Frequency Therapeutics — Hearing Loss Regeneration

[Lucifer]

It's Trobalt but with different delivery size suited for children. They expect Phase 3 to start this year.

The only thing about the Trobalt reformulation is that with the discontinued Trobalt it had benefits in reducing your tinnitus and hyperacusis but once you stopped taking it symptoms would return. That's why I believe you need FX-322 to fix the underlying issue. I hope Frequency Therapeutics releases it asap. The wait is killing me.

 

[FGG]

Based on FDA statistics, the chances that FX-322 will be approved is about 10%. If they are super successful and receive Fast Track status than maybe it could be available in 2023 (?).

My bet for what hits the market in a reasonable time is XEN-496, although it's in a completely different category of drugs and is also very risky due to side effects.

Important to note that those are *general* statistics for FDA trial failure rate but it varies widely by class of drugs. Some classes have an abysmal success rate, e.g., Alzheimer's drugs (close to zero drugs get approved in this space). It's hard to say where hearing regeneration drugs will fall because it hasn't previously been possible.

But it is easier to predict success of a drug that isn't as subject to the placebo effect. As was said in the Tinnitus Talk Podcast "you can't squint your ears" to get better hearing results. You either hear better or you don't. The phase 2A data should provide a lot of information.

 

[serendipity1996]

The only thing about the Trobalt reformulation is that with the discontinued Trobalt it had benefits in reducing your tinnitus and hyperacusis but once you stopped taking it symptoms would return. That's why I believe you need FX-322 to fix the underlying issue. I hope Frequency Therapeutics releases it asap. The wait is killing me.

Yeah I don't really fancy the idea of having to take something like Trobalt indefinitely as a band-aid solution.

 

[serendipity1996]

Important to note that those are *general* statistics for FDA trial failure rate but it varies widely by class of drugs. Some classes have an abysmal success rate, e.g., Alzheimer's drugs (close to zero drugs get approved in this space). It's hard to say where hearing regeneration drugs will fall because it hasn't previously been possible.

But it is easier to predict success of a drug that isn't as subject to the placebo effect. As was said in the Tinnitus Talk Podcast "you can't squint your ears" to get better hearing results. You either hear better or you don't. The phase 2A data should provide a lot of information.

Is progenitor cell activation, PCA, a completely novel method that has never been through clinical trials before? I don't really know a great deal about regenerative medicine but it sounds like this is a technique that Frequency Therapeutics has basically pioneered based on Langer and Karp's findings.

 

[WillBeNimble]

I thought XEN-496 was more specific than Trobalt?

Also, I doubt they're just releasing it with the same safety profile and side effects as Trobalt, because that's what got Trobalt pulled.

 

[FGG]

Is progenitor cell activation, PCA, a completely novel method that has never been through clinical trials before? I don't really know a great deal about regenerative medicine but it sounds like this is a technique that Frequency Therapeutics has basically pioneered based on Langer and Karp's findings.

Definitely in the cochlea, haven't heard it used elsewhere but I imagine it's not needed in the small intestines since that body does that innately and that's where this technique was discovered.

Frequency is working on using progenitor cells for other things (apparently for baldness and joint health). I'm not aware of anyone else doing that yet.

 

[Jim51042]

. Some classes have an abysmal success rate, e.g., Alzheimer's drugs

This is a result of the brain being so complicated that science still has a limited understanding of its underlining processes. This doesn't worry me for hearing restoration because while the ear structures are very tiny and inaccessible the mechanism for hearing is so simple an elementary school kid could understand it. So once the hurdle get to and fixing the structures of the ear is complete the ear will re-function as it was originally designed.

A follow-on to this difference in complexity is the idea that a functional lab produced replacement ear will be manufactured decades maybe even centuries before a functional lab produced replacement brain.

 

[Diesel]

In reviewing the drugs where Breakthrough Therapy was either approved or rejected; in particular, therapies that are not related to cancer. It's really hard to imagine FX-322 not receiving Breakthrough status.

