction that we now have the imaging technology, AI, gene sequencing (importantly including unlocking embryonic development genes that produces the structures we are now trying to regenerate), etc etc to tackle the underlying problems to disease and conditions.

Totally agree - they have also made enormous strides in cystic fibrosis treatments, for instance, with the approval of Trikafta (Kaftrio) which has been described as revolutionary as it targets the underlying mechanisms and significantly improves lung function. That's another area of medical research where huge progress has been made.

 

[sensualmosquito]

I hope that this stuff works, and the science is certainly there. It is a drug that is the first of its kind, and there is a lot that we don't quite know about yet. I think it's totally fine to speculate, as we are all hoping for this to work, but in the end I think we'll have to wait until the Phase 2a trials give us some concrete information about its true efficacy.

I was hoping that they would have some results by 2020, but that dumb SARS-CoV-2 decided to show up and ruin things for everyone.

It reminds me about how bad of a year this was for so many of us, including myself. We just need to keep holding on.

 

[frpp]

I think the dream is for regenerative drugs like FX-322, OTO-413, Hough Ear Institute Pill etc to work so well that the next time any of us sees an audiologist they'll be behind a counter wearing a paper hat and asking if we'd like fries with that.

 

[Michael01]

To be honest, I'm hopeful that both FX-322 and OTO-413 can be released together, as in my case I suspect that I may need both to fix my tinnitus problems. I severely doubt that one without the other will have any effect, but I don't know what caused my tinnitus in the first place either, due to the fact that the tools to diagnose tinnitus don't appear to exist yet...

 

[all to gain]

There is no valid reason to not be optimistic about FX-322. So far, no one has put forward a valid, backed up theory as to why it won't at least improve high frequency hearing a little bit. All the negativity can be debunked by basic high school science.

This drug would not have the financial backing of several organizations equaling to several hundred million dollars if it wasn't a strong product.

We aren't talking about a few random scientists at the early stages of randomly testing some chemicals in a lab, making optimistic claims. We are talking about a legitimate product over half way through the process of being released for public consumption, with enthusiastic, big time financial backers.

Perhaps the pessimism is grounded in the fact that this truly is a breakthrough and as such, has never been seen before, which makes it hard to believe but there is nothing beyond blind pessimism that suggests FX-322 won't be beneficial to at least the high frequencies.

I am pessimistic for sure, but I would rather fear the worst and then be pleasantly surprised than vice versa.

 

[ThomasRobert]

Anyone watch the new Netflix series "Deaf U"?

 

[kiki]

If Phase 2a is successful, what is the purpose of the next trial, assuming that the next stage is Phase 2b / 3?

I suspect it might be like this:

Phase 1
・ Safety confirmation
→ Confirmed that it is safe.

Phase 2a
・ Is it effective for multiple injections?
→ If successful, assume the result is effective.

Phase 2b / 3
・ How much can the effect of multiple injections be extended by increasing the number of injections?
→ It 's a little extreme, but, they will compare the effects of the 4-injection group, 8-injection group, 16-injection group, and placebo group. Four injections every other week are repeated at intervals of several months. In addition, some subjects received 16 placebo injections.

I think the content to be investigated in Phase 2b / 3 is the relationship between the number of injections and the drug efficacy. How about that? Are there any other matters to investigate?

Of course, safety is always checked at all phases.

Or will Phase 2b / 3 carry out the same content as Phase 2a for a large number of people, including Europe and Asia?

 

[Michael01]

If a drug like FX-322 is released, are there any diagnostic tools currently available to make sure that it will actually work on the patient? Or is it just hit-and-miss? As if something like this is released I'd like to make sure that it would at least help me in some respect before I spent money on it...

 

[RB2014]

I am pessimistic for sure, but I would rather fear the worst and then be pleasantly surprised than vice versa.

Many of us were in the thread discussing Novartis CGF-166... Sounded very promising, even going into clinical trials and then it just fizzled off and I think it is now dead. We spent years discussing it. I think everyone in this thread is hoping this works or we wouldn't be here.

This has been discussed every 2 or 3 pages on this thread but I think one reason it's extremely implausible that the word score improvements were due to any kind of "learning effect" or poorly controlled trial that allowed for lip reading is that the patients would have had to be "in on it" for this to work.

