Frequency Therapeutics — Hearing Loss Regeneration

[Jurger]

10 dB is important.

If it is not 0 dB, you can improve it and aim for 20 dB and 30d B. Hope appears.

I think it is important that it is not 0 dB.

They haven't been able to repeat the 10 dB improvement on 8 kHz in the latest Phase 1/2 trial. According to Carl LeBel the only hearing signal was the increase in WR scores. That concerns me. And 10 dB improvement on one frequency is within the margin of error on an audiogram. The fact is that they haven't been able to repeat the gain points in that direction either.

 

[Aaron91]

The running theory here was that reduced tinnitus was a byproduct of improved hearing. Since the data now suggest no improved hearing then that raises doubts tinnitus can improve. The burden is on Frequency Therapeutics to supply hard data rather than just 2nd hand anecdotes. Remember that even Lenire had video testimonials and we can see how that one turned out.

The interesting thing is that we now have two anecdotal cases from the trial of tinnitus improving after the interim analysis (i.e. it would not become known to Frequency Therapeutics until the full readout). It's only anecdotal, but assuming the drug does actually restore some kind of input, this would be consistent with the idea that it can take some time for the brain to adapt (neuroplasticity) to the restored input.

12 days? Where did you see that? I thought it took a couple of months.

It's in Will McLean's original paper. I posted it a few pages ago but here it is again:

Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells

@Aaron91, you better not be fuc*!%! with us. I can't stand this rollercoaster of emotion.

I have no reason or incentive to do this and those who know my story would know I'd never do this. As I said, I don't have sight of any paperwork to confirm or disconfirm, nor did I witness the patient receive the injections, but the patient does have a documented, public history of saying they applied and got into the trial. For those wondering what I may be implying here, Lucchino left a big clue in the teleconference call.

I would also like to add that both of the positive anecdotes stated they think they may have gotten two FX-322 shots as they noticed the shots give a burning sensation.

@Aaron91, would you be able to ask those positive anecdotes about when they got their 4 doses, and in which order of those 4 shots did they experience the burning sensation. I'm trying to figure out if they got two shots of placebo first and then two shots of FX-322 or if they got FX-322, Placebo, Placebo, FX-322, etc. I am trying to figure out why they may have experienced those improvements where other participants didn't.

As mentioned previously, all injections of FX-322 were front loaded. In other words, if you were in the 1-dose group, your first injection was FX-322 followed by three injections of placebo. If you were in the 2-dose group, you got a dose of FX-322 every week for two weeks, followed by two weeks of placebo.

This is why I said very early on post read-out, given the reseeding the lawn analogy, that it almost wouldn't matter if you got 1 dose of FX-322 or 4 doses of FX-322 because a hair cell colony takes 12 days to form. We can't know for sure, but injecting anything into the cochlea during that period, whether it's an empty polymer gel or FX-322 sounds too high risk of a move, especially given Chris Loose said they had never done it before in animals. Before the readout I maintained that this move must have been informed from somewhere, but I now think they simply got greedy chasing after those lower frequencies.

Given the above, AND given that Frequency Therapeutics' positive Phase 1/2 data read-out started at day 15, AND given that their pre-clinical work showed a hair cell colony takes 12 days to form, AND assuming Frequency Therapeutics were familiar with the literature that an IHC must form first BEFORE a progenitor can replicate and divide into a hair cell, their decision to go down the weekly injection route is unforgivable, even if you consider just ONE of these factors, let alone all of them together. It boggles my mind and I can't imagine it was something Will McLean agreed to. That is why I said it sounded as if this was a decision made by a manager, not a scientist - 7 day was too on the nose. For those who are not familiar with science industries, there are always huge conflicts between management and the people doing the research. NASA is a classic case, most notably in the Challenger and Columbia disasters. It's almost as if Frequency Therapeutics were already thinking in commercial terms (getting ready to market the injections as "weekly" to audiologists/patients) and they took their eye off the ball completely. I think @Diesel hit the nail on the head when he said that this is a company that got too fast, too loose, too soon and ended up getting a giant kick in the nuts. In all of this, I can't imagine what Will McLean must be thinking, as it was his research that shed light on the 12-day time period. The guy must be livid and I wonder if some heads might roll in the coming months.

