Frequency Therapeutics — Hearing Loss Regeneration

[tarmaced]

I do wonder what the impact of the diet etc. of those in these studies is on individual outcomes.

Many people carry around one or more micronutrient deficiency and modern diets have many setbacks and you can only screen at the most extreme end for trials like this.

 

[kiki]

There were improvements in audiogram (OHCs) in Phase 1b trials. They only tested up to 8 kHz, but I would assume if there was an improvement in 8 kHz then 8-20 kHz should have improvements in audiogram as well.

It's a shame they did not do an extended hearing test in the Phase 1b trials. The audiogram results would have looked much better if they did an extended hearing test.

I have the same idea.

FX-322 regenerates both OHC and IHC, and I think that both PTA and WR have improved.

For now, at high frequencies.

In the latest presentation, Corporate Overview March 2021, please take a look at pages 7 to 14.

Page 14 states that WR is used instead of PTA (up to 8 kHz) to measure intelligibility (Clarity).
They have not yet obtained an authorized 8 kHz or higher audiogram showing improved PTA.

On page 8, it says "High Frequencies are Critical for Intelligibility. For someone with high-frequency hearing loss, words may be indistinguishable – impacting their ability to understand and communicate".

On page 9, "40% of the words in English rely on the use of high frequency consonants" etc. are described.

These descriptions are the same as the high frequency analysis of the national anthem of the previous presentation.

In the figure on page 12, two molecules are working on OHC.

On page 13, "The injection concentrates FX-322 in the cochlear region that detects extended high-frequency sounds, critical for speech intelligibility ".

I think they think that the regeneration of OHC and IHC causes the improvement of WR and PTA at high frequencies of 8 kHz and above. Clearly in patients with doubled WR.
I think that even patients who have not doubled have improved PTA.
I don't think they think that only IHC above 8 kHz will regenerate.

 

[Keith Handy]

There were improvements in audiogram (OHCs) in Phase 1b trials. They only tested up to 8 kHz, but I would assume if there was an improvement in 8 kHz then 8-20 kHz should have improvements in audiogram as well.

It's a shame they did not do an extended hearing test in the Phase 1b trials. The audiogram results would have looked much better if they did an extended hearing test.

I don't believe that the audiogram is a dead or irrelevant topic until we've seen extended audiograms from a non-flawed trial.

 

[OptimusPrimed]

I have the same idea.

FX-322 regenerates both OHC and IHC, and I think that both PTA and WR have improved.

For now, at high frequencies.

In the latest presentation, Corporate Overview March 2021, please take a look at pages 7 to 14.

Page 14 states that WR is used instead of PTA (up to 8 kHz) to measure intelligibility (Clarity).
They have not yet obtained an authorized 8 kHz or higher audiogram showing improved PTA.

On page 8, it says "High Frequencies are Critical for Intelligibility. For someone with high-frequency hearing loss, words may be indistinguishable – impacting their ability to understand and communicate".

On page 9, "40% of the words in English rely on the use of high frequency consonants" etc. are described.

These descriptions are the same as the high frequency analysis of the national anthem of the previous presentation.

In the figure on page 12, two molecules are working on OHC.

On page 13, "The injection concentrates FX-322 in the cochlear region that detects extended high-frequency sounds, critical for speech intelligibility ".

I think they think that the regeneration of OHC and IHC causes the improvement of WR and PTA at high frequencies of 8 kHz and above. Clearly in patients with doubled WR.
I think that even patients who have not doubled have improved PTA.
I don't think they think that only IHC above 8 kHz will regenerate.

They have to regenerate in the correct alignment in order to be functional. If it is random regeneration that might explain the limited impact of the drug. Hearing is highly tuned and requires entropy.

 

[Diesel]

They have to regenerate in the correct alignment in order to be functional. If it is random regeneration that might explain the limited impact of the drug. Hearing is highly tuned and requires entropy.

I agree that alignment probably matters for OHC, since they function in a mechanical nature. However, even damaged OHC seem to function to some extent, so it's possible that a slightly misaligned OHC that is fully regenerated may still provide a benefit over none at all. What I do find interesting is that there hasn't been much commentary/evidence of Progenitor Cell Activation causing a cell to be created that is mis-aligned.