If we consider a highly pessimistic outcome in the Phase 2A, where basically we see more Phase 1/2-like outcomes:

- Safety profile remains favorable as it did in the P1/2 - (No major adverse events)
- Speech Intelligibility improves similarly to Phase 1/2 - (Nearly doubling, atleast 1 significant)
- Standard pure tone only really improves at 8Khz like Phase 1/2
- More patients see similar outcomes as the Phase 1/2 (between 45 and 72 patients)
- Multiple doses do not have any significant effect
- Secondary outcomes are not significant in improvement (No effect on tinnitus, QOL measures unchanged)
- Somehow, magically the UHF audiogram doesnt show improvement (Yeah, not likely, i know)

It will still be well above the qualifying benchmark for Breakthrough Status, relative to other applicants.

- At lease one primary outcome continues to show clinical significance (Speech in quiet)
- Safety profile met
- Improvement over an existing therapy (there are none)

 

[Don Tinny]

Today I read about the Oxford´s vaccine to treat COVID-19 and it just irritates me (sorry for being miserable). They did it so fast! And here we are always projecting our life in 5 or 10 years.

I´m not reading Tinnitus Talk so frequently but it´s always depressing when I come back and there is no exciting news.

 

[Paulmanlike]

@FGG

I have asked for an an extended audiogram and I get told that they don't do them. Audiologists I've been to (private) as well as the audiologists in the NHS. I guess because they really see no point - not many essential noises for day to day function go above 8kHz and no hearing aid will assist for lost frequencies above that range (correct me if I'm wrong). It would only be for my benefit of knowing and they wouldn't be able to sell me hearing aids in the private field or help me in any way. I was tried to sell a hearing aid though for £1,100 just for the masker and the Bluetooth capacity. Unbelievable.

I do see my new regular audiologist now (for wax removal) who I have exchanged a few texts with. I think he finds it intriguing one of his patients has some knowledge in the hearing loss field - we spoke about regeneration and Lenire - I bet he didn't hear about that from his patients.

Important to note that those are *general* statistics for FDA trial failure rate but it varies widely by class of drugs. Some classes have an abysmal success rate, e.g., Alzheimer's drugs (close to zero drugs get approved in this space). It's hard to say where hearing regeneration drugs will fall because it hasn't previously been possible.

But it is easier to predict success of a drug that isn't as subject to the placebo effect. As was said in the Tinnitus Talk Podcast "you can't squint your ears" to get better hearing results. You either hear better or you don't. The phase 2A data should provide a lot of information.

You're exactly right about the Alzheimer's drugs in trials. I was reading up that over 15 years, over 200 drugs were in trials for Alzheimer's and just 3 were approved. Something like that anyway.

But exactly right as well in the hearing field. It's never been done before and the answer is we just don't know what chances of success are.

 

[FGG]

@FGG

I have asked for an an extended audiogram and I get told that they don't do them. Audiologists I've been to (private) as well as the audiologists in the NHS. I guess because they really see no point - not many essential noises for day to day function go above 8kHz and no hearing aid will assist for lost frequencies above that range (correct me if I'm wrong). It would only be for my benefit of knowing and they wouldn't be able to sell me hearing aids in the private field or help me in any way. I was tried to sell a hearing aid though for £1,100 just for the masker and the Bluetooth capacity. Unbelievable.

I do see my new regular audiologist now (for wax removal) who I have exchanged a few texts with. I think he finds it intriguing one of his patients has some knowledge in the hearing loss field - we spoke about regeneration and Lenire - I bet he didn't hear about that from his patients.

You're exactly right about the Alzheimer's drugs in trials. I was reading up that over 15 years, over 200 drugs were in trials for Alzheimer's and just 3 were approved. Something like that anyway.

But exactly right as well in the hearing field. It's never been done before and the answer is we just don't know what chances of success are.

I think some people on the forum were able to get extended audiograms in the UK but I'm not sure where. University settings? It's difficult to get it done here (US) too precisely because hearing aids don't cover those frequencies.

 

[serendipity1996]

@FGG

I have asked for an an extended audiogram and I get told that they don't do them. Audiologists I've been to (private) as well as the audiologists in the NHS. I guess because they really see no point - not many essential noises for day to day function go above 8kHz and no hearing aid will assist for lost frequencies above that range (correct me if I'm wrong). It would only be for my benefit of knowing and they wouldn't be able to sell me hearing aids in the private field or help me in any way. I was tried to sell a hearing aid though for £1,100 just for the masker and the Bluetooth capacity. Unbelievable.

I do see my new regular audiologist now (for wax removal) who I have exchanged a few texts with. I think he finds it intriguing one of his patients has some knowledge in the hearing loss field - we spoke about regeneration and Lenire - I bet he didn't hear about that from his patients.