Actually, around the 17-minute mark in their call they say the increases they saw was less than what they observed "Changes in the WRS are lower than in the past single studies".

My understanding is they are essentially saying curves don't separate at all and are sloping upwards but the the slope is lower than (the FX-322 arm) in the previous single studies.

Clearly the fact the drug did nothing seems to be the crucial factor here. This suggests either the effect observed earlier was a fluke or the multiple injections killed the effect.

Thank you for articulating this. My understanding is almost the same and I think people still haven't quite realised this although I appreciate not everyone had the benefit to listen in to the webcast. Not only were there no differences between any of the groups and placebo, but the differences between the treatment groups themselves "overlapped" as Carl LeBel put it. If we entertain the idea that FX-322 does work in principle (putting aside the debate as to how much), it's almost as if all three treatment groups got the same dose. Again, if we assume the idea that FX-322 works in principle, the only dose that could be is a single dose in effect (if at all). If you pair this with some people lying/faking or "subconsciously deflating" their WR scores to get into the trial, you are left with an extremely messy readout.

Which brings me to my next point, which I think is perhaps mostly directed to our dedicated quant @Zugzug.

We know that Frequency Therapeutics have stated that there is a mismatch between the historical records of some patients and their screening tests AND/OR their original baselines. If I understand correctly, they only have the average of those records at this moment in time. When I first made this point, I said it could be either/or, but it could well be a combination of both - patients lying at screening but then performing normal at baseline and patients lying at screening and then again at baseline. Either way, Frequency Therapeutics should, once they have the individual data to parse through, be able to identify these patients one by one and pick out the outliers. This has made me wonder whether there still is a path to pivotal without redoing Phase 2. @FGG mentioned one company who failed Phase 2 only to sift through the data down the line, pull out a rabbit and go to Phase 3. Another case in point is Cassava Sciences, who released an interim Phase 2 data readout for an Alzheimer's drug in May of last year and their stock price tanked by about 80%. When they released the full data readout early this year, they too pulled out a rabbit and the share price shot up from $8 to $88 and eventually settled circa $50. Both drugs were for different things, but given Frequency Therapeutics already have FDA approval they will be in constant contact with them and I'm wondering: if Frequency Therapeutics can prove this has happened, would the FDA allow them do a selective read-out where they cut out the outliers? I think it's possible. My concern is that it may not be enough, because Frequency Therapeutics have already said there is some kind of dampening effect. This is where we need the remaining Phase 1 trials to do something spectacular. I agree with @FGG in that the severe SNHL trial will prove to be the Litmus test. Again, assuming the drug works, it should confirm or disconfirm the current literature regarding the importance of IHCs. Remember, assuming the super-responder theory is correct, we could see a knock-out readout in this trial unlike any of the other trials. So that is what I'm going to hold out for, along with the 210-day tinnitus read-outs, as I don't think this is an endpoint that would have suffered to the same degree from bias given Frequency Therapeutics didn't communicate any specific criteria for it - unless of course they said all patients must have tinnitus of any kind and patients lied about having tinnitus as well. That would suck.

Finally, I have managed to track down a third patient from the trial and await response. I'll write again if I get a reply.

 

[Ed209]

I have the same kind of fluctuations on my audiograms. An improvement of 10 dB is really not impressive.

That is why a normal audiogram is considered as being anywhere between -10 dB to 20 dB (with a grey area that extends to 25 dB). When you look at it within that context, you can see why 10 dB isn't a significant metric.

 

[r34d1ng]

The interesting thing is that we now have two anecdotal cases from the trial of tinnitus improving after the interim analysis (i.e. it would not become known to Frequency Therapeutics until the full readout). It's only anecdotal, but assuming the drug does actually restore some kind of input, this would be consistent with the idea that it can take some time for the brain to adapt (neuroplasticity) to the restored input.

