Frequency Therapeutics — Hearing Loss Regeneration

[spacehunter]

Yes, I guess the same thing!

The fact right now is FX-322 works in frequencies from 8 kHz - 20 kHz, but that is not enough for the market, knowing that the most people with hearing loss are in the range of 0.20 kHz - 8 kHz!

Of course many would benefit from FX-322 if they have hearing loss in 8 kHz - 20 kHz!

My opinion and hope is that the Phase 2A results show that FX-322 will work in low frequencies too. If not, they will need to start over with another delivery method to reach deeper in the cochlea!

I hope that they will continue Phase 3 even with these "bad results". If they can show that high frequency hearing regeneration can significantly increase words-in-noise and word recognition, then they have still a product for an unmet medial problem. So hopefully continuation to Phase 3 and at the same time in parallel working on the delivery method, which will start from Phase 1 again...

 

[FGG]

I'm not sure. It was from @Aaron91's post #14572 (previous page). I may be spreading fake news. Regardless, from the diagram, at the top, they call the method of Frequency Therapeutics to be "mitotic regeneration." The diagram is supposed to depict two types. The second, involving WNT, is supposed to be the one describing FX-322.

If you Google Image "mitotic regeneration," you get:

View attachment 43729

I was able to find the reference:

Sensory hair cell development and regeneration: similarities and differences

It was avian. It's not the same method. If memory serves, they go over the difference in the Will McLean lecture video.

 

[Aaron91]

Oh, 1) makes a lot of sense. I was confused because I've seen LGR5 being called a gene, protein, and cell. This is maybe an embarrassing thing to admit, but why not just air it out? I thought that LGR5+ were the only support cells in the cochlea. I have a very simple understanding of this; when I see YouTube videos, in my mind, there are like 5 total object types in the ear.

For 2) I'm still confused, but I think this is a good thing. In the figure below, it has "mitosis" but then clearly there is a LGR5+ cell asymmetrically splitting into what appears to be a copy and a hair cell. Am I to understand this diagram as saying there's mitosis and immediately after, one of the copy cells transdifferentiates into a hair cell? In other words, the whole process of one LGR5+ leading to one LGR5+ and one hair cell holds, but it's a two step process?

Thanks.

View attachment 43727

So that diagram was taken from one of Frequency Therapeutics' presentations but @FGG seems to have tracked down the original source - great work.

The diagram in isolation is actually a bit confusing because they've tried to illustrate and integrate two different processes into one diagram. What you are actually seeing from that diagram are the two different ways a hair cell can be generated from a supporting cell. One way is through Atoh1 overexpression or notch inhibition, which leads to direct transdifferentiation, and is illustrated by the bottom set of arrows. The other way is through the wnt pathway, illustrated by the top arrows, which leads to mitotic regeneration and subsequently the formation of a hair cell.

I hope that makes sense, but in all fairness I think the diagram is poorly done. They would have been much better off just making separate diagrams for each process.

 

[Zugzug]

So that diagram was taken from one of Frequency Therapeutics' presentations but @FGG seems to have tracked down the original source - great work.

The diagram in isolation is actually a bit confusing because they've tried to illustrate and integrate two different processes into one diagram. What you are actually seeing from that diagram are the two different ways a hair cell can be generated from a supporting cell. One way is through Atoh1 overexpression or notch inhibition, which leads to direct transdifferentiation, and is illustrated by the bottom set of arrows. The other way is through the wnt pathway, illustrated by the top arrows, which leads to mitotic regeneration and subsequently the formation of a hair cell.

I hope that makes sense, but in all fairness I think the diagram is poorly done. They would have been much better off just making separate diagrams for each process.

I think my source of confusion was over something very pedantic. When I first looked at the diagram, I understood that they were talking about two different methods.

