Frequency Therapeutics — Hearing Loss Regeneration

[MarkRule]

So someone faked their audiogram results to get into the trial? Then they were given placebo and showed improvement which was just their real results?

Why on earth? And which hearing aid manufacturer was behind this?

 

[Bill Bauer]

No, Dr. Shore helped @linearb.

The University of Minnesota device helped @kelpiemsp but their lead (Hubert Lim) bailed on the device for Neuromod. Epic-level sellout.

Thank you for the clarification. I mixed up University of Michigan with University of Minnesota.

Which device is "Neuromod"? Is that the device that became available in Ireland recently that had a disappointing performance? If Neuromod isn't that device, might it be as good as (or identical to) that University of Minnesota device?

I have never paid close attention to research on tinnitus cures, as I figured that once something that works becomes available, I will know. So please forgive my lack of knowledge as far as those devices are concerned. It would help a lot to learn the answers to my questions above...

 

[Aleksandar]

So someone faked their audiogram results to get into the trial? Then they were given placebo and showed improvement which was just their real results?

Why on earth? And which hearing aid manufacturer was behind this?

Whoever they are, I hope they burn in hell because of their involvement.

 

[mrbrightside614]

We keep praying and praying but today I came to the conclusion that God has hearing loss himself.

I feel you for sure. The whole day I had the uncomfortably familiar, bed-binding, skyrocketing anxiety and existential emptiness that I felt during the earliest stages of tinnitus. I really don't feel that bad anymore. They just have to smash their severe category and then they could angle for compassionate use. This is a unique challenge that may not go as swimmingly as their Phase 1 results had, but at least there is some consistency with the dosing.

 

[Pharz]

I really don't see this happening. Single dose has been more effective with FX-322. It's just how to get FX-322 deeper in the round window whether that is by reformulating or additional doses monthly.

Hi Lucifer,

Would you be so kind to tell me how single dose was proven to be effective? I keep reading this on this thread and I feel I must have missed something from the release and the Q&A afterwards. They mentioned they only had positive results from the WR, and that was flawed due to recruiting problems.

My conclusion was that the drug is not effective at all.

I would be really happy if someone would shed some light on this statement of single dose being effective for me.

 

[annV]

Which device is "Neuromod"? Is that the device that became available in Ireland recently that had a disappointing performance? If Neuromod isn't that device, might it be as good as (or identical to) that University of Minnesota device?

Neuromod is the Irish company behind Lenire, which is the device.

 

[mrbrightside614]

Thank you for the clarification. I mixed up University of Michigan with University of Minnesota.

Which device is "Neuromod"? Is that the device that became available in Ireland recently that had a disappointing performance? If Neuromod isn't that device, might it be as good as (or identical to) that University of Minnesota device?

I have never paid close attention to research on tinnitus cures, as I figured that once something that works becomes available, I will know. So please forgive my lack of knowledge as far as those devices are concerned. It would help a lot to learn the answers to my questions above...

No problem. It's 5 am right now so I'm about to go to bed but if I recall correctly, Neuromod's Lenire and Minnesota's respective devices are very dissimilar. Early on there was some hope that Lim's promising research in signal timings could optimize Neuromod's (Ireland) approach, but that didn't come to fruition. Honestly can't remember how Minnesota's device distinguished itself from Shore's, but I remember the two US devices having more commonalities than Neuromod's. Neuromod stimulates the tongue (vagus nerve?) while Shore's stimulated nerves in the neck/jaw.

Can't remember much from Minnesota because it's unfortunately irrelevant now.

 

[r34d1ng]

Hi Lucifer,

Would you be so kind to tell me how single dose was proven to be effective? I keep reading this on this thread and I feel I must have missed something from the release and the Q&A afterwards. They mentioned they only had positive results from the WR, and that was flawed due to recruiting problems.

My conclusion was that the drug is not effective at all.

I would be really happy if someone would shed some light on this statement of single dose being effective for me.

Phase 1/2 showed [statistically significant] signs of functional hearing improvement.

 

[Cernuto]

So someone faked their audiogram results to get into the trial? Then they were given placebo and showed improvement which was just their real results?

Why on earth? And which hearing aid manufacturer was behind this?

Right? The placebo improved their hearing. How dumb does that sound to you? It's another clear indication the FDA process has failed.

