Frequency Therapeutics — Hearing Loss Regeneration

[Spiral]

Best hope at this point is adjust for tinnitus to be permanent, and cherish the people you meet along the way. FX-322 was a little bit over hyped, but the truth is the 'cure' likely hasn't even been conceived at this point. There's too many obstacles like the delivery method in addition to things other than just hair cell regeneration.

It will probably be a cocktail of drugs that work together, injected straight into the cochlea.

 

[ColinUK]

You don't need to be so melodramatic. FX-322 is a forum favorite but they're hardly the only one, and there's a myriad of companies getting in on the action month by month.

Thing is I need something now. This thread was started 5 years ago and today there is not a single piece of evidence that it's helped anyone with tinnitus. All these drugs are years away and I'm sorry but maybe getting something in 5-20 years doesn't really help me. Everything takes forever. This board is littered with clinical trial failures.

My only hope really is Dr. Susan Shore's device, for the tinnitus aspect at least.

These drugs I tend to think are not going to be available in my lifetime (I'm in my 40s).

 

[Tezcatlipoca]

It's too bad they can't look inside our ears and take an image of the cochlea. I would love to know if it's my synapses that are broken, or if it's dead hair cells.

@Diesel is making a good point. I think there's evidence that suggests synapses are more of a problem than hair cell death (in noise-induced hearing loss at least), so if that's true, some of the other drugs in the pipeline can give relief as well.

 

[Keith Handy]

@Diesel is making a good point. I think there's evidence that suggests synapses are more of a problem than hair cell death (in noise-induced hearing loss at least), so if that's true, some of the other drugs in the pipeline can give relief as well.

I don't understand how noise would damage a synapse without damaging the respective hair cell.

 

[Kleiner]

I don't understand why Frequency Therapeutics hasn't added auditory brainstem response (ABR) testing and OHC emissions to its clinical trials.

It's a bit amateurish to use only audiograms. That's what worries me the most.

We just have to wait for the severe hearing loss trial. They will no longer be able to lie if the results are negative.

 

[Diesel]

I don't understand why Frequency Therapeutics hasn't added auditory brainstem response (ABR) testing and OHC emissions to its clinical trials.

It's a bit amateurish to use only audiograms. That's what worries me the most.

We just have to wait for the severe hearing loss trial. They will no longer be able to lie if the results are negative.

They used audiogram, WR and WIN because they are common clinical tests. These tests show what would be observed in a clinical setting.

 

[Diesel]

I'm just not seeing how the severe hearing loss trial is going to show any major improvements.

This was disappointing. We can now limit the type of person it helps and the amount it helps if the severe hearing loss trial is successful.

I'm having an issue with this quote:

"To date, Frequency has shown statistically significant hearing benefits in multiple, independent FX-322 studies"​

The benefits just aren't there. Even those that had improved word scores, many dropped in the follow up visits and the hearing restoration aspect is very limited.

Instead of more trials we need Frequency Therapeutics to figure out how to make it more effective, if it is even possible.

I think they will end up running out of money. Hearing loss was only one application of their advancement. I doubt anyone will give them money to continue, so we will never know what other potential benefits PCA will have.

It is all a matter of business at this point. They have limited resources (time and money) to get FX-322 to the point where the sale of the drug can start generating cash flow and profit. They have until 2023. That's 2 years.

With the funds on hand, Frequency Therapeutics needs to get FX-322 into the market by 2023. To do so, they need to identify the patient population that FX-322 consistently shows improvement. This patient population has to carry them through a Phase 2 and 3, and to FDA approval.

The objective of any drug getting to market isn't to help as many people as possible. It's to identify the patient population that the drug can improve one or more clinical outcomes consistently and safely.

Right now, it appears the market that FX-322 fits the above requirement on is the moderate - moderately severe hearing loss group. If severe shows similar outcomes, the patient population is up to 10M in the US alone.

That's probably their ideal outcome for FX-322 to get to market in 2 years as it currently is formulated. It's not ideal, but considering how widespread SNHL is, up to 10 million patients (20 million ears) is a substantial market for a new drug.

The problem with going back to the drawing board now to redo FX-322 help "everyone" with a reformulation, new delivery, etc is simply a matter of cost. They know in 2 years with the resources they have, they simply cannot achieve this, and get the drug back into a new Phase 1.

The benefit of this targeted approach of a "small" market of up to 10m patients in the US, is that the product then can provide them with the cashflow needed to reformulate and reach a greater patient population. Also, from an FDA standpoint, it appears to be a much faster process to get reformulations through.