You're exactly right about the Alzheimer's drugs in trials. I was reading up that over 15 years, over 200 drugs were in trials for Alzheimer's and just 3 were approved. Something like that anyway.

But exactly right as well in the hearing field. It's never been done before and the answer is we just don't know what chances of success are.

I remember reading an article about Eli Lilly's Alzheimer's drug which failed. I think most of these drug failures were predicated on the amyloid plaque build-up hypothesis which has turned out to be pretty unsuccessful. So companies will have to change tactics. Whereas with hearing regeneration we know what's going wrong - hair cells being damaged/dying, we know what structures to target (hair cells/synapses for hidden hearing loss) so in that way it seems more straightforward.

 

[tommyd87]

In reviewing the drugs where Breakthrough Therapy was either approved or rejected; in particular, therapies that are not related to cancer. It's really hard to imagine FX-322 not receiving Breakthrough status.

If we consider a highly pessimistic outcome in the Phase 2A, where basically we see more Phase 1/2-like outcomes:

- Safety profile remains favorable as it did in the P1/2 - (No major adverse events)
- Speech Intelligibility improves similarly to Phase 1/2 - (Nearly doubling, atleast 1 significant)
- Standard pure tone only really improves at 8Khz like Phase 1/2
- More patients see similar outcomes as the Phase 1/2 (between 45 and 72 patients)
- Multiple doses do not have any significant effect
- Secondary outcomes are not significant in improvement (No effect on tinnitus, QOL measures unchanged)
- Somehow, magically the UHF audiogram doesnt show improvement (Yeah, not likely, i know)

It will still be well above the qualifying benchmark for Breakthrough Status, relative to other applicants.

- At lease one primary outcome continues to show clinical significance (Speech in quiet)
- Safety profile met
- Improvement over an existing therapy (there are none)

I think that you are again accurate and thus there is a good case currently that this would get granted Breakthrough Therapy status. I reckon that even without improvements in those facets (which is very unlikely), the standards will regardless be met. It was also four people having significant statistical improvement if I remember correctly.

I wonder whether Frequency Therapeutics is trying to further improve efficacy first before allowing compassionate use and applying for final approval.

 

[UHPTS]

I thought XEN-496 was more specific than Trobalt?

Also, I doubt they're just releasing it with the same safety profile and side effects as Trobalt, because that's what got Trobalt pulled.

I wish you were right.

After reading this https://www.xenon-pharma.com/product-pipeline/xen496-for-epilepsy/ I concluded that the formula stays the same.

 

[patorjk]

Frequency's news on Friday about raising an additional $42 million was kind of interesting.

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. The Company also plans to increase support for its remyelination program in multiple sclerosis, which it intends to move into the clinic in the second half of 2021, and new areas of research where there is potential to utilize the Company's progenitor cell activation platform.

I'm curious if part of these funds will go to developing a better gel formation that will reach the lower frequencies. It seems like so much depends on the results of phase 2a though.

I've heard people talk about the top-line results getting delayed, but does anyone know if this is happening for sure? And if so, is there a target date for the top-line results?

 

[Emgee]

It was very encouraging to hear that Frequency will look to revisit their expanded access policy after Phase 2a results are analyzed. The company clearly understands that many are in a position of suffering right now.

The Tinnitus Talk Podcast interview was very insightful and informative. Great job by everyone involved. If Phase 2a proves to be successful, we may not be looking at such a long wait to access the drug via compassionate use. There is hope on the horizon.

 

[FGG]

Frequency's news on Friday about raising an additional $42 million was kind of interesting.

I'm curious if part of these funds will go to developing a better gel formation that will reach the lower frequencies. It seems like so much depends on the results of phase 2a though.

I've heard people talk about the top-line results getting delayed, but does anyone know if this is happening for sure? And if so, is there a target date for the top-line results?

I would say they are focused on phase 2a at the moment. He said in the interview that they didn't know what additive effect, if any, multiple dosing would have in terms of penetrance and they are testing from 250 Hz to 16000 Hz.

The delay was mentioned in their Fireside chat a month ago which unfortunately isn't on their website anymore last I checked. There is no updates timeline other than that they aim to keep the delay minimal and have interest in working as fast as possible.