What I mean is that they tested the untreated ear in each patient and did not get word score improvements in any of them (nor the placebo group). This would mean that the treated patients would have to know they got drug vs placebo and be willing to put more effort into a "learning effect" for one ear and not the other (or fake not being able to do this for the untreated ear).

I think that's almost conspiracy theory territory and I'm really not buying it.

I think this is a really good point. We can talk what ifs all day long but I agree that the data in this study should be considered valid.

 

[FGG]

If a drug like FX-322 is released, are there any diagnostic tools currently available to make sure that it will actually work on the patient? Or is it just hit-and-miss? As if something like this is released I'd like to make sure that it would at least help me in some respect before I spent money on it...

An extended audiogram would help. Beyond that, diagnostics aren't great.

 

[FGG]

If Phase 2a is successful, what is the purpose of the next trial, assuming that the next stage is Phase 2b / 3?

I suspect it might be like this:

Phase 1
・ Safety confirmation
→ Confirmed that it is safe.

Phase 2a
・ Is it effective for multiple injections?
→ If successful, assume the result is effective.

Phase 2b / 3
・ How much can the effect of multiple injections be extended by increasing the number of injections?
→ It 's a little extreme, but, they will compare the effects of the 4-injection group, 8-injection group, 16-injection group, and placebo group. Four injections every other week are repeated at intervals of several months. In addition, some subjects received 16 placebo injections.

I think the content to be investigated in Phase 2b / 3 is the relationship between the number of injections and the drug efficacy. How about that? Are there any other matters to investigate?

Of course, safety is always checked at all phases.

Or will Phase 2b / 3 carry out the same content as Phase 2a for a large number of people, including Europe and Asia?

Phase 3 is generally largely a comparison to the "standard of care" and I'm not sure how that would work with this drug but another component of phase 3 is larger safety study for more rare side effects.

 

[Pete88]

If a drug like FX-322 is released, are there any diagnostic tools currently available to make sure that it will actually work on the patient? Or is it just hit-and-miss? As if something like this is released I'd like to make sure that it would at least help me in some respect before I spent money on it...

Not really anything beyond testing your hearing and maybe some insight into your general health, in order to make a guess as to how much of your hearing loss is influenced by other conditions.

Either way, you are kidding yourself if you think you don't have hair cell loss. Those things die as time goes on, especially in modern society with cars, stereos, bars, music, power tools etc. That's why it's actually completely normal for someone in their 30s to not be able to hear 16,000 Hz and beyond while a 20 year old is supposed to be able to.

My assumption is that even if you have various factors influencing your hearing loss and tinnitus, recovering hair cells will help. An audio-hole in your brain will get filled in. This filling can also help cover up the symptoms that the other issues cause.

So I think it isn't as much as "hit or miss" as it is "a degree of benefit" but predicting to what degree it will help you will likely be an educated guess.

 

[FGG]

Many of us were in the thread discussing Novartis CGF-166... Sounded very promising, even going into clinical trials and then it just fizzled off and I think it is now dead. We spent years discussing it. I think everyone in this thread is hoping this works or we wouldn't be here.

I fully believe viral vectored therapies like CGF-166 have a lot of potential... eventually.

I think a problem with this technique (for now) though is that viral-vectored therapies need to be inserted directly into the cochlea and boring a hole into the cochlea is extremely pro-inflammatory and destructive (interestingly, if the Hough Ear Institute Pill was proven highly effective for Cochlear Implant insertion trauma, it might have helped to give it concurrently with the drug) not just due to the mechanical trauma but there are fluid balance shifts until the hole seals apparently.

I believe another potential issue was patient selection. Because of the invasiveness of the surgery, they selected for bilaterally severe to profoundly affected patients.

Some of the profound patients would have had flat epithelia that couldn't be transduced with this particular drug. I think they were also the patients more likely to sign up for a study that required surgery.

If and when they release the data, we can see what patients saw improvements and analyze the ones that didn't. My guess is the severe patients would do much better than the very profound ones but it would be good to see the data, otherwise it's just speculation.

I just checked CGF-166's ClinicalTrials.gov page again and this is interesting:

"Part A and Part B enrollment is complete. Part C enrollment is open"

Which means perhaps the reason they haven't released data is there is a cohort they are still testing? Anyone know? Perhaps that patient group had different selection criteria and might do better?