In the US, just because a drug is designated for a certain severity, doesn't mean the doctor can't prescribe it to see if it helps the patient, provided the risks are low. So for many people here, even though you don't think you fit their patient profile, that doesn't mean you don't stand to gain some benefit.

This is actually all a really common strategy/practice in the drug industry. I'm surprised it hasn't come up more on this thread. You may notice commercials for new drugs on your TV, almost all of the new drugs are for moderate-severe conditions. It's for literally the same reason as we're seeing with FX-322. The drug company found enough of a patient population to support a positive cashflow from the first drug, and that population reliably responds well to it.

 

[serendipity1996]

I don't understand how noise would damage a synapse without damaging the respective hair cell.

Well, Liberman has shown that the synapses are the most vulnerable to acoustic trauma, moreso than hair cells. I suspect many of us with a "normal" audiogram have significant synapse loss even if our hair cell loss is limited.

 

[Diesel]

I don't understand how noise would damage a synapse without damaging the respective hair cell.

Noise insults cause wear to both the hair cell and synapse. I am becoming more convinced from recent research that the synapses indeed are more fragile/sensitive to sound insults than the hair cells/stereocilia.

Therefore, it's possible that those who have absorbed many noise insults or a single acoustic trauma that while they probably have regions of the cochlea where hair cells are dead/highly damaged. They're just as likely to have cells that are still functional, but missing synaptic connection.

 

[GlennS]

Are we supposed to believe that hearing loss is the only field of medicine that will never ever have any developments?

Not all medical problems are equally solvable. We're not exactly talking about discovering Penicillin or even inventing mRNA vaccines. This is akin to expecting medical science to solve limb regeneration. That's about as hard as fusion power or anti-gravity would be for physics.

 

[GlennS]

Thing is I need something now.

I've needed something "now" since 1992. I have learned to somehow deal with this monkey on my back one day at a time, riding the constant ebb and flow of despair, depression, and mental distraction. The sense that I "need" something comes from yearning to get back to the mythical state of life before tinnitus. But my life has shown that it's possible to claw your way forward and even get ahead in some areas despite harboring an invisible handicap. I don't like feeling as though my full potential has been blunted by this but there are still things of value I have achieved and feel I still can achieve.

 

[Gb3]

Best hope at this point is adjust for tinnitus to be permanent, and cherish the people you meet along the way. FX-322 was a little bit over hyped, but the truth is the 'cure' likely hasn't even been conceived at this point. There's too many obstacles like the delivery method in addition to things other than just hair cell regeneration.

It will probably be a cocktail of drugs that work together, injected straight into the cochlea.

Wait, they haven't figured out a cure?

 

[serendipity1996]

Professor David Baguley who focuses on tinnitus and hyperacusis certainly believes there's reason to be optimistic about hearing therapies in the pipeline. I think we need to be realistic about FX-322 but we are still progressing.

 

[OptimusPrimed]

I've needed something "now" since 1992. I have learned to somehow deal with this monkey on my back one day at a time, riding the constant ebb and flow of despair, depression, and mental distraction. The sense that I "need" something comes from yearning to get back to the mythical state of life before tinnitus. But my life has shown that it's possible to claw your way forward and even get ahead in some areas despite harboring an invisible handicap. I don't like feeling as though my full potential has been blunted by this but there are still things of value I have achieved and feel I still can achieve.

This is very accurate. Tinnitus, hyperacusis and dysacusis are major annoyances but much can still be accomplished even when fighting these demons daily. I do long for silence and normal hearing though. Really miss it. My hope is that one day these treatments will be good enough to get me closer to hearing normal again. Because I do know there is normal hearing; although at this point it's so far gone that I almost forget what that sounded/felt like.

I disagree though on the hearing regeneration being akin to limb growth. Growing a new limb would entail activating multiple body systems... growing muscles, bone, vascular systems, lymphatic systems, integumentary considerations, nerve innervation that connects to the rest of the body. Regenerating hearing, while not a simple endeavour; basically surrounds around regrowing or repairing the sensory hair cells (OHC and IHC), and also the synapses below them that run to the auditory nerve. Cochlear implants have shown that even if the auditory nerve wasn't stimulated for a long time the brain picks up the new signals and adjusts rapidly to accommodate the new data.

Don't forget that cochlear implants are also advancing at a rapid pace now and they are aiming to have one developed that sounds 99% like normal hearing very soon.

Future is bright friend.