 

[FGG]

I remember reading an article about Eli Lilly's Alzheimer's drug which failed. I think most of these drug failures were predicated on the amyloid plaque build-up hypothesis which has turned out to be pretty unsuccessful. So companies will have to change tactics. Whereas with hearing regeneration we know what's going wrong - hair cells being damaged/dying, we know what structures to target (hair cells/synapses for hidden hearing loss) so in that way it seems more straightforward.

Turns out the amyloid plaque hypothesis people had all the power, influence, funding and set research back at least decades. Just like TRT for tinnitus (though in the later case, its damage was primarily to set up the myth that tinnitus was already "treatable")

 

[Lucifer]

Turns out the amyloid plaque hypothesis people had all the power, influence, funding and set research back at least decades. Just like TRT for tinnitus (though in the later case, its damage was primarily to set up the myth that tinnitus was already "treatable")

I always see fake ads online for how to cure tinnitus. Those ads are really fucked up as people assume there is a cure for tinnitus.

 

[patorjk]

I would say they are focused on phase 2a at the moment. He said in the interview that they didn't know what additive effect, if any, multiple dosing would have in terms of penetrance and they are testing from 250 Hz to 16000 Hz.

The delay was mentioned in their Fireside chat a month ago which unfortunately isn't on their website anymore last I checked. There is no updates timeline other than that they aim to keep the delay minimal and have interest in working as fast as possible.

As an aside, he seemed to indicate that he thought additional doses would help. His reasoning that each injection wouldn't be exactly the same, leading to the medicine hitting different progenitors or possibly going deeper - I thought that seemed pretty logical. I do worry that maybe injections are happening too close together, but I'm assuming they've done enough research to know when a progenitor can divide again. Though that's another question I have - is it one progenitor per hair cell? And if it is and a progenitor already has a hair cell, what happens?

I also wonder if progenitors "use up" the medicine once they encounter it, or if the same molecules can cause multiple progenitors to divide. If the former is the case, I bet additional doses will help a lot, and maybe it'll show that the upper frequencies are fixed first, and then additional doses help the lower frequencies. However, this is just pure speculation.

 

[Chriscom]

Amazing interview! Cannot thank the Tinnitus Talk Podcast team enough. This is just so impressive.

 

[mrbrightside614]

​

The time has finally come!

Today we are publishing perhaps our most long-awaited episode of the Tinnitus Talk Podcast. It's also an episode that has cost us more time and resources than ever. After exchanging many dozens of emails with the company, preparing our questions diligently, making all the technical arrangements for recording from three (!) locations simultaneously, and many days of editing and transcribing, we are proud to finally present the community with the results of our hard work.

As show of appreciation for those who support the Tinnitus Talk Podcast financially, allowing us to cover our expenses and maintain high quality standards, only Patreon supporters will get access for now. But don't worry, we will make it freely available for everyone else in a week or so!

Listen to the interview

This episode was produced with contributions from two awesome members of this community: @mrbrightside614 and @FGG. And behind the scenes – but no less important - @Markku and @Autumnly have worked hard to provide you with the best listening experience.

View attachment 39865

Once again, thanks so much for @Markku and @Hazel's persistence and commitment to excellence throughout this process. I was super happy to be involved but as I said on the podcast, I've been doing less than well due to circumstances beyond my control and I'm sorry that I'm not very active on these boards much.

The only thing I want to add is that Dr. LeBel touched on the lack of scientific data to defend steroidal interventions in treating tinnitus. While this is true, it's mostly because the studies are very poorly designed. Oftentimes the steroids are administered well outside of the window of therapeutic efficacy, so one can not appropriately deduce that they are ineffective from these studies. Any steroid treatment is still worth a shot if you're in the extremely acute window.

Beyond that, again I am sorry that we could not address the hyperacusis question. My thinking was that they're not measuring it in phase two, and have neither done so much as mention it once during all of their press releases/Fireside chats. I don't think Frequency Therapeutics would be able to speak on whether or not it would be effective through this next phase. If we get to speak with them again after phase 2 I will definitely ask.

Thanks everybody for helping and listening. Special thank you to @FGG for her brilliant mind and big heart.

 

[d'Wooluf]

Important implications for Frequency Therapeutics here:
https://medicalxpress.com/news/2020-07-hair-cell-loss-age-related.html

Basically they're saying that age-related hearing loss (presbycusis) is caused by hair cell loss. This makes the already huge potential market for FX-322 even huger.