Hence my fear that FX-322 will be discontinued if they can't "objectively" prove improvements in audiograms and/or EHF even if it does restore some inner ear structure that alleviates tinnitus, hyperacusis and whatnot.

If FX-322 fails to restore hearing, I really hope they will repurpose the drug and conduct a trial to demonstrate efficacy in reducing tinnitus or hyperacusis.

 

[Lucifer]

@Aaron91, thank you for contacting those patients. It means a lot to me.

Wow, so that Alzheimer's drug that had bad preliminary results for Phase 2, but then when they had the full readout early this year, it was positive and the share price went back up, that's awesome for them.

I really hope that's the case with the Phase 2a trial for FX-322. I still think maybe they did get some improvements but it was too late to add to the Day 90 preliminary results as majority of the candidates got improvements after Day 90.

So in the Phase 1b trial for FX-322, were there any word score improvements shown at Day 15?

 

[Olive27]

Some good news, their stock is at $9 now.

Dead Cat Bounce.

 

[NewLionel]

Dead Cat Bounce.

Is anyone buying FREQ?

I think FX-322 has a good chance, but I'm also a coward... There is serious dollar to be made if it went back up.

 

[HootOwl]

I'm seriously about to flip a coin and see whether I should just get cochlear implants or not!

My quality of life is horrible not being able to understand what I hear!

I figure I'd ask some of you smarter guys what you would do. I just turned 33 in August and feel I'm losing everything. Is FX-322 something you would seriously wait on and be miserable, or would you just get cochlear implants? Please anyone give me some feedback here.

If you can (and I don't pretend this isn't extremely hard) I would at least wait until they release that new form of CI that uses light. @FGG mentioned it before on this thread, and it sounds like it's a substantial jump in implant technology.

However they plan for clinical trials in 2025... and that's so long away.

But if you waited you would likely have your choice between the CI trial or FX-322 - if FX-322 does come to market.

 

[FGG]

If you can (and I don't pretend this isn't extremely hard) I would at least wait until they release that new form of CI that uses light. @FGG mentioned it before on this thread, and it sounds like it's a substantial jump in implant technology.

However they plan for clinical trials in 2025... and that's so long away.

But if you waited you would likely have your choice between the CI trial or FX-322 - if FX-322 does come to market.

It's possible to remove/replace cochlear implants. I wouldn't necessarily wait for an optigenetic CI to come out if I couldn't communicate on a daily basis.

 

[Zugzug]

Okay, I have caught up. I think everyone needs to slow way down.

1. Margin of error is a thing for a reason. We can't say that if someone improved by 10 dB, it must be the drug, but if they were in the placebo arm, it was probably the equipment. PTA is a total wash for this trial. Just give up on it. Bias on PTA wasn't a thing like WR (possibly) and they saw no groupwide improvements (even at EHF!) with plenty large enough sample sizes.
2. Let's say the "lying" was a mix of low screen, normal baseline and low screen, low baseline. Cases of the former are less concerning because the people at least did the trial right. All it means is that the filter was a little out of whack, but the data is accurate. In other words, in this case, people would start closer to the ceiling so there would be less space for separation between groups. But, assuming there are also cases of the latter, this would be offset by "fake" super responders, which we can only assume is proportional in placebo and treatment groups.
3. We need to slow waaaay down on the lawn theory. Even if McLean showed 12 days was required in the lab, it's totally different in vivo. I have made the point that "7 days" is a stupid scientific number, but we still don't know the degree to which this impacted everything.
   
   Just days ago, we were completely sold on their theory that multiple doses would push the 8 kHz barrier. Now we are acting like the lawn theory must be true. There are other things to consider.
   
