Frequency Therapeutics — Hearing Loss Regeneration

[d'Wooluf]

Try to look at it from the vantage point of those with hearing damage, not the corporate board. Patients judging this treatment are going to want to see improvements in the audiogram before anything else.

I don't care about the numbers particularly but I do care about being able to hear sounds again that I no longer can. That includes soft talkers and cicadas in the evening. The audiogram is currently the only way to measure that. Without audiogram improvements you're also left with the question of what the hell's going on. Increasing loudness is what was supposed to happen when you regenerate hair cells. They're going to try to sell a drug that delivers 'clarity' improvements. Err... how does it work? I'd like them to know!

Do you put your foot down and refuse the drug?

I would unless clarity improvements were very significant and consistent. This business about just getting FX-322 to market and then good things will follow sounds like a cargo cult to me.

 

[Tezcatlipoca]

I don't care about the numbers particularly but I do care about being able to hear sounds again that I no longer can. That includes soft talkers and cicadas in the evening. The audiogram is currently the only way to measure that. Without audiogram improvements you're also left with the question of what the hell's going on. Increasing loudness is what was supposed to happen when you regenerate hair cells. They're going to try to sell a drug that delivers 'clarity' improvements. Err... how does it work? I'd like them to know!

I would unless clarity improvements were very significant and consistent. This business about just getting FX-322 to market and then good things will follow sounds like a cargo cult to me.

The mental gymnastics are wild. If FX-322 does go to market, both you and @GlennS are getting it the second you can. Why are you even arguing otherwise.

 

[Diesel]

Increasing loudness is what was supposed to happen when you regenerate hair cells. They're going to try to sell a drug that delivers 'clarity' improvements. Err... how does it work? I'd like them to know!

Increasing loudness is not what is supposed to happen at all. That would mean external sound gets louder with the application of FX-322. This is what hearing aids do. If it were a biological change, loudness sounds like hyperacusis.

When new cells are regenerated, those areas become more sensitive to a quieter, lower energy range sounds. Which aids in more clearer hearing. Also, if there are more functioning stereocilia in the cochlea, the brain has more information to work with and is able to filter sound in noisy environments, also a function of clarity.

 

[Lukee]

Sh*t, if it's safe and doesn't do anything, I'll take it. Can't be that much different than the TRU NIAGEN sitting in the back of my drawer.

This isn't an ad for Tru Niagen but I'm starting to think that it actually improved my hearing. I checked an old audiogram from 2016 (done during a general checkup, not issue related) and compared my February 2021 (just after tinnitus onset) and May 2021 audiograms.

2016 and February 2021 both showed the same drop off (about 25 dB) at 6-8 kHz.
May 2021, 8 kHz it is 0 dB. It could be a fluke at the audiogram but my hearing is super sharp even with this constant hiss. The only thing I could attribute to the increase was Nicotinamide Riboside that I took for two months.

 

[tommyd87]

I don't care about the numbers particularly but I do care about being able to hear sounds again that I no longer can. That includes soft talkers and cicadas in the evening. The audiogram is currently the only way to measure that. Without audiogram improvements you're also left with the question of what the hell's going on. Increasing loudness is what was supposed to happen when you regenerate hair cells. They're going to try to sell a drug that delivers 'clarity' improvements. Err... how does it work? I'd like them to know!

I would unless clarity improvements were very significant and consistent. This business about just getting FX-322 to market and then good things will follow sounds like a cargo cult to me.

Hang on though... don't outer and inner hair cells do completely different things? Thus doesn't this make it entirely plausible that a treatment like FX-322 works by treating inner hair cells only could aid clarity without aiding volume?

 

[GlennS]

both you and @GlennS are getting it the second you can. Why are you even arguing otherwise.

You're presuming that I don't walk the talk? Nope. Improved WR scores alone don't cut it for me. I need to 'see the beef'. I had an early reservation for Lenire and I canceled that too once it became clear to me the results didn't live up to the hype. Feel free to lay down a wager if you insist on knowing better how I will behave in the future than I do.

 

[GlennS]

Increasing loudness is not what is supposed to happen at all.