 

[xblaOG]

I just wished we had a participant in the FX-322 clinical trial who we could ask questions about their tinnitus.

 

[Tezcatlipoca]

Professor David Baguley who focuses on tinnitus and hyperacusis certainly believes there's reason to be optimistic about hearing therapies in the pipeline. I think we need to be realistic about FX-322 but we are still progressing.

That's what I'm always saying, so thanks for backing me up. I've spoken to many people outside of Tinnitus Talk and a lot of them weren't that big on FX-322, they had it in like #6 of their most promising list.

 

[RB2014]

This is very accurate. Tinnitus, hyperacusis and dysacusis are major annoyances but much can still be accomplished even when fighting these demons daily. I do long for silence and normal hearing though. Really miss it. My hope is that one day these treatments will be good enough to get me closer to hearing normal again. Because I do know there is normal hearing; although at this point it's so far gone that I almost forget what that sounded/felt like.

I disagree though on the hearing regeneration being akin to limb growth. Growing a new limb would entail activating multiple body systems... growing muscles, bone, vascular systems, lymphatic systems, integumentary considerations, nerve innervation that connects to the rest of the body. Regenerating hearing, while not a simple endeavour; basically surrounds around regrowing or repairing the sensory hair cells (OHC and IHC), and also the synapses below them that run to the auditory nerve. Cochlear implants have shown that even if the auditory nerve wasn't stimulated for a long time the brain picks up the new signals and adjusts rapidly to accommodate the new data.

Don't forget that cochlear implants are also advancing at a rapid pace now and they are aiming to have one developed that sounds 99% like normal hearing very soon.

Future is bright friend.

FX-322 was my last hope to get my hearing back. When I first started this thread, I was moderate/severe. I am now moderate/profound. It looks like a cochlear implant is in my future. Can you provide any links to the cochlear implant that is 99 percent like normal hearing?

It is all a matter of business at this point. They have limited resources (time and money) to get FX-322 to the point where the sale of the drug can start generating cash flow and profit. They have until 2023. That's 2 years.

With the funds on hand, Frequency Therapeutics needs to get FX-322 into the market by 2023. To do so, they need to identify the patient population that FX-322 consistently shows improvement. This patient population has to carry them through a Phase 2 and 3, and to FDA approval.

The objective of any drug getting to market isn't to help as many people as possible. It's to identify the patient population that the drug can improve one or more clinical outcomes consistently and safely.

Right now, it appears the market that FX-322 fits the above requirement on is the moderate - moderately severe hearing loss group. If severe shows similar outcomes, the patient population is up to 10M in the US alone.

That's probably their ideal outcome for FX-322 to get to market in 2 years as it currently is formulated. It's not ideal, but considering how widespread SNHL is, up to 10 million patients (20 million ears) is a substantial market for a new drug.

The problem with going back to the drawing board now to redo FX-322 help "everyone" with a reformulation, new delivery, etc is simply a matter of cost. They know in 2 years with the resources they have, they simply cannot achieve this, and get the drug back into a new Phase 1.

The benefit of this targeted approach of a "small" market of up to 10m patients in the US, is that the product then can provide them with the cashflow needed to reformulate and reach a greater patient population. Also, from an FDA standpoint, it appears to be a much faster process to get reformulations through.

In the US, just because a drug is designated for a certain severity, doesn't mean the doctor can't prescribe it to see if it helps the patient, provided the risks are low. So for many people here, even though you don't think you fit their patient profile, that doesn't mean you don't stand to gain some benefit.

This is actually all a really common strategy/practice in the drug industry. I'm surprised it hasn't come up more on this thread. You may notice commercials for new drugs on your TV, almost all of the new drugs are for moderate-severe conditions. It's for literally the same reason as we're seeing with FX-322. The drug company found enough of a patient population to support a positive cashflow from the first drug, and that population reliably responds well to it.

Good information.

It will be interesting to see how the next trial progresses.

What if it only helps 50 percent of the people in that trial? Can you really market a drug that only helps a percentage of those 10 million customers?

Also what about the people that came back to lower word scores in the follow-up visit? We can help you understand words better for 6 to 9 months and then after a year you are back to square one.

Again I am just seeing limited benefits even if they can reproduce the results in the "successful" trial they had. Don't get me wrong, I am rooting for Frequency Therapeutics to make it work so they can stay viable as a company.

 

[Tezcatlipoca]

I don't worry about money with Frequency Therapeutics. They're about to enter the ALS game. That should give them more investors.