   For example, there's an apples to oranges time comparison problem; let me explain. So in all 4 cohorts, the last injection of anything (lawn theory relevant) is at day 28. If we measure 90 days from this date (day 118), then the groups obviously have different amounts of time with FX-322 in them. If we measure 90 days from the date of the last FX-322 shot (so different absolute days for different groups), then we are comparing groups with different "lawn effect" levels because they were all injected with something on the same days. This problem is not nearly as straightforward to make sense of.
   
   As an aside, does anyone know which of the two they actually did? I know "day 90" doesn't mean absolute day 90, but I'm not sure otherwise. It's still a problem.
4. It's not sexy to say this, but the remaining trials are much more valuable than the anecdotes. Even then, all they will really do is help us on an emotional level. They will have to redo Phase 2. I would be blown away otherwise.
5. If they get unblinded and they see individually disproportionate baseline discrepancies in the placebo group by chance, the performances in the treatment groups would have to be damn strong to override that. It doesn't appear like that's the case.

tl;dr: There will be another Phase 2. Sorry.

 

[Jack Straw]

You're confusing getting in early with stubbornly holding after the news is bad and the stock has already crashed. Different points in time.

One trial was bad with biased results that can't be trusted...

 

[FGG]

Okay, I have caught up. I think everyone needs to slow way down.

1. Margin of error is a thing for a reason. We can't say that if someone improved by 10 dB, it must be the drug, but if they were in the placebo arm, it was probably the equipment. PTA is a total wash for this trial. Just give up on it. Bias on PTA wasn't a thing like WR (possibly) and they saw no groupwide improvements (even at EHF!) with plenty large enough sample sizes.
2. Let's say the "lying" was a mix of low screen, normal baseline and low screen, low baseline. Cases of the former are less concerning because the people at least did the trial right. All it means is that the filter was a little out of whack, but the data is accurate. In other words, in this case, people would start closer to the ceiling so there would be less space for separation between groups. But, assuming there are also cases of the latter, this would be offset by "fake" super responders, which we can only assume is proportional in placebo and treatment groups.
3. We need to slow waaaay down on the lawn theory. Even if McLean showed 12 days was required in the lab, it's totally different in vivo. I have made the point that "7 days" is a stupid scientific number, but we still don't know the degree to which this impacted everything.
   
   Just days ago, we were completely sold on their theory that multiple doses would push the 8 kHz barrier. Now we are acting like the lawn theory must be true. There are other things to consider.
   
   For example, there's an apples to oranges time comparison problem; let me explain. So in all 4 cohorts, the last injection of anything (lawn theory relevant) is at day 28. If we measure 90 days from this date (day 118), then the groups obviously have different amounts of time with FX-322 in them. If we measure 90 days from the date of the last FX-322 shot (so different absolute days for different groups), then we are comparing groups with different "lawn effect" levels because they were all injected with something on the same days. This problem is not nearly as straightforward to make sense of.
   
   As an aside, does anyone know which of the two they actually did? I know "day 90" doesn't mean absolute day 90, but I'm not sure otherwise. It's still a problem.
4. It's not sexy to say this, but the remaining trials are much more valuable than the anecdotes. Even then, all they will really do is help us on an emotional level. They will have to redo Phase 2. I would be blown away otherwise.
5. If they get unblinded and they see individually disproportionate baseline discrepancies in the placebo group by chance, the performances in the treatment groups would have to be damn strong to override that. It doesn't appear like that's the case.

tl;dr: There will be another Phase 2. Sorry.

I think the drug works but I agree that they will need to repeat Phase 2 but I think the fact alone that they had better single injection results supports the 4 shot protocol being a disadvantage regardless of the reason (disturbance/lawn theory or not). The person with Meniere's who wasn't surprised that the multiple dose protocol didn't work made a good point as well about fluid pressure.

 

[Philip83]

The running theory here was that reduced tinnitus was a byproduct of improved hearing. Since the data now suggest no improved hearing then that raises doubts tinnitus can improve. The burden is on Frequency Therapeutics to supply hard data rather than just 2nd hand anecdotes. Remember that even Lenire had video testimonials and we can see how that one turned out.