I was confused by the word "mitotic" because that would mean the splitting of a progenitor cell into two daughter progenitor cells. But I thought FX-322 induced asymmetric division (1 new hair cell, 1 new progenitor). I guess this is so pedantic that it doesn't really matter. Big picture, is that the other drugs lead to transdifferentiation and FX-322 leads to intact support cells.

 

[FGG]

I hope that makes sense, but in all fairness I think the diagram is poorly done.

It really is.

Side note: I wish I had talent as a visual/graphic artist because biological illustrating would have been a really fun career (that there is a big demand for) and one I may not even have had to quit with my ear issues.

 

[Frédéric]

I dropped out of this conversation a bit but understood that some were wondering what the role of VPA in the formulation of FX-322 was. By reflex, I did a very quick search on the net with the keywords "valproic acid" and "tinnitus", and I found this link:

Valproic Acid-induced Hearing Loss and Tinnitus

Then I realized it was already posted on this forum:

Depakote (Valproate)

And in an indirect manner (search "valproic acid" on this forum):

Epilim (Sodium Valproate)

I don't know if that will help us to understand the role of VPA.

 

[FGG]

I dropped out of this conversation a bit but understood that some were wondering what the role of VPA in the formulation of FX-322 was. By reflex, I did a very quick search on the net with the keywords "valproic acid" and "tinnitus", and I found this link:

Valproic Acid-induced Hearing Loss and Tinnitus

Then I realized it was already posted on this forum:

Depakote (Valproate)

And in an indirect manner (search "valproic acid" on this forum):

Epilim (Sodium Valproate)

I don't know if that will help us to understand the role of VPA.

This is so weird. I was *just* reading about this. It seems this occurred in people with notable pre-existing hearing loss. It can't be classically ototoxic because it is not occurring in people with normal hearing. Also, it's very, very rare even with very high doses. So, it's definitely a puzzle.

That case study in your first link screams viral etiology (specifically CMV) to me though because she was born with it and it was bilateral but very asymmetrical.

Really makes me wonder if VPA's potent action on herpesvirus viral latency is a factor here (I linked to an article earlier on this). If so, I guess the good news, though, is that when VPA is given with an anti viral it helps kill the virus as it is coming out of latency. Personally, after my readings on this, I plan to take Acyclovir with this drug.

I read something else on VPA possibly increasing reactive oxygen species but only with excessive noise exposure. So I would also be very protective of my ears while the VPA is in my system.

Edit: also if it was classically ototoxic, Frequency would know because they added VPA directly to cells.

 

[GlennS]

Tinnitus might originate at the 8 kHz - 20 kHz range tough, so good for us; the first generation of the formula almost certainly won't get rid of our tinnitus, but I suspect it will give us a good amount of relief.

This. I'm all for Frequency Therapeutics pivoting towards tinnitus rather than feeling like they have to chase lower frequencies. It's a big enough market as it is.

 

[Diesel]

This. I'm all for Frequency Therapeutics pivoting towards tinnitus rather than feeling like they have to chase lower frequencies. It's a big enough market as it is.

If the TFI scores look promising from the upcoming data, tinnitus will become another benefit in addition to word score and hearing-in-noise.

 

[Zugzug]

This. I'm all for Frequency Therapeutics pivoting towards tinnitus rather than feeling like they have to chase lower frequencies. It's a big enough market as it is.

I bet they can do both if the Phase 2a results are solid. It will require marketing to optimize the EHF and tinnitus market. I believe this is (among other reasons) why they hired Kevin Franck.

Pushing the medicine deeper is an ongoing challenge for their core researchers. By the way, I'm sure they have a lot more ideas on this subject than we give them credit for. They are probably concerned about exclusive rights to the patents and not speaking too soon. I feel pretty damn good about a team with Robert Langer though.

 

[Guywithapug]

 

[AfroSnowman]

This. I'm all for Frequency Therapeutics pivoting towards tinnitus rather than feeling like they have to chase lower frequencies. It's a big enough market as it is.

Me too, of course I have ultra high frequency tinnitus so I might be a little biased.