 

[Diesel]

What if it only helps 50 percent of the people in that trial? Can you really market a drug that only helps a percentage of those 10 million customers?

Also what about the people that came back to lower word scores in the follow-up visit? We can help you understand words better for 6 to 9 months and then after a year you are back to square one.

Again I am just seeing limited benefits even if they can reproduce the results in the "successful" trial they had. Don't get me wrong, I am rooting for Frequency Therapeutics to make it work so they can stay viable as a company.

On only helping 50%:

It depends on your definition of "help"... All the drug has to do to meet FDA guidelines is demonstrate statistical significance on a single endpoint. Based on the tiny, tiny, Phase 1/2 sample, it's done that for Moderate-Moderately-Severe hearing loss participants. The outcome won't be binary, whether it helps or not... If it was the case that 50% of participants with Moderate-Moderately Severe hearing loss showed improvement at 1 or more primary clinical endpoint in a Phase 2 or 3, then this drug is going to market. Many drugs do significantly less and still get approval.

On declining word scores after 13 - 21 Months:

As we all know with hearing loss, it continues to degrade from birth to death. It appears that the word scores may have degraded because FX-322 wasn't able to penetrate the entire cochlea, so those untouched, fairly worn original equipment hair cells that were still in the Moderate+ hearing loss levels continued to wear. It also stands to reason that no synapses were repaired for untouched hairs, so that could contribute to losses. It appears to me that the hearing that was treated with FX-322 at 8 kHz was retained. So, that's hardly "square 1." We all should know by now that hearing loss is cumulative, and we're looking at patients that have accumulated a substantial amount of damage.

At any rate, some of those patients still retained an improvement anywhere from 1-2 years. Frequency Therapeutics has mentioned that patients may need to come back to "re-up" their treatment. Would it be so awful to have to get annual injections to keep your hearing at an improved / manageable state? Or would you to prefer to have nothing and be trending to a cochlear implant? I'd go with the former.

 

[OptimusPrimed]

They need to find a way to push FX-322 further into the cochlea. FX-322 only restores hair cells between 20,000 Hz and 6,000 Hz. A good deal of hearing damage that working people (military, law enforcement, construction, etc) have is in the 2000 Hz-4000 Hz range.

 

[Tezcatlipoca]

They need to find a way to push FX-322 further into the cochlea. FX-322 only restores hair cells between 20,000 Hz and 6,000 Hz. A good deal of hearing damage that working people (military, law enforcement, construction, etc) have is in the 2000 Hz-4000 Hz range.

IMO the placebo + repeated injections is what's fucking it up.

Everytime FX-323 has been injected into a cochlea only once and then left alone, it has performed.

 

[Hamsti]

Do we know or can we guess why the FX-322 is not working on age-related hearing loss?

I thought it was just regenerating hair cells where there weren't any.

Could it be related to arteriosclerosis, which is more common in old age?

 

[GlennS]

They need to find a way to push FX-322 further into the cochlea. FX-322 only restores hair cells between 20,000 Hz and 6,000 Hz. A good deal of hearing damage that working people (military, law enforcement, construction, etc) have is in the 2000 Hz-4000 Hz range.

Sounds like excuses to me. At this point I have my doubts that FX-322 really is even restoring hair cells between 20 kHz and 6 kHz.

Everytime FX-323 has been injected into a cochlea only once and then left alone, it has performed.

And where are the audiograms to prove that--rather than just wishy-washy WR scores?

Sorry to come across sort of rude but I think this thread has petered out to die-hard optimists reaffirming their faith by grasping at straws akin to a rosary bead ritual. I'll change my pessimistic tune when there is new evidence to justify it but the data available now isn't really that encouraging.

 

[Paulmanlike]

I've seen a few comments about FX-322 not being effective for age-related hearing loss - but these results haven't been released yet? Or am I missing something?

 

[Zugzug]

Do we know or can we guess why the FX-322 is not working on age-related hearing loss?

I thought it was just regenerating hair cells where there weren't any.

Could it be related to arteriosclerosis, which is more common in old age?

We don't know. The suggestion of a vascular component is valid, IMO, even if it doesn't explain everything away.

By the way, from the patent, page 181, the following table shows the ages of responders and non-responders.

Notice that in Phase 1/2, most participants were upper 50s and age had no demonstrative impact on response. Obviously, things go downhill much quicker for older people, but upper 50s is certainly in the range of vascular changes.

My belief: The drug does work for the right person, but between the formulation, delivery, hair cell distribution (random, particularly for IHC loss), other things like vascular changes, and many other unknowns, it's just not that effective, as is.