 

[FGG]

As an aside, he seemed to indicate that he thought additional doses would help. His reasoning that each injection wouldn't be exactly the same, leading to the medicine hitting different progenitors or possibly going deeper - I thought that seemed pretty logical. I do worry that maybe injections are happening too close together, but I'm assuming they've done enough research to know when a progenitor can divide again. Though that's another question I have - is it one progenitor per hair cell? And if it is and a progenitor already has a hair cell, what happens?

I also wonder if progenitors "use up" the medicine once they encounter it, or if the same molecules can cause multiple progenitors to divide. If the former is the case, I bet additional doses will help a lot, and maybe it'll show that the upper frequencies are fixed first, and then additional doses help the lower frequencies. However, this is just pure speculation.

I had the same thought, if the drug binds to the first progenitor cell it encounters, the drug will get "used up" repairing the cells at the base first so it seems logical that the only way to know the penetrance is with multiple dosing as they are doing.

 

[Lucifer]

Once again, thanks so much for @Markku and @Hazel's persistence and commitment to excellence throughout this process. I was super happy to be involved but as I said on the podcast, I've been doing less than well due to circumstances beyond my control and I'm sorry that I'm not very active on these boards much.

The only thing I want to add is that Dr. LeBel touched on the lack of scientific data to defend steroidal interventions in treating tinnitus. While this is true, it's mostly because the studies are very poorly designed. Oftentimes the steroids are administered well outside of the window of therapeutic efficacy, so one can not appropriately deduce that they are ineffective from these studies. Any steroid treatment is still worth a shot if you're in the extremely acute window.

Beyond that, again I am sorry that we could not address the hyperacusis question. My thinking was that they're not measuring it in phase two, and have neither done so much as mention it once during all of their press releases/Fireside chats. I don't think Frequency Therapeutics would be able to speak on whether or not it would be effective through this next phase. If we get to speak with them again after phase 2 I will definitely ask.

Thanks everybody for helping and listening. Special thank you to @FGG for her brilliant mind and big heart.

I wonder if any patients in the current clinical trials have disclosed and stated that they have hyperacusis and which type? They could ask the current and previous patients if they have noticed any improvements in their hyperacusis. There is bound to be at least a few patients that suffer from hyperacusis.

 

[Lucifer]

I had the same thought, if the drug binds to the first progenitor cell it encounters, the drug will get "used up" repairing the cells at the base first so it seems logical that the only way to know the penetrance is with multiple dosing as they are doing.

So there's a chance that with more doses it can still reach the lower frequencies but would be much easier with a new delivery method?

 

[WillBeNimble]

Important implications for Frequency Therapeutics here:
https://medicalxpress.com/news/2020-07-hair-cell-loss-age-related.html

Basically they're saying that age-related hearing loss (presbycusis) is caused by hair cell loss. This makes the already huge potential market for FX-322 even huger.

Eh, above a certain point, fighting age related hearing loss is pointless. I can imagine FX-322 only being given out to children/teenagers only in the cases of extreme damage/tinnitus.

 

[UHPTS]

Eh, above a certain point, fighting age related hearing loss is pointless. I can imagine FX-322 only being given out to children/teenagers only in the cases of extreme damage/tinnitus.

Why would fighting age related hearing loss be pointless?

 

[Diesel]

Eh, above a certain point, fighting age related hearing loss is pointless. I can imagine FX-322 only being given out to children/teenagers only in the cases of extreme damage/tinnitus.

Presbycusis usually starts at age 50. An age when people are in the late stages of their career, raising children, planning for retirement. The economic gains had by keeping their quality of life up and productive could be extended with regenerative medicine. It seems to reach a majority state in the 65-75 population, where hearing aids are almost certainly required. Quality of life is a driver at that level.

Today, people aged 50-74 in the US is a massive market, that spends a lot of money on adult health products/services.

Treating presbycusis with regen medicine very much fits into a model where "ear health" visits become an annual health service like dentist/eye visits.

 

[d'Wooluf]

Eh, above a certain point, fighting age related hearing loss is pointless.

Above what point and why? Do you know that hearing loss is a major risk factor for cognitive decline? Start saving people's hearing at 70, society may save billions in aged care costs. If you just want to look at it in dollar terms...

I can imagine FX-322 only being given out to children/teenagers only in the cases of extreme damage/tinnitus.

Again, why?