Frequency Therapeutics — Hearing Loss Regeneration

Carl LeBel on Expanded Use during the Tinnitus Talk Podcast:

"[...]firstly and importantly our position on expanded access is due to really the fact that we don't fully feel that we've been able to characterise the safety profile of the drug yet. And so loosening the philosophy of sharing drug, this is a hard time to do that. We don't understand the risk-benefit profile just yet. So I think that we're certainly interested once we get this next set of data that we can revisit that based on what the profile looks like[...]"

He also goes on to say that this info will possibly be revealed during this current phase of development.

I know their website states that production is a reason that they aren't offering expanded use, but I'd trust the much more recent info, which is straight from the horse's mouth so to speak.

In my opinion, the podcast confirms that a lack of data regarding the safety profile is the primary reason expanded use is not being offered. I don't think production is an issue or he would have mentioned as much. I think Astella has the resources to pump out FX-322 almost immediately, as soon as they & Frequency decide that's what they want to do.

Of course, things might take longer, but I think there's a solid chance we could gain access to this by mid 2021.
Yeah, I agree. On their website, they cite ease of manufacturing as one of the advantages of their PCA approach:

  • "Eliminates need to remove and grow live cells ex vivo"
  • Produces treatments using standard, small-molecule manufacturing methods"
https://www.frequencytx.com/science/pca-approach/
 
Simple question... Will FX-322 help with all the different types of tinnitus?

Such as head Tinnitus, stress induced, pulsatile, somatosensory?
It will help neurotinnitus caused ONLY by inner ear damage. It will not help pulsatile and somatic tinnitus, nor help middle ear related damage. But, these tinnitus issues have their own separate treatments that address the root cause.
 
Yeah, I agree. On their website, they cite ease of manufacturing as one of the advantages of their PCA approach:

  • "Eliminates need to remove and grow live cells ex vivo"
  • Produces treatments using standard, small-molecule manufacturing methods"
https://www.frequencytx.com/science/pca-approach/
I don't doubt Astellas already has the know-how and capability to make the drug. Safety concerns do make sense, they don't want to invest in producing large quantities to end up scrapping them, or harming people and end up in a class-action lawsuit.

It is also not so clear the logistics of the process for requesting the drug. There may be some ramp up time to administer the process that Frequency Therapeutics is not yet prepared for.
 
Just reading about Expanded Use requirements on the FDA website.

Does anyone know anything about the Expanded Access studies mentioned by the FDA?

Is it possible that Frequency may use their $42MM Private placement to conduct Expanded Access studies that may be a fit for people with tinnitus but don't qualify for the Phase 2A or Phase 3?

Or am I just getting caught up in the semantics?
 
Again with the FDA-bashing. I'm pretty sure the FDA doesn't make money at any point in this process. My conspiracy theory is that Frequency Therapeutics strung it along for months while they negotiated with Astellas and then filed the IPO. I don't have any proof for my theory either.
Do you believe companies never hide behind the FDA process in order to bilk investors on drugs these companies know will fail?
Are you making that up or do you have occupational experience with that?
I have experience. You've read the FDA comic books about how they are from the government and here to help?
Do you know how the FDA finds ways to extend/delay the process for the approval? From what I have read they charge one fee for approval and that's it.
The FDA is a spoon fed entity of overrated sh*t. A type of monopoly.

This is FX-322 topic, I don't want to derail it with comments about FDA. Someone start FDA thread and I will contribute my FDA dislike there.
 
FX-322 is one of my big hopes, the other one is Susan Shore.

All my fingers crossed that this will work for some of us!!!

Another question: Would you invest in the FREQ stock? I'm thinking about it...
 
Just reading about Expanded Use requirements on the FDA website.

Does anyone know anything about the Expanded Access studies mentioned by the FDA?

Is it possible that Frequency may use their $42MM Private placement to conduct Expanded Access studies that may be a fit for people with tinnitus but don't qualify for the Phase 2A or Phase 3?

Or am I just getting caught up in the semantics?
Despite all the well meaning public statements, Frequency Therapeutics is a for-profit company with stockholders. As a business, it doesn't make much sense to use that $42m fund on expanded access. It's better for them to quickly go through the whole clinical trials shebang for quick product release. Frequency Therapeutics still need the capital to establish phase 3, then setup larger production, marketing, etc. Despite many people having hearing loss and tinnitus, it's still not well known to the majority.

Also, Frequency Therapeutics have other drugs in development, which was mentioned in their press release, regarding the $42m fund, about putting effort into multiple sclerosis.

