Frequency Therapeutics — Hearing Loss Regeneration

[HootOwl]

Worst of all, there were 0.0 improvements in the audiogram, which was my last remaining hope for tinnitus improvement.

I wouldn't use the audiogram as a means of assessing tinnitus improvement. I have substantial notches that match my tinnitus tones. But they don't show up on an audiogram because they are at very random frequencies. I even have a complete flat line in my EHF at 0 dB, but sweep testing up in those areas revealed massive gaps in my hearing ability.

If regenerative medicine reduces my tinnitus by making new hair cells or synapses, I am 99.9% sure my audiogram won't change as a result.

I can't imagine I am a total outlier in this regard.

 

[serendipity1996]

This is where fake WR scores were discussed after the phase I/II results. It's on page #161, so you can read it there. It's very interesting to see what is said compared to now.

The video that was posted, teaching you how to fake it, is in the quoted post (I haven't watched it, so I'm not sure what is said).

It is disappointing that they weren't more rigorous in this regard to stop this being a possibility in Phase 2a, especially with (retail) investors' money being at stake. They wouldn't care about that, though, as long as the more pivotal investment partners got their money out safely first before the drop occurred. There's no definitive proof of this, but something does stink a little bit. Forget the money, they should have nailed this trial design for their own scientific integrity.

If you watch the video, it is not actually teaching people 'how to fake it.' It discusses how difficult it would be to actually fake a test if you read the description and also the comments posted by the guy, e.g "I think you grossly misunderstood the point of the video. It shows how futile it is to even attempt to Fake a hearing loss. Watch it again with the correct lens."

 

[Mr Mister]

"The Phase 2a interim results also showed an unexpected apparent level of hearing benefit in the placebo group that did not occur in previous trials and exceeded well-established published standards, potentially suggesting bias due to trial design."​

I wrote here already a year ago that there must have been bias in the Phase 1/2 (I think it was) data as it is simply impossible to show substantially improved words scores while having unchanged audiogram in the speech frequency region. These disappointing results were pretty inevitable.

Audiogram is all that is needed, word scores are not reliable. They are taking science one step ahead but a cure is still far far away. Unfortunately.

 

[Olive27]

I really hope that's the case. I'm praying that the results are positive for age-related and severe hearing loss trials. I'm more worried about the severe category even though we have a positive anecdote saying that he had improvements in his word scores and 3 frequency bands and can also hear birds and sing and has no tinnitus 5 months after his last dose of FX-322.

Bullshit. Hearsay. Nothing official confirmed. This group needs to get down with the scientific facts which all points to failure at the moment.

 

[Olive27]

There is too much speculation here again, regarding the results perhaps not being that bad. Oh no.

In addition to the rather confusing and inexplicable results (placebos), FX-322 simply did not show any effect that could somehow help us with tinnitus. Period.

10% better WR is nothing. Such small improvements can simply be due to the daily fluctuations. Or equipment. It's just nothing.

Worst of all, there were 0.0 improvements in the audiogram, which was my last remaining hope for tinnitus improvement.

Some FREQUENCY THERAPEUTICS people are now millionaires because of their stock sales before March 23rd. Probably mostly from the money of people who were emotionally invested. That hurts even more.

Maybe because of my warnings, especially on March 22nd, I saved a few people here from great losses. That's the only positive thing for me.

Due to my hopelessness, I unfortunately had the first glimpses of mean depression today, which I had got rid of with hard work for half a year.

I can't hide anything from my girlfriend either. We're already talking openly about my handicap, but of course I downplayed the whole thing. "It just annoys me sometimes", but "it doesn't affect me", but unfortunately it does way too much. For example, I haven't slept through for a mostly a year. I'm always tired. Before that I could sleep like a koala. Any music, and I love music, sounds terrible with a scratchy ear.

I always lived in the hope that somehow relief could be found.