We need a study that doesn't have a control group, placebo, or any other dumb stuff. Take a person truly hard of hearing, inject it into their ear and then ask them if they can hear better. Why make it anymore complicated than that? I'm sure anyone pushing 80 years old has hearing loss. Recruit a few of them. Do the study at a top notch university.

 

[Lucifer]

Phase 1/2 showed [statistically significant] signs of functional hearing improvement.

@Pharz, this is your answer. I like to also add that the reason the multiple dosing of FX-322 might have failed as they quoted about seeding of the lawn and that with successive doses of FX-322 weekly it has affected the regrowing process and it may have been better to try a monthly doses instead.

I don't know why but the seeding of the lawn was never what I thought might happen with multiple doses of FX-322 weekly not working properly.

If the age-related and severe hearing loss trials show meaningful improvements I expect them to start a pivotal phase early next year. If only age-related show meaningful improvements but the severe category showed little or no improvement I think the FDA should be lenient and allow them to go to the pivotal phase as it works for mild to moderate hearing loss.

The FDA should allow them to keep the current delivery method as it helps with mild and moderate hearing loss but let them rework on a delivery method once FX-322 comes out in the market with their current delivery method.

 

[KotaDomowa]

It's strange... I can't even be sad about these results. Maybe because I've recently started to have problems with my eyesight and I don't believe that I will feel safe and healthy as before 2018. Or maybe because decola supplements soothe my tinnitus.
And because it's not the end of the game, there are also projects other than FX-322.

 

[kiki]

The answer is no: not one person in their Phase 2a improved on the audiogram, including extended high frequencies. Furthermore, they apparently ran a parallel new Phase 1/2 trial. Again, not one patient improved on the audiogram, including extended high frequencies. Listen to their webcast from yesterday, last few minutes.

Thank you.
There is no hope anymore.

 

[Gee82]

Just thinking out loud. If I understood correctly, hidden hearing loss is not shown on audiograms, even at high frequencies. Let's say FX-322 hits and improves that hidden frequency, then that improvement won't show up either on the audiogram even if it's actually happened. Call it "hidden improvement"? But the patient can still benefit from it — see better word score, anecdotal decreased tinnitus, etc. I was let down by the lack of changes in the audiograms, but thinking twice I question if they are any relevant.

I'm not sure if it makes sense at all or maybe I'm just trying to save the unsavable out of despair.

 

[Keith Handy]

I say this half jokingly, but they should offer Compassionate Use as a preventative measure from further gaming of future trials. If anything, doesn't this show just how far people are willing to go for some sort of relief?

Better yet — just run a tinnitus trial, separate from the others.

 

[Olive27]

As much as it saddens me the fact is FREQ does not work! The WR and WIN is always going to be a subjective measurement which is why seeing results on the audiogram is so important. We haven't seen any of this even on the EHF. You can argue as much as you want that the audiogram is outdated etc but it is the only accurate measure!

 

[RichieTheKid]

[QUOTE="Aaron91, post: 587713, member: 41442" I only have two words for you. No prizes for guessing what those words might be.[/QUOTE]
Happy Birthday? (just trying to lighten the mood).

 

[tomytl]

As much as it saddens me the fact is FREQ does not work! The WR and WIN is always going to be a subjective measurement which is why seeing results on the audiogram is so important. We haven't seen any of this even on the EHF. You can argue as much as you want that the audiogram is outdated etc but it is the only accurate measure!

Agree, unfortunately, it's far away from a robust regenerative effect. It is hard to accept after years of hope.

Others will try their candidates but there won't anything on the market in the so called near future.

I hit my head on the table.

 

[Philip83]

They also got only two doses of FX-322.

How could anyone know that the got two doses since the data has not been unblinded yet? Am I missing something?

 

[Diesel]

As much as it saddens me the fact is FREQ does not work! The WR and WIN is always going to be a subjective measurement which is why seeing results on the audiogram is so important. We haven't seen any of this even on the EHF. You can argue as much as you want that the audiogram is outdated etc but it is the only accurate measure!

Audiogram is flawed too. The patient could fake the deficit just like word score, and not click the button when they first hear the tone so it looks like they have a greater loss. It also shows a total of 11 specific frequencies across the 22,000 that most can hear, so isn't that representative. Also, it doesn't test for IHC function. Also, for people with dysacusis/distorted hearing, it produces errors in tone matching. The audiogram hasn't changed since the 40's - how many other medical tests are we still using today that are 80 years old that haven't had some revision?