Also, alignment for IHC does not seem to be an indicator of performance.

 

[FGG]

They have to regenerate in the correct alignment in order to be functional. If it is random regeneration that might explain the limited impact of the drug. Hearing is highly tuned and requires entropy.

So you are saying you think even if it regenerated one row of hair cells (IHCs) correctly, it may have regenerated OHCs in some haphazard way?

Two arguments against this:

1) LeBel specifically said there were no supernummary cells created in rodents or in cochlear explants. The hair cells are only created in their "spot" otherwise supernummary cells would result.

2) If your assumption were true, we would expect mild cases would have seen more improvement (because the architecture is more intact and there is really only one place for the new cell to go). That wasn't shown clinically.

 

[RB2014]

Without a doubt, whatever the living biology is doing to regenerate cells in the cochlea doesn't seem to align with what was observed in vivo. Which appears to be unexpected on the surface; but also somewhat likely considering that they are performing science on people for the first time in human history.

What I was trying to get is how it's not just oversimplification is to disregard all of the evidence and point to the audiogram; it's also lazy.

The honest attempt to understand what changes in the underlying biology may have led to word score increases alone that led @FGG to point to IHC regrowth appears to have some merit.

Now that Frequency Therapeutics has hired Jeffery Lichtenhan to specifically lead their hearing diagnostics effort; who appears to have some significant credentials in researching and developing novel hearing metrics. If the firm starts using various OAE methods to better understand IHC/OHC/synapse restoration, but still cannot validate any audiogram improvements, are we going to disregard those results as well?

Totally agreed!

 

[Lucifer]

I don't believe that the audiogram is a dead or irrelevant topic until we've seen extended audiograms from a non-flawed trial.

I agree. Do we know if they are doing an extended hearing test for the age-related and severe hearing loss trials?

 

[Diesel]

Do we know if they are doing an extended hearing test for the age-related and severe hearing loss trials?

Yes for both.

 

[Keith Handy]

Yes for both.

So... June?

 

[Diesel]

So... June?

Age Related should be as late as June.

Severe should be September.

 

[RingingBrother]

Please let that be true. If they are able to do the pivotal phase without redoing Phase 2, then that's a godsend and saves alot of time.

That would save a lot of time if they can go to Phase 3 soon. If the single dose trials all perform well, maybe FX-322 can reach the market by around 2024.

 

[Street Novelist]

Age Related should be as late as June.

Severe should be September.

Severe hearing loss trial says Q3... it could be July, August or September.

 

[Lucifer]

That would save a lot of time if they can go to Phase 3 soon. If the single dose trials all perform well, maybe FX-322 can reach the market by around 2024.

If they don't have to repeat Phase 2, then 2023 could be the year FX-322 comes out. 2022 is possible if the pivotal phase follow-up after FX-322 dosing is 90 days only.

 

[Pharz]

Hmm. I thought this thread would have slowly shut down given the (lack of) results.

Do you guys have hope for FX-322 and if yes, why?

Are there any other proper clinical trials going on for hearing loss and tinnitus?

 

[paul mclean]

Hmm. I thought this thread would have slowly shut down given the (lack of) results.

Do you guys have hope for FX-322 and if yes, why?

Are there any other proper clinical trials going on for hearing loss and tinnitus?

I actually have higher hopes for Otonomy's OTO-413 than Frequency Therapeutics' FX-322 to be honest. Otonomy are behind Frequency Therapeutics but there a numerous studies going on with BDNF and neurotrophin-3 growth factors repairing synapses in the cochlear.

I have cochlear synaptopathy/hidden hearing loss so those drugs would be more suited to treating my condition. OTO-413 has to redo their Phase 1/2 study again for some reason that I forgot but yeah. Things are coming along albeit slowly.

 

[Lucifer]

Hmm. I thought this thread would have slowly shut down given the (lack of) results.

Do you guys have hope for FX-322 and if yes, why?

Are there any other proper clinical trials going on for hearing loss and tinnitus?