Let's not get too hung up on semantics. That's just a layman's way of saying improved audiograms.

 

[Zugzug]

I would unless clarity improvements were very significant and consistent. This business about just getting FX-322 to market and then good things will follow sounds like a cargo cult to me.

Just a run of the mill visceral reaction to reading this is that you may benefit from reading more about the difference between OHC and IHC function.

 

[Diesel]

Let's not get too hung up on semantics. That's just a layman's way of saying improved audiograms.

It's still an incorrect description.

 

[Street Novelist]

So, now we wait until August/September?

Does anyone know? We have to keep playing the waiting game?

 

[Zugzug]

Let's not get too hung up on semantics. That's just a layman's way of saying improved audiograms.

With all due respect, I think you suffer from hardcore Dunning-Kruger when it comes to hearing research. @Diesel has been relegated to a Kindergarten biology teacher so he has to simplify things, only to see it backfire.

Firstly, when he says that "increasing loudness is not what is supposed to happen at all," he is NOT creating an upside down world and saying that "we would not want improved hearing thresholds." You read everything looking to see that narrative, no matter what.

What he is saying is that when you regenerate OHC, the brain doesn't develop loudness hyperacusis (i.e. increase in central gain as a result of weakened input). If anything, it's the opposite — the central gain "loudness" is less because of restored input.

Put simply, OHC mechanically amplify low-level noises for the IHC to process. Then 95% of afferent neurons are Type I, which send hearing signal to the brain.

Let me say it loud and clear: Everyone wants to see audiogram improvements. There's no "ah, it doesn't even matter, audiograms are useless" aspect. Of course, audiograms matter for hearing. In real world settings, they also matter for clarity because the volume of noise is not fixed and comfortable.

For example, if your friend whispers to you and you have audiogram problems, you may also have clarity issues making out what they are saying. The isolated role of IHC in clarity is totally different. The WR test fixes the volume at a comfortable level. I know I've explained this to you before, but imagine your friend talking to you and you have no issues at all hearing them. But it just sounds like noisy, unclear garbage. This is the difference between "clarity problems" from IHC vs OHC.

If your friend talks and it feels like they were whispering and you say "repeat please," that's an OHC issue. If your friend shouts "cat" and you think they said "cap," that's more an IHC issue.

We all love audiograms. I would marry one if I could. God knows I'm lonely as fuck. But they aren't all there is to this thing.

 

[ploughna]

Is it still fair to stay that there could well be decent audiogram improvements above 8 kHz but we just don't know yet? From the phase 1 trials it was reported some improvements at 8 kHz, but above that wasn't measured. The upcoming reports from single dose trials where 8-16 kHz is being measured should answer this with a bit more certainty.

 

[Coleoptere]

This isn't an ad for Tru Niagen but I'm starting to think that it actually improved my hearing. I checked an old audiogram from 2016 (done during a general checkup, not issue related) and compared my February 2021 (just after tinnitus onset) and May 2021 audiograms.

2016 and February 2021 both showed the same drop off (about 25 dB) at 6-8 kHz.
May 2021, 8 kHz it is 0 dB. It could be a fluke at the audiogram but my hearing is super sharp even with this constant hiss. The only thing I could attribute to the increase was Nicotinamide Riboside that I took for two months.

That sound like a miracle what we once expected from FX-322. Can you please provide details about dosage etc.?

 

[Jurger]

Is it still fair to stay that there could well be decent audiogram improvements above 8 kHz but we just don't know yet? From the phase 1 trials it was reported some improvements at 8 kHz, but above that wasn't measured. The upcoming reports from single dose trials where 8-16 kHz is being measured should answer this with a bit more certainty.

The ultra high frequencies were already measured in Phase 2a. FX-322 didn't do anything.

 

[Jurger]

With all due respect, I think you suffer from hardcore Dunning-Kruger when it comes to hearing research. @Diesel has been relegated to a Kindergarten biology teacher so he has to simplify things, only to see it backfire.

Firstly, when he says that "increasing loudness is not what is supposed to happen at all," he is NOT creating an upside down world and saying that "we would not want improved hearing thresholds." You read everything looking to see that narrative, no matter what.