 

[Aaron91]

This is so weird. I was *just* reading about this. It seems this occurred in people with notable pre-existing hearing loss. It can't be classically ototoxic because it is not occurring in people with normal hearing. Also, it's very, very rare even with very high doses. So, it's definitely a puzzle.

That case study in your first link screams viral etiology (specifically CMV) to me though because she was born with it and it was bilateral but very asymmetrical.

Really makes me wonder if VPA's potent action on herpesvirus viral latency is a factor here (I linked to an article earlier on this). If so, I guess the good news, though, is that when VPA is given with an anti viral it helps kill the virus as it is coming out of latency. Personally, after my readings on this, I plan to take Acyclovir with this drug.

I read something else on VPA possibly increasing reactive oxygen species but only with excessive noise exposure. So I would also be very protective of my ears while the VPA is in my system.

Edit: also if it was classically ototoxic, Frequency would know because they added VPA directly to cells.

It's interesting you should mention this because I think a question @serendipity1996 has had is, VPA aside, how critical is it to minimise our noise exposure post-treatment with FX-322? Would the developing hair cells in an adult body be more vulnerable to damage than they usually are in utero? Are developing cells, in general, more prone to damage?

I suppose if and when Frequency Therapeutics go to market they will have some advice on this, but for those of us who will want to travel to America rather than wait for the drug to come to Europe, this poses some difficult questions with regards to travelling and exposing oneself to a noisy airplane ride for the best part of 10 hours.

 

[FGG]

It's interesting you should mention this because I think a question @serendipity1996 has had is, VPA aside, how critical is it to minimise our noise exposure post-treatment with FX-322? Would the developing hair cells in an adult body be more vulnerable to damage than they usually are in utero? Are developing cells, in general, more prone to damage?

I suppose if and when Frequency Therapeutics go to market they will have some advice on this, but for those of us who will want to travel to America rather than wait for the drug to come to Europe, this poses some difficult questions with regards to travelling and exposing oneself to a noisy airplane ride for the best part of 10 hours.

Just stay a few extra weeks in the US just in case. Really. You'd likely have to with repeat injections anyway.

 

[patorjk]

They added a new job to their website:

Co-op, Microscopy Image Analysis

I believe this was added within the last few days. I only realized it was new because it was the bottom listing, where previously "Co-op, Delivery Innovation" was the bottom listing.

One thing I infer from this is that it probably means we're going to get at least "good enough" results from Phase 2a, otherwise they wouldn't be adding new job postings at this time (I would imagine they have to have an idea of the results now).

Also, I decided to look at an archived version of this page to see which job postings had been filled:

Current Opportunities

The one that caught my eye: "Vice President/Senior Director, Quality". I'm guessing they'll announce that soon, as sort of a way to fill a news gap. So maybe we'll see them announce that person next week, and then 1 or 2 weeks later we'll get the news. However, I have no idea, I'm just speculating.

 

[Aaron91]

Just stay a few extra weeks in the US just in case. Really. You'd likely have to with repeat injections anyway.

That was pretty much what I was thinking. Was just wondering whether it would be something like 3 weeks or 3 months.

 

[Diesel]

They added a new job to their website:

Co-op, Microscopy Image Analysis

I believe this was added within the last few days. I only realized it was new because it was the bottom listing, where previously "Co-op, Delivery Innovation" was the bottom listing.

One thing I infer from this is that it probably means we're going to get at least "good enough" results from Phase 2a, otherwise they wouldn't be adding new job postings at this time (I would imagine they have to have an idea of the results now).

Also, I decided to look at an archived version of this page to see which job postings had been filled:

Current Opportunities

The one that caught my eye: "Vice President/Senior Director, Quality". I'm guessing they'll announce that soon, as sort of a way to fill a news gap. So maybe we'll see them announce that person next week, and then 1 or 2 weeks later we'll get the news. However, I have no idea, I'm just speculating.