The single dosing of FX-322 has shown meaningful improvements in word scores and audiogram in Phase 1b. They only did an audiogram test up to 8 kHz but if you look at the presentation they mention 3 out of the 6 patients had improvements up to 3 frequency bands. If they had done an extended hearing test up to 20 kHz, the results of the audiogram would be on par to the word score improvements shown in Phase 1b, therefore showing an improvement in both IHCs and OHCs.

 

[Diesel]

Hmm. I thought this thread would have slowly shut down given the (lack of) results.

Do you guys have hope for FX-322 and if yes, why?

Are there any other proper clinical trials going on for hearing loss and tinnitus?

FX-322 seems to have an effect as a single dose drug for specific hearing loss patients. Phase 2A failed from poor study design, not drug itself.

 

[corza000]

I actually have higher hopes for Otonomy's OTO-413 than Frequency Therapeutics' FX-322 to be honest. Otonomy are behind Frequency Therapeutics but there a numerous studies going on with BDNF and neurotrophin-3 growth factors repairing synapses in the cochlear.

I have cochlear synaptopathy/hidden hearing loss so those drugs would be more suited to treating my condition. OTO-413 has to redo their Phase 1/2 study again for some reason that I forgot but yeah. Things are coming along albeit slowly.

Didn't the founder and chairman of Otonomy cash all of his money out? Doesn't exactly instil confidence. If he thought it would be successful I doubt he would sell all of his stake at a discount. That being said, I remember the initial results were actually quite good. Something doesn't add up.

As for FX-322, something had to fail. It had too much expectation and hype behind it. I mean people wouldn't be cheating to get in the trial for it if it wasn't. But let's be realistic. If FX-322 has only the ability to increase Word Recognition Scores, then it is still a wonder drug. At its worst it could still be amazing.

 

[Gb3]

Any chance they do like a 4-dose study, each injection spread out over 90 days?

 

[GlennS]

Phase 2A failed from poor study design, not drug itself.

That has yet to be proven. A better way of stating the situation is that FX-322's fate is dangling by a thread based on said hypothesis.

 

[Diesel]

That has yet to be proven. A better way of stating the situation is that FX-322's fate is dangling by a thread based on said hypothesis.

Dangling by a thread is still not dead.

 

[Keith Handy]

Any chance they do like a 4-dose study, each injection spread out over 90 days?

They suggested they may do a more spread-out multi-dose study in the future.

 

[Pharz]

I have cochlear synaptopathy/hidden hearing loss so those drugs would be more suited to treating my condition. OTO-413 has to redo their Phase 1/2 study again for some reason that I forgot but yeah. Things are coming along albeit slowly.

How do you know what type of hearing loss do you have and where the damage has happened? Is there a way to know?

The single dosing of FX-322 has shown meaningful improvements in word scores and audiogram in Phase 1b. They only did an audiogram test up to 8 kHz but if you look at the presentation they mention 3 out of the 6 patients had improvements up to 3 frequency bands. If they had done an extended hearing test up to 20 kHz, the results of the audiogram would be on par to the word score improvements shown in Phase 1b, therefore showing an improvement in both IHCs and OHCs.

I am a little bit pessimistic about the WR scores now to be honest, given what happened during the recruitment process. I really hope their new results in Summer would show meaningful improvements in the (especially extended) audiograms.

Didn't the founder and chairman of Otonomy cash all of his money out? Doesn't exactly instil confidence. If he thought it would be successful I doubt he would sell all of his stake at a discount. That being said, I remember the initial results were actually quite good. Something doesn't add up.

As for FX-322, something had to fail. It had too much expectation and hype behind it. I mean people wouldn't be cheating to get in the trial for it if it wasn't. But let's be realistic. If FX-322 has only the ability to increase Word Recognition Scores, then it is still a wonder drug. At its worst it could still be amazing.

Isn't trading with insiders' information banned in the US? This is ridiculous in my opinion.

 

[Diesel]

Isn't trading with insiders' information banned in the US? This is ridiculous in my opinion.

In the case of Otonomy, Jay Lichter disposed of his stake in Otonomy through a Form 4 with the SEC. This is the correct and legal way for a manager to do so.

 

[Jack V]

I have said this before but if "focus" could actually double word scores, hearing loss would be treated with motivational speakers and pep talks.