What he is saying is that when you regenerate OHC, the brain doesn't develop loudness hyperacusis (i.e. increase in central gain as a result of weakened input). If anything, it's the opposite — the central gain "loudness" is less because of restored input.

Put simply, OHC mechanically amplify low-level noises for the IHC to process. Then 95% of afferent neurons are Type I, which send hearing signal to the brain.

Let me say it loud and clear: Everyone wants to see audiogram improvements. There's no "ah, it doesn't even matter, audiograms are useless" aspect. Of course, audiograms matter for hearing. In real world settings, they also matter for clarity because the volume of noise is not fixed and comfortable.

For example, if your friend whispers to you and you have audiogram problems, you may also have clarity issues making out what they are saying. The isolated role of IHC in clarity is totally different. The WR test fixes the volume at a comfortable level. I know I've explained this to you before, but imagine your friend talking to you and you have no issues at all hearing them. But it just sounds like noisy, unclear garbage. This is the difference between "clarity problems" from IHC vs OHC.

If your friend talks and it feels like they were whispering and you say "repeat please," that's an OHC issue. If your friend shouts "cat" and you think they said "cap," that's more an IHC issue.

We all love audiograms. I would marry one if I could. God knows I'm lonely as fuck. But they aren't all there is to this thing.

I've read this thread marginally since FX-322 failed in Phase 2a, but where did this OHC/IHC thing come from? Has it actually been confirmed this is the reason why in Phase 1/2 audiograms didn't show any results, but WR scores did (well, for 65% of patients the drug didn't do anything for clarity in either, but those are details)?

 

[Jurger]

The mental gymnastics are wild. If FX-322 does go to market, both you and @GlennS are getting it the second you can. Why are you even arguing otherwise.

I would take garlic pills, Himalaya kiwi's or breast milk if it had any chance of improving my crappy hearing, that doesn't make those things any more effective.

 

[Zugzug]

I've read this thread marginally since FX-322 failed in Phase 2a, but where did this OHC/IHC thing come from? Has it actually been confirmed this is the reason why in Phase 1/2 audiograms didn't show any results, but WR scores did (well, for 65% of patients the drug didn't do anything for clarity in either, but those are details)?

That's less so what the back and forth is about. The overall competency of the drug is still disputed/unknown. The entire discussion is about how OHC/IHC do different things (this is not speculative at all) and a desire to diagnose what's going on in FX-322 treated ears. Is there some IHC regrowth? If so, is it a small percentage of people? Is the delivery so bad that OHC regrowth is negligible in almost all patients?

Much more about discussion than any proofs, as of today.

 

[Diesel]

I've read this thread marginally since FX-322 failed in Phase 2a, but where did this OHC/IHC thing come from? Has it actually been confirmed this is the reason why in Phase 1/2 audiograms didn't show any results, but WR scores did (well, for 65% of patients the drug didn't do anything for clarity in either, but those are details)?

A few sources have been cited here since the Phase 2A ended, one actually referencing the outcome of the interim readout, pointing to IHC being more important for complex sound detection needed for WR and WIN.

Audiograms have also been discussed to death here as a better indicator of OHC health, and not IHC.

 

[Lukee]

That sound like a miracle what we once expected from FX-322. Can you please provide details about dosage etc.?

It is not FX-322 for sure. My tinnitus was left mostly unchanged so the only thing I can go off is an audiogram. I would bet my life on the treatment but I think there is some evidence that it works on some level. I took one pill daily (I think it's 350 mg) and that's it.

 

[kiki]

FX-322 didn't do anything.

So far, no official announcement has been made.

Also, I think they should have only obtained group-based significance information in the interim presentation.

 

[Andrei90]

FX-322 has already restored hair cells in donated cochlea. I would say that's enough to have some faith in the drug.

I remember reading this a few times before. If this is the case, then what is causing there to be no results in the audiogram test? Did the participants mention any other improvements such as clarity of speech in a noisy environment?

 

[Jurger]

So far, no official announcement has been made.

Also, I think they should have only obtained group-based significance information in the interim presentation.

Their own press release said they saw no improvement in ultra high frequencies in Phase 2a...