I would love to quit my job and spend the whole day in front of my computer with masking sounds and beer to be distracted.

But I can't give up on my girl. Not this girl.

Unfortunately, my sarcasm doesn't help me anymore.

It's a shame I can't invite you to Oktoberfest. Maybe someone will invite me to the USA at your expense. After all, I am already vaccinated with COVID-19, as a high-risk patient (I only have 2 healthy lung lobes). Well, I still have a bit of sarcasm in me.

So, I'm starting to get really drunk today. Better than ADs.

The Truth whether we like it or not!

 

[Aaron91]

Word scores and audiograms don't have to match once you are in. It's quadruple blinded and they don't kick you out once you are in. You just have to pass the initial screen and maybe that's the problem (this should again be really obvious once unblinded individual data is out)...

Also, I stand by my comment that when you are looking for non severe audiograms but also want at least moderately bad word scores, you are selecting for a relatively narrow population of genuine patients. This puts the odds of "selecting for liars" at much higher than it would otherwise be. Not to mention Frequency Therapeutics messing up by telling people word scores would be an important part of Phase 2a criteria to avoid the ceiling effect seen in some of Phase 1 participants.

I agree that the severe trial will be illuminating.

In the meantime, there is no scenario where one of the 3 groups isn't lying unless you believe the placebo effect can double word scores (I don't).

Could anyone shed some light on whether unblinding themselves (but not the patients) from the beginning would be acceptable to the FDA moving forward to avoid something like this from happening again? I understand blinding adds a huge amount of credibility to the results, but I can't see any other way of being absolutely sure something like this doesn't happen again. I wish using the untreated ear as a control was enough for the FDA.

 

[ploughna]

Might not have been so much deliberately 'lying/cheating' as deliberately not giving it a best effort. I find myself really concentrating on the words when doing a WR test - just take a more relaxed approach to it and I can easily imagine getting a significant proportion wrong. Same end result however, so I guess it doesn't really matter

 

[Street Novelist]

So, they currently have a severe hearing loss trial underway. When are those results supposed to be released?

 

[Zugzug]

As for the extent of cheating, I guess this remains a question mark, but for Frequency Therapeutics to have used it as an excuse in the first place, it would have to be, by definition, widespread. It was telling to me that Lucchino said they had combed through social media and found people sharing info about what it took to get into the trial. Make no mistake: Frequency Therapeutics have gone through this thread over the last month since they got the results. There's no doubt in my mind about this. FGG is right in that someone (be it Frequency Therapeutics, Phase 1 patients or Phase 2 patients) is lying, but I think the only question that needs answering here is whether we believe Frequency Therapeutics are credible. There was clearly no incentive for Phase 1b patients to lie, so that trial was legit as far as I'm concerned. It's then very binary. If you infer Frequency Therapeutics are credible, the answer is clear: Phase 2 patients lied. Given Frequency Therapeutics' pedigree, I'm inclined to say they are credible, despite this awful readout.

I think the company was overly naive, but not lying. Actually, my opinions of the placebo effect were shaped by what LeBel said regarding "you can't fake words." I think they trusted humanity too much. Maybe I'm a shill.

With this being said, I do think two things can be happening. Firstly, there was cheating and secondly, the drug is really not that great. The lack of audiograms were very underwhelming. I realize we can say that they didn't test all frequencies, but come on, would we have questioned this if the results were positive? Would we have said "maybe they happened to get lucky with a few select frequencies?" Of course not. The audiogram is bad, but it's not usually that bad for OHC loss.

As a converted bear, the best I can see this is some validity to the IHC theory with varying degrees of individual responders. The delivery sucks and doesn't produce a widespread treatment. Maybe someone could take the drug, have IHC regrowth, then a month later take the drug and see OHC regrowth, but I won't buy this until there's proof.

I still believe in hearing regeneration. It's definitely not all a hoax. Frequency Therapeutics is overly naive, but not a bunch of frauds. But the product we had in mind, including helping tinnitus, will be years away.