Also, I'm not trying to be negative, but getting our hopes up too high right now is premature. They're still in phase 2. Everything hinges on phase 2 results.
 
FX-322 is one of my big hopes, the other one is Susan Shore.

All my fingers crossed that this will work for some of us!!!

Another question: Would you invest in the FREQ stock? I'm thinking about it...
I am hoping these two will be successful too, and I am hoping that FX-322 will be successful for many. I have bought about 15 shares.
 
It will help neurotinnitus caused ONLY by inner ear damage. It will not help pulsatile and somatic tinnitus, nor help middle ear related damage. But, these tinnitus issues have their own separate treatments that address the root cause.
My audiologist said that all tinnitus is caused by hearing loss (brain creates a sound to fill in for hearing loss) but the tinnitus may be be manifested in different ways/pathways (auditory nerve, neck (spinal nerve), etc.).

Do we know for sure this doesn't help somatic tinnitus, or is it a guess?
 
My audiologist said that all tinnitus is caused by hearing loss (brain creates a sound to fill in for hearing loss) but the tinnitus may be be manifested in different ways/pathways (auditory nerve, neck (spinal nerve), etc.).

Do we know for sure this doesn't help somatic tinnitus, or is it a guess?
I'm sure it will not help pulsatile or somatic tinnitus. Not all tinnitus is caused from hearing loss. If you have pulsatile tinnitus, then it's a blood circulatory issue. The blood circulatory issue needs to be resolved. If your somatic tinnitus is from a pinched or irritated auditory nerve from tmj disorder or neck issues, then like pulsatile tinnitus, that person need to resolve the TMJ or neck issue. These are not caused by hearing loss. Restoring cochlear damage will not help pulsatile or somatic tinnitus.

Pulsatile and somatic tinnitus has a completely different pathology than neurotinnitus.

EDIT: The same logic applies to middle ear damage for which the underlying issue is the abnornal bone conduction and has no relation to inner ear damage. For example, otosclerosis needs to fix the stapes middle ear bone with surgery... not regenerating damaged hair cells.

EDIT 2: I'm sorry if this is bad news for you if you have somatic or pulsatile tinnitus. :(
 
My audiologist said that all tinnitus is caused by hearing loss (brain creates a sound to fill in for hearing loss) but the tinnitus may be be manifested in different ways/pathways (auditory nerve, neck (spinal nerve), etc.).

Do we know for sure this doesn't help somatic tinnitus, or is it a guess?
Eh I would say all tinnitus is caused by hearing interference, not loss.

Eg. Hydrops can cause it and it can resolve with hydrops.

Things like TMJ and neck tinnitus fit that category too.
 
Despite all the well meaning public statements, Frequency Therapeutics is a for-profit company with stockholders. As a business, it doesn't make much sense to use that $42m fund on expanded access. It's better for them to quickly go through the whole clinical trials shebang for quick product release. Frequency Therapeutics still need the capital to establish phase 3, then setup larger production, marketing, etc. Despite many people having hearing loss and tinnitus, it's still not well known to the majority.

Also, Frequency Therapeutics have other drugs in development, which was mentioned in their press release, regarding the $42m fund, about putting effort into multiple sclerosis.

Also, I'm not trying to be negative, but getting our hopes up too high right now is premature. They're still in phase 2. Everything hinges on phase 2 results.
I agree with most of this, except for the press release from FREQ re: the $42MM placement;

"The Company plans to use the net proceeds from the private placement to further advance the clinical development of FX-322, its lead product candidate in Phase 2a development for sensorineural hearing loss, by gaining additional insights regarding the patient populations and severity of hearing loss that FX-322 may treat."

I interpret this as validating the effectiveness of FX-322 on a population of patients that are outside of the parameters of the current Phase 2A, and likely Phase 3.

As an investor, I see this as an investment in some type of peripheral research / trial that enables Frequency to apply its drug to more types of hearing loss. And that means more money, more quickly.

Could very well be presbycusis considering the recent studies finding that it's basically just SNHL. But, it could very well be other classes of treatable hearing loss markets. High frequency hearing loss seems to be a growing market that affects younger people, and seems common for members of this forum.

I asked about the expanded access trial, because according to what I am reading from the FDA, that these trials can be done outside of official trial and may not have as stringent requirements.
 
Eh I would say all tinnitus is caused by hearing interference, not loss.

Eg. Hydrops can cause it and it can resolve with hydrops.

Things like TMJ and neck tinnitus fit that category too.
Also other causes related to conductive issues like ear drum hole(s), damaged middle ear bones etc.
 