 

[Philip83]

I remember reading this a few times before. If this is the case, then what is causing there to be no results in the audiogram test? Did the participants mention any other improvements such as clarity of speech in a noisy environment?

All the trial reports are on FREQ's website that explain this.

 

[Diesel]

Their own press release said they saw no improvement in ultra high frequencies in Phase 2a...

Actually.. it doesn't.

Frequency Therapeutics Releases New Data from Two FX-322 Clinical Studies; Plans to Advance Single-Dose Regimen

 

[Zugzug]

Actually.. it doesn't.

Frequency Therapeutics Releases New Data from Two FX-322 Clinical Studies; Plans to Advance Single-Dose Regimen

Related:

If I recall (sorry, can't listen to the webcasts), didn't leadership say that there were no significant audiogram changes in the EHF range during the Phase 1/2, even after follow up?

Considering that the multi-dose experiment "dampened" the WR improvements, it's probably fair to expect negligible EHF audiogram improvements by day 210 of Phase 2a. At least, this is what I'm expecting personally.

 

[ploughna]

Actually.. it doesn't.

Frequency Therapeutics Releases New Data from Two FX-322 Clinical Studies; Plans to Advance Single-Dose Regimen

That was why I asked the question - I couldn't find any mention. Yet another datapoint we'll learn more about later!

 

[Diesel]

Related:

If I recall (sorry, can't listen to the webcasts), didn't leadership say that there were no significant audiogram changes in the EHF range during the Phase 1/2, even after follow up?

Considering that the multi-dose experiment "dampened" the WR improvements, it's probably fair to expect negligible EHF audiogram improvements by day 210 of Phase 2a. At least, this is what I'm expecting personally.

I'll have to go re-listen to the webcast. In my notes, there was a question about EHF performance compared to placebo where LeBel stated that he couldn't see any. However, the placebo group saw improvements as well due to bias problems, so the data at a group level overall was so fucked they probably could not comment on any differences with any confidence.

 

[Chad Lawton]

Anyone record this latest event? I missed it.

Here is the link to the recording:

Frequency Therapeutics (kvgo.com)

From an investor perspective, I think it was actually a pretty good presentation.

 

[Jack V]

I'll have to go re-listen to the webcast. In my notes, there was a question about EHF performance compared to placebo where LeBel stated that he couldn't see any. However, the placebo group saw improvements as well due to bias problems, so the data at a group level overall was so fucked they probably could not comment on any differences with any confidence.

I believe they said there was no difference between placebo improvements and drug improvements.

Since no one knew if they got placebo or drug, both groups were equally impacted by bias, and both groups showed similar "improvement."

Unfortunately, that's not a meaningless result. It suggests the drug was not effective.

Otherwise, you would see bias "improvement" + actual improvement, i.e. more improvement, among the drug-receiving cohort.

 

[Zugzug]

I believe they said there was no difference between placebo improvements and drug improvements.

Since no one knew if they got placebo or drug, both groups were equally impacted by bias, and both groups showed similar "improvement."

Unfortunately, that's not a meaningless result. It suggests the drug was not effective.

Otherwise, you would see bias "improvement" + actual improvement, i.e. more improvement, among the drug-receiving cohort.

I tend to see validity to your argument here. Bias is a baked in aspect of every placebo-controlled study. I outlined in my bear thesis (something I'm going to narcissistically reference from time to time) that given the 3:1 treatment to placebo ratio, the expected value of cheater benefit (however few there are) could actually benefit the treatment groups more. I also pointed out the damning fact that if a "cheater" got the placebo and saw no improvements, they would be inspired to tank again at the end because by tanking the placebos, they increase their chances of getting the actual drug (when it goes to market) as soon as possible.

Where I'm a hair bullish is that I do have some hope for individual responders. I think there could be (however small) a population type that sees nice IHC gains. To me, that's progress and the start of a breakthrough, as it would be the first regenerative medication for the ear with even some evidence of in vivo response.

At a systemic level, I don't see this drug delivering the goods until a new delivery method. While it's probably true that there was a dampening effect from multi-dose, I'm not expecting riveting single dose results in the next Phase 2, though I'm hoping there's enough to clear the trial.