 

[FGG]

Could anyone shed some light on whether unblinding themselves (but not the patients) from the beginning be acceptable to the FDA moving forward to avoid something like this from happening again? I understand blinding adds a huge amount of credibility to the results, but I can't see any other way of being absolutely sure something like this doesn't happen again. I wish using the untreated ear as a control was enough for the FDA.

The only other way would be having consistent long term word scores being an additional "stability" measure.

 

[Tezcatlipoca]

But the drug doesn't work... hence no improvements in the EHF audiogram in the recent FX-322-111 trial. It's all placebo unfortunately.

There's a couple of trials showing it does work. This one just sucked, but the science is there.

 

[FGG]

I think the company was overly naive, but not lying. Actually, my opinions of the placebo effect were shaped by what LeBel said regarding "you can't fake words." I think they trusted humanity too much. Maybe I'm a shill.

With this being said, I do think two things can be happening. Firstly, there was cheating and secondly, the drug is really not that great. The lack of audiograms were very underwhelming. I realize we can say that they didn't test all frequencies, but come on, would we have questioned this if the results were positive? Would we have said "maybe they happened to get lucky with a few select frequencies?" Of course not. The audiogram is bad, but it's not usually that bad for OHC loss.

As a converted bear, the best I can see this is some validity to the IHC theory with varying degrees of individual responders. The delivery sucks and doesn't produce a widespread treatment. Maybe someone could take the drug, have IHC regrowth, then a month later take the drug and see OHC regrowth, but I won't buy this until there's proof.

I still believe in hearing regeneration. It's definitely not all a hoax. Frequency Therapeutics is overly naive, but not a bunch of frauds. But the product we had in mind, including helping tinnitus, will be years away.

What do you think doubled the word scores in Phase 1 then?

 

[Lucifer]

There's a couple of trials showing it does work. This one just sucked, but the science is there.

So in these trials did Frequency Therapeutics do an extended hearing test? Isn't the highest 20 kHz?

 

[Aaron91]

I think the company was overly naive, but not lying. Actually, my opinions of the placebo effect were shaped by what LeBel said regarding "you can't fake words." I think they trusted humanity too much. Maybe I'm a shill.

With this being said, I do think two things can be happening. Firstly, there was cheating and secondly, the drug is really not that great. The lack of audiograms were very underwhelming. I realize we can say that they didn't test all frequencies, but come on, would we have questioned this if the results were positive? Would we have said "maybe they happened to get lucky with a few select frequencies?" Of course not. The audiogram is bad, but it's not usually that bad for OHC loss.

As a converted bear, the best I can see this is some validity to the IHC theory with varying degrees of individual responders. The delivery sucks and doesn't produce a widespread treatment. Maybe someone could take the drug, have IHC regrowth, then a month later take the drug and see OHC regrowth, but I won't buy this until there's proof.

I still believe in hearing regeneration. It's definitely not all a hoax. Frequency Therapeutics is overly naive, but not a bunch of frauds. But the product we had in mind, including helping tinnitus, will be years away.

The thing is, there are clearly two subgroups of super-responders in both the Phase 1/2 and Phase 1b trials who almost doubled or more than doubled their word scores. I think we all agree this is very strange. It's too much of a coincidence to me. I wonder if Frequency Therapeutics, assuming they're able to filter out the outliers/fakes from Phase 2 once they're unblinded at the individual level, they can then see if there's a similar subgroup of patients from Phase 2 who were also super-responders that matched in description to the super-responders from the other two trials.

I think it's fair to suggest that the drug is clearly working in some patients and not others, not necessarily that the drug isn't great. This is where I think @Diesel's breakdown of different pathologies for different people (IHC vs OHC vs synaptic loss) is quite pertinent. I think multiple doses spread over longer periods of time will confirm this. Chris Loose said yesterday they will run multiple doses again in parallel to other studies but with bigger gaps in time. Hardly surprising given Will McClean's own paper says it takes 12 days to form a hair cell colony. I wonder what he had to say about the weekly dosing....