Believe me, no amount of caffeine, sleep or "focus" allows me to unscramble the word jumbles on the TV. Even if I sat right in front of it and give it 100% of my focus.

Great point, well said.

The issue for Phase I, however, is that we're not sure if the 3 participants who scored well did so because their hearing loss was treated, or they simply experienced a test-taking performance boost.

While focus and pep talks can't treat hearing loss, test performance can and does vary a great deal, and there might have been a number of subtle factors conspiring to raise test scores.

Nonetheless, following Phase I, we give the drug the benefit of the doubt and assume those 3 people did well because it treated their hearing loss. However, in light of no signal detected in Phase II, it's reasonable to reevaluate. I understand that's typical - results with a handful of participants at the outset can be subsequently undermined (or confirmed) through expanded, more rigorous later stage trials.

What would be compelling is if the gains of Phase I could be repeated with an expanded population. If 50% of 100 participants showed gains in a Phase II trial, that's persuasive. And I desperately want that to be true. But until those results exist, and right now we're at 0% in Phase II, I'm not sure we can still assume those 3 "super responders" were responding to FX-322.

 

[Jack V]

FX-322 seems to have an effect as a single dose drug for specific hearing loss patients. Phase 2A failed from poor study design, not drug itself.

We don't know that.

 

[Diesel]

The issue for Phase I, however, is that we're not sure if the 3 participants who scored well did so because their hearing loss was treated, or they simply experienced a test-taking performance boost.

While focus and pep talks can't treat hearing loss, test performance can and does vary a great deal, and there might have been a number of subtle factors conspiring to raise test scores.

Then how do we explain the follow-up for the 3 highlighted in blue after 13+ months? Did FX-322 give them a little confidence booster that lasted a year? And that they consistently retained that 10 dB+ improvement at 8 kHz? Did FX-322 make them quicker with the button on the audiogram? What's even more interesting, is that all three in blue, those "super responders" all noticed a consistent decrease after a year-19 months. Kind of like they aged evenly...

 

[FGG]

Great point, well said.

The issue for Phase I, however, is that we're not sure if the 3 participants who scored well did so because their hearing loss was treated, or they simply experienced a test-taking performance boost.

While focus and pep talks can't treat hearing loss, test performance can and does vary a great deal, and there might have been a number of subtle factors conspiring to raise test scores.

Nonetheless, following Phase I, we give the drug the benefit of the doubt and assume those 3 people did well because it treated their hearing loss. However, in light of no signal detected in Phase II, it's reasonable to reevaluate. I understand that's typical - results with a handful of participants at the outset can be subsequently undermined (or confirmed) through expanded, more rigorous later stage trials.

What would be compelling is if the gains of Phase I could be repeated with an expanded population. If 50% of 100 participants showed gains in a Phase II trial, that's persuasive. And I desperately want that to be true. But until those results exist, and right now we're at 0% in Phase II, I'm not sure we can still assume those 3 "super responders" were responding to FX-322.

I will reiterate this point. "Performance boosts" and placebo cannot do things that have historically not been possible. I.e. concentrating doesn't help someone get out of a wheelchair.

If the "super responders'" response was more moderate, your point would be more valid.

There are two possibilities here: fraud or the drug regrows IHCs (the part measured by word scores and not audiogram).

I would expect the percentage of responders to go up when they design a trial to select who got genuinely low word scores and they have indicated that's how they are proceeding.

 

[Jack V]

Then how do we explain the follow-up for the 3 highlighted in blue after 13+ months? Did FX-322 give them a little confidence booster that lasted a year? And that they consistently retained that 10 dB+ improvement at 8 kHz? Did FX-322 make them quicker with the button on the audiogram? What's even more interesting, is that all three in blue, those "super responders" all noticed a consistent decrease after a year-19 months. Kind of like they aged evenly...

View attachment 44556

One explanation is that the drug worked.

Another explanation is that other factors were responsible.

I don't know.

However, given the lack of any signal whatsoever in Phase II, it's reasonable to tilt towards the latter UNTIL Frequency Therapeutics demonstrates a response with a larger population under rigorous controls.