Frequency Therapeutics — Hearing Loss Regeneration

[Jrblovsky]

The fact of the matter is:

"Working beyond a reasonable doubt" is displayed by statistical significant and clinically meaningful improvements in the data when reviewed by the FDA.

Even the "Meh" scenarios that I outlined might just push Primary Outcome #2 into significance.

Also, the Review Team at the FDA isn't all physicians. It consists of medical physicians, statisticians, chemists, biologists, toxicology specialists, and pharmacists. So it will be given a broad view by a number of different backgrounds.

Tinnitus won't be factored for Breakthrough Therapy Designation at all. It's an experimental outcome.

I hope you're right and they can get this stuff out soon. Being disabled by a noise in my head sucks. I also have an MBA and want to actually use it.

So realistically the earliest FX-322 goes to market is 2027?

 

[Diesel]

I hope you're right and they can get this stuff out soon. Being disabled by a noise in my head sucks. I also have an MBA and want to actually use it.

So realistically the earliest FX-322 goes to market is 2027?

Yeah, I can understand your frustration having a heavy piece of paper and not being able to get the benefits.

Based on the pace that Frequency Therapeutics is moving with FX-322 today, considering when the Phase 1 started, and comparing to other clinical trials that received Fast Track, product release could be as early as 2023 or as late as 2027.

I think a Breakthrough Designation and 1-year Pivotal Phase 2b/3 would pull that late estimate up to 2025.

 

[Keith Handy]

Being disabled by a noise in my head sucks. I also have an MBA and want to actually use it.

I have skills and talents I want to use, and people I want to collaborate with, but concentrating on anything now is like walking face first into the gusts of a sandstorm.

 

[Zugzug]

View attachment 43481

Not gonna lie, still hung up on this chart showing the calculated concentration of both FX-322 molecules in the perilymph. Maybe someone here with a better understanding of Pharmacokinetics / Pharmacodynamics can shed some light on this one?

We know that the two-molecule concentration was high enough to have a therapeutic effect at 8 kHz on the audiogram, AND that the effective window occurs between 1-3 hours after injection.

So, looking at the 8 kHz reference, I am inferring that CHIR needs to be at a minimum of about 500 ng/ml and VPA 10,000 ng/ml for a sustained period of at least 2 hours at any location in the cochlea to start the progenitor cell activation process.

Considering how the concentration curve looks for CHIR, I would suspect that by a second injection a week later, there would be a baseline of concentration in the perilymph, so additional CHIR concentration need to activate those progenitor cells would reach slightly more deeply into the cochlea.

VPA is where I have a problem. It appears to be absorbed quickly at the base; and even as deep as 2 kHz in the cochlea it is absorbed without (presumably) causing the therapeutic effect. Since both drugs are not at a high enough concentration level long enough. This creates a problem based on the chart. There is no wave of VPA flowing into the cochlea creating that baseline concentration that would be needed to increase concentration after multiple injections. Furthermore, it seems to be absorbed really quickly. So, I don't see how there would be enough VPA left in the cochlea after a 7 day window.

Any thoughts by anyone here?

Several thoughts, some optimistic and some pessimistic:

1) We know the drug worked at 8 kHz so the graphs give us an idea of an upper bound on the minimum concentration of CHIR and VPA required. Maybe the actual required amount in the endolymph is somewhere between the 8 kHz and the 2 kHz result? i.e. the 8 kHz amount is "overkill." But if this is the case, is it really likely that it's overkill for both components?

2) It may be difficult to extrapolate from a few hour to 7 days. Even if some CHIR remains, it's hard to say that it's a whole lot. Moreover, the VPA decay looks really quick, which isn't a good sign.

3) I'm sure this is a technical thing that is worked into their computer models, but what are the dynamics when the drug goes from the endolymph to the perilymph and passes through the basilar membrane? Is there any reason to believe that the same graphs (but maybe scaled differently) would hold up similarly in the endolymph?

4) Did they choose "7 days" between doses because of conservative safety reasons? I have no understanding of this issue, but it seems like purely theoretically and ignoring safety, the best way to push it deeper is to continuously inject, rather than wait a week. Is this a barrier that cannot be overcome so the only option is to reformulate?

I think putting this all together, particularly the VPA graph, my hunch is that EHF outcomes will be a success. The different cohorts will produce some stratification, but it will be more like 1 dose and 4 doses are reasonably different in EHF outcomes (including tinnitus), but 1 dose vs 2 doses or 2 doses vs 4 doses will not be that significant.

 

[Guywithapug]

I have skills and talents I want to use, and people I want to collaborate with, but concentrating on anything now is like walking face first into the gusts of a sandstorm.