 

[Lucifer]

What do you think doubled the word scores in Phase 1 then?

I still think FX-322 works. How come people doubled their word scores in Phase 1? It just doesn't make sense to me.

If the severe hearing loss trial can prove that there were improvements for them, then it's less likely that the Phase 1b results were fake.

When are the results released from the severe hearing loss trial?

 

[r34d1ng]

I'm seeing it as of this morning...

https://www.streetinsider.com/dr/news.php?id=18169286

Check this one out.

 

[Chad Lawton]

But the drug doesn't work... hence no improvements in the EHF audiogram in the recent FX-322-111 trial. It's all placebo unfortunately.

It works in single dose trials. The drug "didn't work" when they poked multiple holes in people's ear drums day after day. Cochlear hair cells are nerves and nerves take months to years to completely heal. I think it was irresponsible on FREQ's part to have a trial where you inject the patient 4 days in a row. Injections 3 to 6 months apart would have been much more reasonable.

 

[Zugzug]

What do you think doubled the word scores in Phase 1 then?

I mean, obviously the drug isn't a total hoax. I think most of the issues are delivery. My best guess is that there's some subset of people who have good IHC responses. In other words, a responder is a nice responder. Maybe there's some luck involved or having hearing loss in the right way. I'm not sure. The sample size is so small that we should be pretty critical of the one patient in Phase 1 with plenty low enough baseline WR who didn't improve much at all.

 

[FGG]

So in these trials did Frequency Therapeutics do an extended hearing test? Isn't the highest 20 kHz?

Apparently testing 16 kHz to 20 kHz is so hard to calibrate that it's generally considered unreliable. A lot of places that do EHF have 16 kHz as the cut off.

 

[chinup]

Why has my tinnitus spiked since getting the FX-322 news?

Mine has too. It kept me up last night for the first time in months. Clearly a stress component. Also paying way more attention to it now that I know I'll be stuck with it for a very long time.

 

[Tezcatlipoca]

Check this one out.

Isn't that great news? FREQ will still be getting investors and they can continue to develop FX-322.

 

[FGG]

Interesting question... I suppose it would depend on how afraid you would be about getting "caught" should any discrepancies surface and how aware you are of the blinding process.

If you're unfamiliar with the extent of blinding, you might think that the trialing center (or the researchers) would be comparing your initial audiogram - that permitted you admittance to the trial - to the second audiogram created as a baseline for the trial itself.

I'm kind of turning this over in my head now.

The other scenario would be as you described. But - if they only lied once on the initial assessment, and not at the second baseline, once the data is unblinded Frequency should be able to see that clearly. Maybe what you proposed is true, and Frequency was blinded as soon as the baseline audiogram was created so they were never able to catch any fraudulent activity.

I think even if you weren't familiar with blinding, anyone trying to game the system would think "what do I have to lose? They kick me out of a trial I wouldn't have been qualified for anyway?"

 

[ColinUK]

I just don't understand at all what has happened and am just shocked by it all. This has been in development for years. Lots of respected scientists, fancy videos and presentations. I totally bought into the science behind it, it all seemed to make sense.

Then this backed by doubling of word scores improved audiograms and durable results from the safety trial, it wasn't even a question of if it worked but how well.

Now that a few people have been made very rich, we get the results and guess what, it does nothing absolutely nothing, even in the single dose trial a 10% improvement in one test criteria for only 34% of the participants means it does nothing.

I am totally gutted for myself and everyone that suffers but I think I am done following anything now. Help is coming from nowhere. You just got to figure out a way to deal with this on your own and cope as best you can.

I so believed in this but I can't honestly believe it went from all the promise to nothing. Without something shady going on, it just doesn't add up at all.