A quality role would likely report up to the Manufacturing Chief, so I doubt there would be an announcement. Either way, it's all promising to see that the plans for manufacturing FX-322 are presumably in the works as of the start of this year.

 

[Diesel]

That was pretty much what I was thinking. Was just wondering whether it would be something like 3 weeks or 3 months.

Based on what we've seen from the Phase 1/2, it looks like most of the benefit of a single injection was observed 15 days after the injection. So, it might stand to reason that the hair cell is mostly grown by that time.

I would think that it would be recommended that a patient wear ear plugs for so many days after the injection, and/or avoid exposure to loud settings to not stunt the growth of the new hair cell, and to possibly avoid infection.

If the hair cells are indeed developing as that had in the womb, premature babies are often fitted hearing protection if their hearing has not fully developed. I expect to avoid damaging cells that are in development.

 

[Aaron91]

If the hair cells are indeed developing as that had in the womb, premature babies are often fitted hearing protection if their hearing has not fully developed. I expect to avoid damaging cells that are in development.

Talk about an interesting fun fact, I had no idea they did this with premature babies! I think I'll definitely be taking a lot care post-treatment whatever the case.

 

[serendipity1996]

Based on what we've seen from the Phase 1/2, it looks like most of the benefit of a single injection was observed 15 days after the injection. So, it might stand to reason that the hair cell is mostly grown by that time.

I would think that it would be recommended that a patient wear ear plugs for so many days after the injection, and/or avoid exposure to loud settings to not stunt the growth of the new hair cell, and to possibly avoid infection.

If the hair cells are indeed developing as that had in the womb, premature babies are often fitted hearing protection if their hearing has not fully developed. I expect to avoid damaging cells that are in development.

This is so interesting - I was born 11 weeks premature and spent the first 10 weeks in a neonatal unit but I'm not sure if I would have been fitted with hearing protection. I read that neonatal units actually tend to be quite noisy too. I wonder if that could have contributed to cumulative noise damage.

 

[john paul]

Tinnitus might originate at the 8 kHz - 20 kHz range tough, so good for us; the first generation of the formula almost certainly won't get rid of our tinnitus, but I suspect it will give us a good amount of relief.

Exactly, nearly anyone with with noise induced tinnitus will have fried that upper range. This is where all our problems stem from IMO.

 

[john paul]

Based on what we've seen from the Phase 1/2, it looks like most of the benefit of a single injection was observed 15 days after the injection. So, it might stand to reason that the hair cell is mostly grown by that time.

I would think that it would be recommended that a patient wear ear plugs for so many days after the injection, and/or avoid exposure to loud settings to not stunt the growth of the new hair cell, and to possibly avoid infection.

If the hair cells are indeed developing as that had in the womb, premature babies are often fitted hearing protection if their hearing has not fully developed. I expect to avoid damaging cells that are in development.

I wonder if a dose of steroids would help things along.

 

[Drachen]

I'd checked FREQ's stock history today and thought after seeing the decline that results had been posted and weren't favorable, but I'm relieved to see that isn't the case. I guess this is just the typical volatility of a biomed offering.

We're almost there folks. Really hoping and praying that these results are beyond everyone's expectations and keep this hype train on track.

 

[Keith Handy]

This is so interesting - I was born 11 weeks premature and spent the first 10 weeks in a neonatal unit but I'm not sure if I would have been fitted with hearing protection. I read that neonatal units actually tend to be quite noisy too. I wonder if that could have contributed to cumulative noise damage.

I know someone who was born very premature and lost her sight at the age of nine, and I wonder if that was likewise due to an unprotected vulnerability in the neonatal period. On that same note, I wonder if Frequency Therapeutics' regenerative technologies have any applicability down the road for retinal restoration.

 

[Aaron91]

I know someone who was born very premature and lost her sight at the age of nine, and I wonder if that was likewise due to an unprotected vulnerability in the neonatal period. On that same note, I wonder if Frequency Therapeutics' regenerative technologies have any applicability down the road for retinal restoration.