I feel like this too, but then the other day I saw a picture on Facebook of a baby with no leg and a prosthetic to get by. It really re-instills that I must keep a positive attitude because others face great adversity too.

I am lucky where I had good hearing for almost 40 years. It could have been worse. I can't imagine how I would have lived my life if this had happened in my teens for instance.

 

[Guywithapug]

I'm sure Frequency Therapeutics have considered many different approaches to drug delivery but I can't help but wonder if it's not possible to aerosolize the solution and deliver it under low pressure, like fogging the cochlea if you will. It may take multiple sessions but think reaching the lower frequency areas would be achievable.

I thought of this whilst vaping a little while ago. Sometimes my genius... it's almost frightening.

 

[UHPTS]

I'm sure Frequency Therapeutics have considered many different approaches to drug delivery but I can't help but wonder if it's not possible to aerosolize the solution and deliver it under low pressure, like fogging the cochlea if you will. It may take multiple sessions but think reaching the lower frequency areas would be achievable.

...or as a suppository.

 

[Aaron91]

Several thoughts, some optimistic and some pessimistic:

4) Did they choose "7 days" between doses because of conservative safety reasons? I have no understanding of this issue, but it seems like purely theoretically and ignoring safety, the best way to push it deeper is to continuously inject, rather than wait a week. Is this a barrier that cannot be overcome so the only option is to reformulate?

I vaguely recall reading somewhere that there is a limitation in volume to how much you can inject anything into an animal cochlea (can't remember which animal) as it is very fragile, which is why I also asked the question previously in this thread as to whether there is some kind of anatomical limit to the human cochlea. I can't for the life of me remember where I read that though so I may be completely imagining it.

In any case, one would have thought that if Frequency Therapeutics thought a higher volume first dose was appropriate, they would have opted for that instead of, or at least in addition to, multiple doses over several weeks for Phase 2. So I think there must be something we're unaware of.

 

[GBB]

I'm mostly poking fun because my own tinnitus is debilitating, but how are people on this site on one hand saying they need disability and can't work, meanwhile in this thread "hey guys just ran a proprietary Binghoff regression after I coded a script to scrape the data sets from the Frequency Therapeutics back end server - here's my 45 page takeaways - note the caveats section where I walk through the assumptions in my model... feel free to reach out to me day or night."

 

[FGG]

I'm mostly poking fun because my own tinnitus is debilitating, but how are people on this site on one hand saying they need disability and can't work, meanwhile in this thread "hey guys just ran a proprietary Binghoff regression after I coded a script to scrape the data sets from the Frequency Therapeutics back end server - here's my 45 page takeaways - note the caveats section where I walk through the assumptions in my model... feel free to reach out to me day or night."

I personally don't know how anyone without a background in science does this.

I had about 20 years+ combined total of science education and a medical career so this stuff is more natural and doesn't require a huge amount of effort but ask me to learn anything new and I absolutely couldn't do it right now or even focus very well (look at the sheer amount of typos or putting in the wrong word that I do... I just can't focus well). I'm literally floored by the people without a medical background that contribute as much as they do. They are so impressive.

 

[Zugzug]

I vaguely recall reading somewhere that there is a limitation in volume to how much you can inject anything into an animal cochlea (can't remember which animal) as it is very fragile, which is why I also asked the question previously in this thread as to whether there is some kind of anatomical limit to the human cochlea. I can't for the life of me remember where I read that though so I may be completely imagining it.

In any case, one would have thought that if Frequency Therapeutics thought a higher volume first dose was appropriate, they would have opted for that instead of, or at least in addition to, multiple doses over several weeks for Phase 2. So I think there must be something we're unaware of.

I agree. They have a team of geniuses so obviously they choose these guidelines for a reason. I do think they will solve the dosing problem, relatively soon. The latest thing in the cochlea that I have the most interest in understanding is the basilar membrane.

My understanding is that the drug goes into the endolymph and diffuses into the perilymph. But I have read that only the surface of the basilar membrane (stereocilia) is in endolymph, while the hair cells and support cells are in perilymph. Why not shoot the drug directly into the round window in a way that avoids the endolymph altogether?

 

[FGG]

I agree. They have a team of geniuses so obviously they choose these guidelines for a reason. I do think they will solve the dosing problem, relatively soon. The latest thing in the cochlea that I have the most interest in understanding is the basilar membrane.

My understanding is that the drug goes into the endolymph and diffuses into the perilymph. But I have read that only the surface of the basilar membrane (stereocilia) is in endolymph, while the hair cells and support cells are in perilymph. Why not shoot the drug directly into the round window in a way that avoids the endolymph altogether?