FX-322 is one of my big hopes, the other one is Susan Shore.

All my fingers crossed that this will work for some of us!!!

Another question: Would you invest in the FREQ stock? I'm thinking about it...
I think we will see positive results with both Dr. Susan Shore and FX-322.

If Shore ever gets her device out!

I bought a sizable amount of FREQ stock.
 
Do you believe companies never hide behind the FDA process in order to bilk investors on drugs these companies know will fail?

I have experience. You've read the FDA comic books about how they are from the government and here to help?

The FDA is a spoon fed entity of overrated sh*t. A type of monopoly.

This is FX-322 topic, I don't want to derail it with comments about FDA. Someone start FDA thread and I will contribute my FDA dislike there.
Done:

FDA Rage Thread

Feel free to make a post there ha.
 
Question regarding support cells: Is it one support cell per hair cell, and if not, how does the newly created hair cell know where to go? Does it just migrate to an open position? Also, if it is one support cell per hair cell, what happens when a support cell with a functioning hair cell gets the drug?

I was thinking about this the other day and realized that though I have a basic understanding of how the drug works, when I start thinking about the details of what's going on, everything kind of falls apart.

Lastly, on a more corny note, it feels like it's taking forever for September 30th to get here, and the song "Wake me up when September ends" now has new meaning to me (even though that deadline may now be meaningless).
 
Question regarding support cells: Is it one support cell per hair cell, and if not, how does the newly created hair cell know where to go? Does it just migrate to an open position? Also, if it is one support cell per hair cell, what happens when a support cell with a functioning hair cell gets the drug?

I was thinking about this the other day and realized that though I have a basic understanding of how the drug works, when I start thinking about the details of what's going on, everything kind of falls apart.

Lastly, on a more corny note, it feels like it's taking forever for September 30th to get here, and the song "Wake me up when September ends" now has new meaning to me (even though that deadline may now be meaningless).
There is definitely more than one support cell per hair cell based on all the diagrams included in papers I have seen.

As far as what happens when a support cell with a functional hair cell gets the drug, it seems like a new produced hair cell in that scenario doesn't incorporate because on the Tinnitus Talk Podcast, it was mentioned they didn't see supernumerary hair cells.

What I suppose happens then is either support cells with functional hair cells don't get activated for some reason (and maybe there is something about dead hair cells that prime progenitor cells for activation with chemical signaling or lack of?) or hair cells get made but don't have an attachment site so get reabsorbed by the body.

Thinking about this more...

If the drug does still interact with support cells that have normal hair cells, this could explain why repetitive dosing could be a lot more effective as this will enable drug to bypass sections of cochlea that are already binding with drug.
 
Question regarding support cells: Is it one support cell per hair cell
Here are a couple of diagrams that can help flesh out your understanding of the different kinds of support cells, and the ones that are LGR5+.

They really helped me.

E840C02A-391A-4229-BB20-2E195533931F.jpeg

1706B8C2-5E08-4FB8-859D-A97179E61F55.jpeg
 
Despite all the well meaning public statements, Frequency Therapeutics is a for-profit company with stockholders. As a business, it doesn't make much sense to use that $42m fund on expanded access. It's better for them to quickly go through the whole clinical trials shebang for quick product release. Frequency Therapeutics still need the capital to establish phase 3, then setup larger production, marketing, etc. Despite many people having hearing loss and tinnitus, it's still not well known to the majority.

Also, Frequency Therapeutics have other drugs in development, which was mentioned in their press release, regarding the $42m fund, about putting effort into multiple sclerosis.

Also, I'm not trying to be negative, but getting our hopes up too high right now is premature. They're still in phase 2. Everything hinges on phase 2 results.
While I agree with this chain of thinking and have posted as much before, I think it takes a certain amount of cynicism to believe that Frequency isn't genuinely looking at Expanded Access after Carl LeBel just said on the Tinnitus Talk Podcast that it was something that they are "certainly interested" in.

He said this right after citing the lack of safety profile as the primary cause impeding Expanded Access. He even goes so far as to say that phase 2 results may be the thing that gets them into Expanded Access, depending on what they look like.

If it were due to money, I think he would have leaned more on the production side of things as an excuse. I don't think hoping for mid next year is much of a stretch, so long as phase 2A results prove FX-322 to be relatively safe. This seems likely, based on phase 1 data.
 
Here are a couple of diagrams that can help flesh out your understanding of the different kinds of support cells, and the ones that are LGR5+.

They really helped me.