By the way, there's been a lot of talk about synapses. According to the clinical trial, here's the inclusion criteria:

In other words, the patients needed audiogram issues (hair cell loss) to get in, so it's not like they all entered this trial with pristine hair cells and just needed a synapse drug.

 

[Kleiner]

We don't know. The suggestion of a vascular component is valid, IMO, even if it doesn't explain everything away.

By the way, from the patent, page 181, the following table shows the ages of responders and non-responders.

View attachment 44994

Notice that in Phase 1/2, most participants were upper 50s and age had no demonstrative impact on response. Obviously, things go downhill much quicker for older people, but upper 50s is certainly in the range of vascular changes.

My belief: The drug does work for the right person, but between the formulation, delivery, hair cell distribution (random, particularly for IHC loss), other things like vascular changes, and many other unknowns, it's just not that effective, as is.

By the way, there's been a lot of talk about synapses. According to the clinical trial, here's the inclusion criteria:

View attachment 44995

In other words, the patients needed audiogram issues (hair cell loss) to get in, so it's not like they all entered this trial with pristine hair cells and just needed a synapse drug.

Frequency Therapeutics says study FX-322-112 subjects have no sensorineural hearing loss:

"By design, the study recruited subjects with no medical history of noise-induced or sudden sensorineural hearing loss (SSNHL)"​

I don't understand how it's possible.

 

[frpp]

On only helping 50%:

It depends on your definition of "help"... All the drug has to do to meet FDA guidelines is demonstrate statistical significance on a single endpoint. Based on the tiny, tiny, Phase 1/2 sample, it's done that for Moderate-Moderately-Severe hearing loss participants. The outcome won't be binary, whether it helps or not... If it was the case that 50% of participants with Moderate-Moderately Severe hearing loss showed improvement at 1 or more primary clinical endpoint in a Phase 2 or 3, then this drug is going to market. Many drugs do significantly less and still get approval.

On declining word scores after 13 - 21 Months:

As we all know with hearing loss, it continues to degrade from birth to death. It appears that the word scores may have degraded because FX-322 wasn't able to penetrate the entire cochlea, so those untouched, fairly worn original equipment hair cells that were still in the Moderate+ hearing loss levels continued to wear. It also stands to reason that no synapses were repaired for untouched hairs, so that could contribute to losses. It appears to me that the hearing that was treated with FX-322 at 8 kHz was retained. So, that's hardly "square 1." We all should know by now that hearing loss is cumulative, and we're looking at patients that have accumulated a substantial amount of damage.

At any rate, some of those patients still retained an improvement anywhere from 1-2 years. Frequency Therapeutics has mentioned that patients may need to come back to "re-up" their treatment. Would it be so awful to have to get annual injections to keep your hearing at an improved / manageable state? Or would you to prefer to have nothing and be trending to a cochlear implant? I'd go with the former.

If it gave me my hearing back and stopped the spasms, I'd get shots bi-weekly xD

 

[Diesel]

Frequency Therapeutics says study FX-322-112 subjects have no sensorineural hearing loss:

"By design, the study recruited subjects with no medical history of noise-induced or sudden sensorineural hearing loss (SSNHL)"
I don't understand how it's possible.

"No medical history" is the key here...

For NIHL:
These are people that probably had careers where they were not exposed to dangerous noise levels on a regular basis, and otherwise didn't partake in activities that were also at dangerous noise levels. Therefore, they never had a need to see an ENT / Audiologist until they were older.

Example: I have an aunt who is in her late-60's and was an accountant by trade, lived in a small town in the midwest, and otherwise busy being a mother and grandmother. So, not a lot of extreme noise exposure in her life. Her hearing has declined over the past few years, and she probably needs hearing aids. It's hard to point to NIHL as the cause at her age.

 

[Zugzug]

Frequency Therapeutics says study FX-322-112 subjects have no sensorineural hearing loss:

"By design, the study recruited subjects with no medical history of noise-induced or sudden sensorineural hearing loss (SSNHL)"​

I don't understand how it's possible.

That doesn't mean no sensorineural hearing loss. It just means the loss was from aging factors and accumulation of damage.

 

[Kleiner]

Okay, thank you for your explanations.

I don't understand the difference between age-related IHC / OHC loss and NIHL / SSHL, maybe there is a physiological difference.

I imagine that for trial FX-322-113 the excuse will be the absence of support cells.

Very hard to believe in this drug now.

But their science is very interesting. I hope another company will use it in the future.