From what I understand the perilymph has a bit of a directional flow from apex to base and is also not very accessible from the round window. With canalostomy, you could access either though.

 

[Philip83]

I agree. They have a team of geniuses so obviously they choose these guidelines for a reason. I do think they will solve the dosing problem, relatively soon. The latest thing in the cochlea that I have the most interest in understanding is the basilar membrane.

My understanding is that the drug goes into the endolymph and diffuses into the perilymph. But I have read that only the surface of the basilar membrane (stereocilia) is in endolymph, while the hair cells and support cells are in perilymph. Why not shoot the drug directly into the round window in a way that avoids the endolymph altogether?

I have by no means any knowledge of this, but my audiologist told me that any poking into the actual cochlea is super dangerous and could easily cause a deadly infection.

 

[Zugzug]

I'm mostly poking fun because my own tinnitus is debilitating, but how are people on this site on one hand saying they need disability and can't work, meanwhile in this thread "hey guys just ran a proprietary Binghoff regression after I coded a script to scrape the data sets from the Frequency Therapeutics back end server - here's my 45 page takeaways - note the caveats section where I walk through the assumptions in my model... feel free to reach out to me day or night."

Haha, my suspicion is that there's a lot of people just referencing back to their area of expertise. I drank coffee for the first time in years yesterday and saw some improvement in brain fog so I learned about the basic delivery of the drug. I also read parts of the Frequency Therapeutics transcript to understand this.

I have a background in mathematical analysis and some statistics background so I can read the papers and easily follow along with the stuff about statistical significance, p-values, and confidence intervals. I used to study mathematical biology so I know bits and pieces of how neurons communicate. Everything that's truly "new" is really hard to learn. I've also been learning this stuff for two years (and still a total novice lol).

You have a background in finance so I'm sure you follow along with that stuff effortlessly (compared to the rest of us). FGG is a genius with a medical background. Diesel is a medical prodigy who basically just fell from heaven. There are many other contributors who are very bright.

 

[Jrblovsky]

I agree. They have a team of geniuses so obviously they choose these guidelines for a reason. I do think they will solve the dosing problem, relatively soon. The latest thing in the cochlea that I have the most interest in understanding is the basilar membrane.

My understanding is that the drug goes into the endolymph and diffuses into the perilymph. But I have read that only the surface of the basilar membrane (stereocilia) is in endolymph, while the hair cells and support cells are in perilymph. Why not shoot the drug directly into the round window in a way that avoids the endolymph altogether?

I wonder if the Frequency Therapeutics staff follow this board? There are some interesting things posted here regarding biotech.

 

[Zugzug]

From what I understand the perilymph has a bit of a directional flow from apex to base and is also not very accessible from the round window. With canalostomy, you could access either though.

That makes sense, but when I look at the following picture, it looks like the round window leads directly into the perilymph in the scala tympani. I'm confused as to how it more naturally goes into the endolymph. It looks like the perilymph gradient would just reject the drug from the start.

 

[Diesel]

I wonder if the Frequency Therapeutics staff follow this board? There are some interesting things posted here regarding biotech.

Yes. Someone at Frequency Therapeutics is watching.

 

[Keith Handy]

I'm mostly poking fun because my own tinnitus is debilitating, but how are people on this site on one hand saying they need disability and can't work, meanwhile in this thread "hey guys just ran a proprietary Binghoff regression after I coded a script to scrape the data sets from the Frequency Therapeutics back end server - here's my 45 page takeaways - note the caveats section where I walk through the assumptions in my model... feel free to reach out to me day or night."

It seems like a paradox at first, but I think it totally makes sense that we would be like this. It isn't that our brains stopped working; it's that they're so distracted by one thing that they're working solely on that.

I hope my years of audio experience is helping add something worthwhile to the mix with the others' experience with medicine, business, biology, statistics, and so on. We're going to emerge from this as a Wonderteam.

 

[Diesel]

That makes sense, but when I look at the following picture, it looks like the round window leads directly into the perilymph in the scala tympani. I'm confused as to how it more naturally goes into the endolymph. It looks like the perilymph gradient would just reject the drug from the start.

View attachment 43517

I would suspect that sound waves are traveling through the perilymph in the direction specified in a compression wave, like it does through water. Then, the sound energy would exit out of the round window into the air in the middle ear? However, a liquid-state molecule like FX-322 diffusing into the perilymph at the round window would not necessarily be pushed out. It's likely that the traveling sound compression waves might help to stir the perilymph and help to diffuse FX-322 inward. So, perhaps exciting that perilymph with a specific set of frequencies might help move the liquid diffusion at an accelerated rate...