View attachment 40105

View attachment 40106
So it looks like this method can restore 1/3 of lost OHCs. Therapeutic, for certain. Hopefully this is the stepping stone to getting the next round of regeneration, though. Or that the IPC can work for that first OHC as well. Then it would be 2/3 of OHCs.
 
So it looks like this method can restore 1/3 of lost OHCs. Therapeutic, for certain. Hopefully this is the stepping stone to getting the next round of regeneration, though. Or that the IPC can work for that first OHC as well. Then it would be 2/3 of OHCs.
I don't think you can extrapolate percentages from a schematic. Besides, that's 2-D drawing, we would need multiple views to assess that because even going by the first drawing it looks like one row interacts with the LGR5+ cell and in the second, one cell interacts with two hair cells.

If it only regenerates the first two rows, hypothetically, that could explain why it is being studied for up to severe loss. Though he did say on the podcast, they think there would be benefit up until the flat epithelial stage.
 
While I agree with this chain of thinking and have posted as much before, I think it takes a certain amount of cynicism to believe that Frequency isn't genuinely looking at Expanded Access after Carl LeBel just said on the Tinnitus Talk Podcast that it was something that they are "certainly interested" in.

He said this right after citing the lack of safety profile as the primary cause impeding Expanded Access. He even goes so far as to say that phase 2 results may be the thing that gets them into Expanded Access, depending on what they look like.

If it were due to money, I think he would have leaned more on the production side of things as an excuse. I don't think hoping for mid next year is much of a stretch, so long as phase 2A results prove FX-322 to be relatively safe. This seems likely, based on phase 1 data.
You tell me that a for-profit pharmaceutical company is not going to try to get something out as quickly as possible :)

It is all about providing proof required to get FX-322 through the Expanded Access requirements. While they won't want to ever give away their commercial intentions conclusively, they will suggest what they might be considering if it is an option.

One obvious thing that Frequency has shown so much throughout this is that they are actually amazingly focused on complying with the FDA procedures/processes and delivering the best pharmaceutical product possible. I am pretty sure that if they need to delay things due to trying to meet their obligations that they will because they want the best outcome. Thus we might not get given the option to take FX-322 through Expanded Access. Although at this time I am actually certain that they will attempt to do all they can to get given a pass to release FX-322.
 
I don't think you can extrapolate percentages from a schematic. Besides, that's 2-D drawing, we would need multiple views to assess that because even going by the first drawing it looks like one row interacts with the LGR5+ cell and in the second, one cell interacts with two hair cells.

If it only regenerates the first two rows, hypothetically, that could explain why it is being studied for up to severe loss. Though he did say on the podcast, they think there would be benefit up until the flat epithelial stage.
Can you please explain what is the flat epithelial stage and what that entails? I was doing self pure tone measuring and I can not hear 15 kHz at all at any volume while my good ear can hear 15 kHz at the lowest volume. Is complete or near deafness at that range considered flat epithelial?
 
Can you please explain what is the flat epithelial stage and what that entails? I was doing self pure tone measuring and I can not hear 15 kHz at all at any volume while my good ear can hear 15 kHz at the lowest volume. Is complete or near deafness at that range considered flat epithelial?
I'm interested in this too, although my audiologist told me that there are some serious limitations in doing testing at home. Headphones, the volume, the ability at being able to hear certain frequencies all come into play. I have been told that these tests could in theory be accurate but in reality they probably are not at all.

Also I have been told that you could have a deficiency at, for example, 3000 Hz and yet be able to hear at 20000 Hz. There tends to be variation between patients and they don't know why.

What we also know is that the theory put out on hearing regeneration hasn't really been tested beyond being a theory. What has been hypothesised may be true, but until this has actually been tested through clinical investigations we won't know whether hearing regeneration can actually happen or not.
 
Can you please explain what is the flat epithelial stage and what that entails? I was doing self pure tone measuring and I can not hear 15 kHz at all at any volume while my good ear can hear 15 kHz at the lowest volume. Is complete or near deafness at that range considered flat epithelial?
Flat epithelia happens with profound hearing loss (greater 90 dB). I'm not sure of it is an acute or chronic feature of that sort of loss but it's associated with it.

I have a 60 dB loss at 12000 Hz but I can't hear it at any volume on my phone or computer in my worst ear but an audiologist still measured mine at 60 dB.

Get an extended audiogram if you haven't already there are serious limitations to trying to measure it at home.
 