The reality is, all the standard tests are imperfect. You need all of them to get a crude idea of hearing improvement. But first, you need honest people.

 

[r34d1ng]

Just thinking out loud. If I understood correctly, hidden hearing loss is not shown on audiograms, even at high frequencies. Let's say FX-322 hits and improves that hidden frequency, then that improvement won't show up either on the audiogram even if it's actually happened. Call it "hidden improvement"? But the patient can still benefit from it — see better word score, anecdotal decreased tinnitus, etc. I was let down by the lack of changes in the audiograms, but thinking twice I question if they are any relevant.

I'm not sure if it makes sense at all or maybe I'm just trying to save the unsavable out of despair.

This is what worries me the most, to be honest. What if FX-322 actually regenerates some inner structure (synapses and whatnot) improving subjective conditions (tinnitus, hyperacusis, WR, intelligibility, etc.), but it is shut down because it cannot be proved objectively?

 

[Emgee]

Right? The placebo improved their hearing. How dumb does that sound to you? It's another clear indication the FDA process has failed.

The FDA is a bureaucratic institution that does more harm than good. Case in point.

 

[Chestnut94]

Dear Tinnitus Talk users,

I've also been following this thread for a long time. These latest results are a bummer, but I also think that we shouldn't write FX-322 off as a failure yet, because there have been good results from Phase 1. There has been an improvement in hearing, which is still a major breakthrough. From what I've read from Carl LeBel, the problem now probably lies in the use of multiple doses in a short time, which renders the treatment useless, because the inner ear doesn't get enough time to regenerate.

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

But I'm also reading now that those Phase 1 results were invalid. Is that true?

Please correct me if I'm wrong. I'm also just looking for answers.

 

[Jukka]

Others will try their candidates but there won't anything on the market in the so called near future.

How about SPI-1005?

 

[Diesel]

This is what worries me the most, to be honest. What if FX-322 actually regenerates some inner structure (synapses and whatnot) improving subjective conditions (tinnitus, hyperacusis, WR, intelligibility, etc.), but it is shut down because it cannot be proved objectively?

Many drugs just improve subjective conditions and get approved... consider most anti-depressants, for example.

What Frequency Therapeutics could do is eliminate the incentive to cheat, which they inadvertently did do by requiring the WR deficit. Instead, allow ANYONE with any level of measured hearing loss (mild-severe) get a dose or more (on a new schedule). This eliminates the incentive to cheat. Fully randomize placebo, 1x, 2x.

Now, what they would need to do once all are unblinded, divide up the entrants into classes like they did in the Phase 1/2. Mild down to Severe. If the group is large enough, a few from every class should have gotten placebo, 1x, 2x.

For primary outcomes, the mild grown probably will see the ceiling effect on normal measures, but experimental outcomes like QoL, TFI, EHF may show some improvement.

The lower groups may show more efficacy at 1x, 2x.

There may be some placebo effect, but it's likely to be focused in that mild class, which is expected.

 

[Princebeyel]

I'm confused. How would they know they only got two doses of FX-322 if everyone, including patients, is still blinded at the individual level? You even then say it was an unknown amount.

I've just woken up and all I feel about this process is complete and utter anger because I've realised there's only one of two possibilities: either this drug doesn't do anything in humans and we've all been misled, or a bunch of selfish, desperate people have knowingly lied to get into the trial and potentially ruined the one and only chance for the rest of us to rebuild our lives. I am livid. If you are one those patients and happen to be lurking this forum, I only have two words for you. No prizes for guessing what those words might be.

They said that only two of the injections burned when injected. So that's how they knew or thought they only received two of FX-322.

 

[FGG]

How about SPI-1005?

And someone in the Sound Pharmaceuticals thread is already paying a lab to make this for them now...

 

[r34d1ng]

Many drugs just improve subjective conditions and get approved... consider most anti-depressants, for example.