Omg... it just occurred to me...

Somehow we're going to find out that listening to pink noise helps pull FX-322 into the cochlea, giving all the Jastreboffians the validation they finally wanted.

 

[FGG]

That makes sense, but when I look at the following picture, it looks like the round window leads directly into the perilymph in the scala tympani. I'm confused as to how it more naturally goes into the endolymph. It looks like the perilymph gradient would just reject the drug from the start.

View attachment 43517

Hmm... I found an article a long time ago that said an advantage of canalostomy was that it accessed both endolymph and perilymph whereas the IT route/round window delivery only accessed endolymph but your diagram contradicts that. So I looked it up again and found this:

Communication Pathways to and from the Inner Ear and their Contributions to Drug Delivery

Which also suggests it goes into perilymph. So it appears that what I read awhile ago was either wrong or I had read it wrong.

But that does mean the perilymph gradient doesn't reject the drug because it's obviously diffusing through. So maybe the flow is minimal?

 

[Keith Handy]

I'm mostly poking fun because my own tinnitus is debilitating, but how are people on this site on one hand saying they need disability and can't work, meanwhile in this thread "hey guys just ran a proprietary Binghoff regression after I coded a script to scrape the data sets from the Frequency Therapeutics back end server - here's my 45 page takeaways - note the caveats section where I walk through the assumptions in my model... feel free to reach out to me day or night."

By the way... I couldn't not look it up.

 

[Zugzug]

Hmm... I found an article a long time ago that said an advantage of canalostomy was that it accessed both endolymph and perilymph whereas the IT route/round window delivery only accessed endolymph but your diagram contradicts that. So I looked it up again and found this:

Communication Pathways to and from the Inner Ear and their Contributions to Drug Delivery

Which also suggests it goes into perilymph. So it appears that what I read awhile ago was either wrong or I had read it wrong.

But that does mean the perilymph gradient doesn't reject the drug because it's obviously diffusing through. So maybe the flow is minimal?

I wonder if the patient lying down neutralizes or even reverses the gradient.

 

[scotty03874]

Yeah, I can understand your frustration having a heavy piece of paper and not being able to get the benefits.

Based on the pace that Frequency Therapeutics is moving with FX-322 today, considering when the Phase 1 started, and comparing to other clinical trials that received Fast Track, product release could be as early as 2023 or as late as 2027.

I think a Breakthrough Designation and 1-year Pivotal Phase 2b/3 would pull that late estimate up to 2025.

Fingers crossed it's before 2025. I want my hearing loss suffering to end. The tinnitus isn't the problem for me, it's more the hearing loss. Let's go FREQ, make it happen!

 

[FGG]

Fingers crossed it's before 2025. I want my hearing loss suffering to end. The tinnitus isn't the problem for me, it's more the hearing loss. Let's go FREQ, make it happen!

I *hate* my tinnitus but hearing loss itself is worse for me too.

 

[wwtsai]

Fingers crossed it's before 2025. I want my hearing loss suffering to end. The tinnitus isn't the problem for me, it's more the hearing loss. Let's go FREQ, make it happen!

I'd be pretty happy to fix my hearing loss, but it'd be like a second chance at life if I can get rid of/significantly reduce my tinnitus.

 

[twa]

Can you provide some references in this subject? I always wondered why the heck so many of my colleagues that abused their ears the same or even worse do not suffer from tinnitus, but I do.

I know it is very frustrating. I do not remember where I read it, but it was something to the effect that scientists think they have identified a gene that may be responsible for tinnitus. There are people like my 80-year-old father with hearing loss who has intermittent mild tinnitus and then there is me with moderate/loud tinnitus. In my humble opinion there may be a genetic predisposition for tinnitus and under the right conditions it may develop.

 

[Guywithapug]

I *hate* my tinnitus but hearing loss itself is worse for me too.

I'm the other way, I'd eventually get used to the hearing imbalance but the tinnitus is most distressing.

 

[GregCA]

I *hate* my tinnitus but hearing loss itself is worse for me too.

I have a hard time picking between Scylla & Charybdis.

 

[Piney]

I would like to know why they used limiting factors on speech recognition for their trials. If you can't decipher one word in speech recognition, but after FX-322 you can, wouldn't that be a marker for improvement? Or if you can't decipher any words, are they saying FX-322 will not work?

 

[FGG]

I would like to know why they used limiting factors on speech recognition for their trials. If you can't decipher one word in speech recognition, but after FX-322 you can, wouldn't that be a marker for improvement? Or if you can't decipher any words, are they saying FX-322 will not work?

Not being able to decipher one word is pretty unusual. Are in you the profound range?