 

[FGG]

I found this which suggests single IT injections just reach the base of the cochlea while "repeat dosing or extended release" are needed to get drug closer to the apex.

Principles of Local Drug Delivery to the Inner Ear

With that in mind, phase 1 is not at all a good indication of the frequency range of FX-322.

 

[tommyd87]

To be honest, I'm hopeful that both FX-322 and OTO-413 can be released together, as in my case I suspect that I may need both to fix my tinnitus problems. I severely doubt that one without the other will have any effect, but I don't know what caused my tinnitus in the first place either, due to the fact that the tools to diagnose tinnitus don't appear to exist yet...

Different companies are making each medicine so I cannot see this happening. I can see Otonomy obviously investigating and/or working out how to combine OTO-413 and OTO-6XX together. I think this would take time since OTO-6XX has just signed the partnership agreement with Kyorin, to seemingly take this through the clinical trials and also there would probably need to be further FDA trials and approval for the new dosing.

 

[GBB]

Does anyone think it's feasible we could get FX-322 in Q3/Q4 of next year if all goes well?

 

[Diesel]

I found this which suggests single IT injections just reach the base of the cochlea while "repeat dosing or extended release" are needed to get drug closer to the apex.

Principles of Local Drug Delivery to the Inner Ear

With that in mind, phase 1 is not at all a good indication of the frequency range of FX-322.

LeBel mentioned that they believed each IT injection would enter the cochlea in "waves" as each was absorbed, potentially reaching deeper into the cochlea. If that is the case, I wonder if basic liquid diffusion principles apply here? Think about dropping a dropper of food coloring into a test tube. As each drop of food coloring is added, the prior diffused drop is essentially pushed deeper into the test tube.

 

[tommyd87]

"Part A and Part B enrollment is complete. Part C enrollment is open"

Which means perhaps the reason they haven't released data is there is a cohort they are still testing? Anyone know? Perhaps that patient group had different selection criteria and might do better?

I cannot see where what you have stated about the Norvartis trial is listed on the Clinical Trials page, sorry.

I found this which suggests single IT injections just reach the base of the cochlea while "repeat dosing or extended release" are needed to get drug closer to the apex.

Principles of Local Drug Delivery to the Inner Ear

With that in mind, phase 1 is not at all a good indication of the frequency range of FX-322.

So there is a method to their madness. This makes even more sense why they are not looking at an alternative method of dosing at this time. Hopefully the outcomes will look promising from the multi dosing and it is eventually going to show that more dosing means more benefit.

There is also quite a high possibility of significant success using other medicine delivery techniques. This makes me feel confident that the dosing issue is being well handled and looked into at this time.

I think the dream is for regenerative drugs like FX-322, OTO-413, Hough Ear Institute Pill etc to work so well that the next time any of us sees an audiologist they'll be behind a counter wearing a paper hat and asking if we'd like fries with that.

At this stage, considering how some audiologists reckon that they are the best things ever, it would make me laugh if their operations crumbled apart from audiological tests.

 

[Jurger]

I found this which suggests single IT injections just reach the base of the cochlea while "repeat dosing or extended release" are needed to get drug closer to the apex.

Principles of Local Drug Delivery to the Inner Ear

With that in mind, phase 1 is not at all a good indication of the frequency range of FX-322.

All the more reason to be excited about Phase 2a results. It really should answer most questions we still have about the drug.

 

[Pete88]

I found this which suggests single IT injections just reach the base of the cochlea while "repeat dosing or extended release" are needed to get drug closer to the apex.

Principles of Local Drug Delivery to the Inner Ear

With that in mind, phase 1 is not at all a good indication of the frequency range of FX-322.

Cool, so this basically is backing up the repeat dosage method that Frequency Therapeutics is hoping will work... which at least gives more confidence that it's not just a blind, hopeful suggestion.

I would assume that the multiple injection method would work better if the 4 injections were given in the same sitting, like using the last injection to push the prior injection further.

Just my crude, uneducated thought. I understand that the theory is that each shot is soaked up by the first damaged part it comes in contact with, which clears the way for the next shot to go deeper 2 weeks later... I would just assume that pushing more of the drug deeper would work and cover the whole cochlea in one sitting.