I remember in the early days of the company they seemed to suggest that their technology could potentially have application in many other areas of the body. It would appear in more recent years that communication has dried up and they don't seem to have any other pre-clinical drug other than the MS one, which we should be hearing more about later this year. I am wondering whether this change in communication is because they're focusing more resources on FX-322 or because they ran into some unexpected hurdles with other tissues that they're still trying to work around.

 

[Diesel]

I remember in the early days of the company they seemed to suggest that their technology could potentially have application in many other areas of the body. It would appear in more recent years that communication has dried up and they don't seem to have any other pre-clinical drug other than the MS one, which we should be hearing more about later this year. I am wondering whether this change in communication is because they're focusing more resources on FX-322 or because they ran into some unexpected hurdles with other tissues that they're still trying to work around.

I think it's that they are focusing as many resources as possible on FX-322 since the cash cow potential is huge, and they'll be able to fund future clinical trials for other diseases/disorders using the PCA approach with actual cash flow. Also, since hearing loss has no treatments whatsoever, they have a much more direct path to approval for a drug that shows even partial improvement at some endpoints.

Some have mentioned that Frequency Therapeutics has already issued patents for regenerating hair follicles, and they have mentioned some research into regenerating certain types of muscle tissue. I suspect that trials for these areas of the body will be much longer, more expensive, and at a higher risk for approval considering there are treatments on the market today that may be seen by the FDA as competitive. The market potential is a bit of an unknown to me, which may be a deterrent right now.

They also may not as easily qualify for Fast Track status, which would be even less ideal for the bottom line. Which brings me back to my original comment explaining why they are focusing so heavily on FX-322... it's like a Goldilocks opportunity for the firm.

Langer mentioned in the January webcast that there were "10 other areas (other than hearing cells) of the body where they were researching PCA application." You all can speculate what they may be investigating.

 

[Tezcatlipoca]

I think it's that they are focusing as many resources as possible on FX-322 since the cash cow potential is huge, and they'll be able to fund future clinical trials for other diseases/disorders using the PCA approach with actual cash flow. Also, since hearing loss has no treatments whatsoever, they have a much more direct path to approval for a drug that shows even partial improvement at some endpoints.

Some have mentioned that Frequency Therapeutics has already issued patents for regenerating hair follicles, and they have mentioned some research into regenerating certain types of muscle tissue. I suspect that trials for these areas of the body will be much longer, more expensive, and at a higher risk for approval considering there are treatments on the market today that may be seen by the FDA as competitive. The market potential is a bit of an unknown to me, which may be a deterrent right now.

They also may not as easily qualify for Fast Track status, which would be even less ideal for the bottom line. Which brings me back to my original comment explaining why they are focusing so heavily on FX-322... it's like a Goldilocks opportunity for the firm.

Langer mentioned in the January webcast that there were "10 other areas (other than hearing cells) of the body where they were researching PCA application." You all can speculate what they may be investigating.

FREQ is sitting on a gold mine. They could very well become one of the most important pharmaceutical companies if their formula can truly be applied to all cells.

 

[Trevor_phillips]

After you receive FX-322 injections at the ENT (if we assume FX-322 is successful in the clinical trials and becomes available to all of us):

Can taking food supplements such as Ginkgo biloba, Acetyl-L-Carnitine, and Magnesium enhance cellular/synaptic growth and help in regeneration quality?

 

[Lucifer]

After you receive FX-322 injections at the ENT (if we assume FX-322 is successful in the clinical trials and becomes available to all of us):

Can taking food supplements such as Ginkgo biloba, Acetyl-L-Carnitine, and Magnesium enhance cellular/synaptic growth and help in regeneration quality?

I was thinking about this as well. I would definitely take NAC and Magnesium before and after getting injected with FX-322.

I don't see how you can get side effects from taking both NAC and Magnesium.

 

[weab00]

Any morning now we wake up, the results will be out guys.