I mean, what if FX-322 is killed/shut down (e.g., due to incapacity to objectively prove improvements in audiograms or EHF) before Frequency Therapeutics can conduct specific trials on specific subjective conditions? I feel like FX-322 is hanging by a thread, with Phase 1b serving as the thread. If they can't prove positive results from Phase 1b when the full readout is released in June (for what it is worth, I don't expect the full readout of Phase 2a to show anything meaningful), FX-322 and Frequency Therapeutics may well be doomed...

 

[Aaron91]

They said that only two of the injections burned when injected. So that's how they knew or thought they only received two of FX-322.

Sounds plausible but I don't think that's enough to make any kind of wider inference, unfortunately. I do recall FX-322 having a stable form of vitamin C in it, so I wonder if that contributes to the burning at all (assuming it was FX-322).

 

[Diesel]

Re the additional Phase 1b trials that were announced quite out of the blue if remember correctly - I wonder if these studies were made up quickly due to early indication that Phase 2a was not doing well and Frequency Therapeutics needed something to reinforce original trial results and keep an iron in the fire. I could be misinformed on this so shoot it down if need be.

@FGG, @Zugzug, I didn't know that WR was not an important factor in recruitment in Phase 1/2 and this has given me a bit of hope (how about the Phase 1b trials though?). The next Phase 1b studies will be really interesting, however, still not enough to prove anything even if results appear good unless I'm missing something.

I'm coming to the conclusion that worst case scenario is that the good WR result from the Phase 1/2 & 1b trial were fluke, or bias (which I have slightly more confidence that this is unlikely now), or best case scenario it works but can't be proven with audiogram because likely it is down to something like only IHC regenerate, or both IHC and OHC regenerate but only IHC regenerate functionally.

I need to be re-convinced again that FX-322 even works. Good results from the Phase 1b trials will go a way to doing that but not conclusively.

They should just say fuck it and run another Phase 1b study on the home-bound, bed-bound, pain-ridden, crippled tinnitus and noxacusis sufferers and see if we get our social lives, music, careers, family and friend connections, quality of life back.

This is an interesting thought. I think they didn't know about the Phase 2A that far back. Re-listening to the call this morning, I heard executives that were in the process of pivoting. If they had thought it out more, there would have been a much more controlled presentation with an actual deck, and some deep rationale for the new game plan, and how it would benefit investors + patients. None of that happened. They probably got the results, shit their pants, got back on the phone with the FDA, and came up with the single-dose strategy. This pivoting activity, and the way it was handled with a teleconference call, shows that they're in red-alert right now, and have been for a short period of time. Not to mention, the Q&A was happening in real-fucking-time... if they were in a prepared spin mode... there would have been no Q&A, it would have been polished.

So, I doubt they realized it back then, when setting up the new Phase 1bs. When they announced them, if you recall, they had to go back to many of their original backers to ask for another round of funding and dilute the overall holdings in the company. If the meeting had a negative spin at that time, I suspect some of the advisors would have backed out, and not been so willing to fork out millions for a pivot that early.

When Frequency Therapeutics announced the Age-Related Hearing Loss Study, it was a few months after new research was published (I believe by Mass Eye & Ear) that indicated Presbycusis was largely predicted by hair cell loss from observations of hundreds of cochleas. So, they probably looked at that and thought FX-322 would be a good treatment to expand the marketability of the product. Therefore, a Phase 1B would be needed to prove safety, and if successful would enable inclusion of that specific patient population into later studies.

For the Severe Hearing Loss Phase 1B trial. Total speculation, but they may have observed that there are a lot of progenitors left in a severe hearing loss cochlea. You might also notice that Severe was added to the open-label trial much later. So, it's hard to see that as a pivot.

Also, since the time of pivot, all the way through recently... those same backers continued to hold FREQ through the most recent drop. Why would they give more money to the firm, knowing that a significant loss was about to happen? Seems like dumb business from the backer's perspective.

 

[Diesel]

I mean, what if FX-322 is killed/shut down (e.g., due to incapacity to objectively prove improvements in audiograms or EHF) before Frequency Therapeutics can conduct specific trials on specific subjective conditions? I feel like FX-322 is hanging by a thread, with Phase 1b serving as the thread. If they can't prove positive results from Phase 1b when the full readout is released in June (for what it is worth, I don't expect the full readout of Phase 2a to show anything meaningful), FX-322 and Frequency Therapeutics may well be doomed...

Frequency Therapeutics has $200MM cash in the bank, hardly hanging by a thread lol.