What we also know is that the theory put out on hearing regeneration hasn't really been tested beyond being a theory.
This is true however the phase 1 results would indicate that there could be serious truth to this theory considering the 10 dB improvement at 8 kHz and word scores getting better could be considered significant.

We have to wait for the phase 2a results and hope they are much more significant. If so then there could be a serious winner here in terms of treatment.

I hope this isn't blind optimism. The theory makes sense. In many ways the human body is like a machine and fixing the broken parts (i.e. IHC, OHC, etc) could result in a much better functioning part.

Sometimes I feel like we are getting into the realm of too futuristic and unreal. However, I'm sure decades ago, many people didn't expect there to be treatments like lung and heart transplants, but it is a possibility now. Surely something like hair cells seem easier once the mechanism to regrow them is in place. Risks seems like it could be minimal too considering they are your OWN hair cells. Regenerative medicine is probably the future.
 
I'm interested in this too, although my audiologist told me that there are some serious limitations in doing testing at home.
Perhaps, but it should be sufficient. The fact that I can hear 14 kHz and 15 kHz very noticeably with my good ear on the lowest volume but I can not hear it at all on my tinnitus ear (even 5x the original volume) is sufficient enough to conclude that I have damage in that UHF range. Also, since I can hear how 15 kHz sounds like in my good ear and my tinnitus sounds almost exactly like 15 kHz is elucidating enough.

The issue with home testing is that we can not reliably test how much damage there is, i.e. the dB threshold.

Since FX-322 works mostly in the high frequencies, I hope I have enough support cells left in the high frequencies.

Edit: I used the ACRN tool at this website to self test the UHF: http://www.generalfuzz.net/acrn/
 
I agree with most of this, except for the press release from FREQ re: the $42MM placement;

"The Company plans to use the net proceeds from the private placement to further advance the clinical development of FX-322, its lead product candidate in Phase 2a development for sensorineural hearing loss, by gaining additional insights regarding the patient populations and severity of hearing loss that FX-322 may treat."

I interpret this as validating the effectiveness of FX-322 on a population of patients that are outside of the parameters of the current Phase 2A, and likely Phase 3.

As an investor, I see this as an investment in some type of peripheral research / trial that enables Frequency to apply its drug to more types of hearing loss. And that means more money, more quickly.

Could very well be presbycusis considering the recent studies finding that it's basically just SNHL. But, it could very well be other classes of treatable hearing loss markets. High frequency hearing loss seems to be a growing market that affects younger people, and seems common for members of this forum.

I asked about the expanded access trial, because according to what I am reading from the FDA, that these trials can be done outside of official trial and may not have as stringent requirements.
Surely, the proceeds will go towards the development of FX-322. While Frequency Therapeutics is also working on a Multiple Sclerosis therapeutic, FX-322 is their leading drug candidate. It shows promise, has a massive target market, and is the closest to approval/release. The private placement is directly tied to this drug.

As we know, clinical trials are very costly. I recently came across the following excerpt from Patricio Ledesma of Sofpromed: "The average cost of phase 1, 2, and 3 clinical trials across therapeutic areas is around $4, 13, and 20 million respectively. Pivotal (phase 3) studies for new drugs approved by the Food and Drug Administration (FDA) of the United States cost a median of $41,117 per patient."

Though I don't think they will pursue this route, expanded access trials would be a great way to gather additional data points and insights (i.e. patients with no audiogram loss, severe tinnitus but mild hearing loss, etc.). This would allow for the potential validation of additional patient populations without taking away from primary measure outcomes. I do, however, believe Phase 2a and a more-inclusive pivotal phase can obtain much of the same information. Regardless of how they choose to capture the data, the funding is there and the leadership is there. I believe we are looking at a breakthrough therapy, and I hope the FDA sees it the same way when Phase 2a results are announced.
 
Perhaps, but it should be sufficient. The fact that I can hear 14 kHz and 15 kHz very noticeably with my good ear on the lowest volume but I can not hear it at all on my tinnitus ear (even 5x the original volume) is sufficient enough to conclude that I have damage in that UHF range. Also, since I can hear how 15 kHz sounds like in my good ear and my tinnitus sounds almost exactly like 15 kHz is elucidating enough.

The issue with home testing is that we can not reliably test how much damage there is, i.e. the dB threshold.

Since FX-322 works mostly in the high frequencies, I hope I have enough support cells left in the high frequencies.

Edit: I used the ACRN tool at this website to self test the UHF: http://www.generalfuzz.net/acrn/
As an aside, the ear isn't supposed to have the same sensitivity to different frequencies:

upload_2020-8-8_8-57-24.png
 

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