 

[HootOwl]

Apparently testing 16 kHz to 20 kHz is so hard to calibrate that it's generally considered unreliable. A lot of places that do EHF have 16 kHz as the cut off.

That makes sense. When they tested above 16 kHz for me it sounded like "shhh shhh". It wasn't a pure sine wave. I wonder if that's part of the calibration procedure.

It was a very stark difference too. At first I thought the headphones I was wearing were shorting out.

 

[Lucifer]

Apparently testing 16 kHz to 20 kHz is so hard to calibrate that it's generally considered unreliable. A lot of places that do EHF have 16 kHz as the cut off.

Do you think Day 210 might show better results like the positive anecdote? It could take awhile to show improvements due to dosing every week and the stepping on the lawn scenario.

So when Frequency Therapeutics said that Phase 2a participants experienced a diminishing effect, does that mean the hearing improvements were the same as having one dose of FX-322 in Phase 1b?

Or does that mean that multiple dosing of FX-322 made hearing improvements worse than Phase 1b?

 

[Lucifer]

Isn't that great news? FREQ will still be getting investors and they can continue to develop FX-322.

This rating was before the bad news came out.

 

[Aaron91]

It works in single dose trials. The drug "didn't work" when they poked multiple holes in people's ear drums day after day. Cochlear hair cells are nerves and nerves take months to years to completely heal. I think it was irresponsible on FREQ's part to have a trial where you inject the patient 4 days in a row. Injections 3 to 6 months apart would have been much more reasonable.

Perhaps a case of getting too greedy too soon. I think we know this was driven with the intention of reaching the lower frequencies and to determine whether there's some kind of relationship between penetration and damage/regeneration. They clearly went way, way too far. A better approach would have been to have spaced out the injections differently within each group. For example, 8 severe patients get them once a week, another 8 severe patients get them bi-weekly, and another 8 patients get them once a month. Same then for each other category. It would complicate and delay the readout, but at least then you'd have some insight into what the ideal time lag between each dose should be. This may of course present its own set of challenges by making it difficult to determine any statistically significant differences.

Perhaps they were better off running an expanded Phase 1 trial where they test the various time lags between dose to inform the time-gap for Phase 2. Ball = dropped.

 

[aot]

Isn't that great news? FREQ will still be getting investors and they can continue to develop FX-322.

Yes but how long, though?

I can't wait ten years for this drug. I just can't.

I was drinking the FX-322 Kool-aid so hard. I was going to start saving money and everything. I wanted to believe that in a few short years I could just get a shot and be normal and live my life again.

I'm so tired of being worried about noise and about my future, and about if anyone would ever want me. I'm sick of putting in earplugs that hurt my ears. I'm sick of all of it. It's my fault for getting my hopes up, but still.

Why did it have to be this ear shit that I got stuck with? Why couldn't I just have gotten shot or had heart attack or lost my legs or something?

I'm just so tired.

 

[FGG]

Do you think Day 210 might show better results like the positive anecdote? It could take awhile to show improvements due to dosing every week and the stepping on the lawn scenario.

So when Frequency Therapeutics said that Phase 2a participants experienced a diminishing effect, does that mean the hearing improvements were the same as having one dose of FX-322 in Phase 1b?

Or does that mean that multiple dosing of FX-322 made hearing improvements worse than Phase 1b?

I think Phase 2a is a wash except perhaps at the individual level. I don't think time will change that.

My eye is on the single dose severe hearing loss group at this point.

 

[mrbrightside614]

It works in single dose trials. The drug "didn't work" when they poked multiple holes in people's ear drums day after day. Cochlear hair cells are nerves and nerves take months to years to completely heal. I think it was irresponsible on FREQ's part to have a trial where you inject the patient 4 days in a row. Injections 3 to 6 months apart would have been much more reasonable.

It wasn't 4 days in a row, but yeah, weekly is still unnecessarily frequent/potentially injurious.