The interesting thing is that we now have two anecdotal cases from the trial of tinnitus improving after the interim analysis (i.e. it would not become known to Frequency Therapeutics until the full readout). It's only anecdotal, but assuming the drug does actually restore some kind of input, this would be consistent with the idea that it can take some time for the brain to adapt (neuroplasticity) to the restored input.

Lenire's testimonials were garbage though, to the point where I didn't even understand why they released them, and nothing even close to the anecdotes we've seen from FX-322, "90% gone", etc.

So there are two anecdotal "leaks" and then also the statement from FREQ themselves about them getting tinnitus improvement anecdotes, correct? It could have been one of those two people telling them, I guess, but it could also be there are additional people with tinnitus improvements. We all know tinnitus assessment is extremely hard and very subjective (prone to placebo reaction), but the TFI scores are still something I'm looking forward to a lot from the complete read out of Phase 2a.

I'm still very discouraged about the fact there were no EHF improvements in the parallel Phase 1b though...

 

[FGG]

I'm still very discouraged about the fact there were no EHF improvements in the parallel Phase 1b though...

If you believe the original Phase 1 cohort were not "plants" or "fakers" (unlike later groups they did not have the incentive to fake word scores as an entry requirement), FX-322 did something substantial to hearing that is not placebo or chance.

With that in mind, some hearing is restored. @Diesel and I have both laid out a plausible case for IHCs (I won't bore everyone and write it out again) being preferred first pass. And, in fact, the word score test itself measures *non-OHC* hearing better. Audiograms only measure OHC function which is also what hearing aids do (act as surrogate OHCs).

I think the way forward for audiogram changes/OHCs is multi injection but spaced much further apart.

They still need to repeat Phase 2 though likely. But the drug works if the original Phase 1 isn't faked. And by now, Frequency Therapeutics would have known if it was.

 

[Zugzug]

If you believe the original Phase 1 cohort were not "plants" or "fakers" (unlike later groups they did not have the incentive to fake word scores as an entry requirement), FX-322 did something substantial to hearing that is not placebo or chance.

With that in mind, some hearing is restored. @Diesel and I have both laid out a plausible case for IHCs (I won't bore everyone and write it out again) being preferred first pass. And, in fact, the word score test itself measures *non-OHC* hearing better. Audiograms only measure OHC function which is also what hearing aids do (act as surrogate OHCs).

I think the way forward for audiogram changes/OHCs is multi injection but spaced much further apart.

They still need to repeat Phase 2 though likely. But the drug works if the original Phase 1 isn't faked. And by now, Frequency Therapeutics would have known if it was.

Maybe it's just me, but my suspicion is that if the theory is correct that IHC are what's being regenerated in word responders only, I think they will come up with a better delivery (maybe even new formulation) before they make sense of the process of regrow IHC to capacity --> regrow OHC.

Who knows, maybe even with full IHC, the drug just doesn't work well with in vivo OHC.

The idea of looking for the order of IHC --> OHC, isn't that something they can at least see in vitro?

 

[Philip83]

If you believe the original Phase 1 cohort were not "plants" or "fakers" (unlike later groups they did not have the incentive to fake word scores as an entry requirement), FX-322 did something substantial to hearing that is not placebo or chance.

With that in mind, some hearing is restored. @Diesel and I have both laid out a plausible case for IHCs (I won't bore everyone and write it out again) being preferred first pass. And, in fact, the word score test itself measures *non-OHC* hearing better. Audiograms only measure OHC function which is also what hearing aids do (act as surrogate OHCs).

I think the way forward for audiogram changes/OHCs is multi injection but spaced much further apart.

They still need to repeat Phase 2 though likely. But the drug works if the original Phase 1 isn't faked. And by now, Frequency Therapeutics would have known if it was.

Yep, I've think I've read everything that you and @Diesel have written in here since the data release. I agree, but I also feel that we're moving the goal posts a little bit when processing the data. I was hoping that Phase 2 would be the first proper proof that audiograms could in fact properly improve, with 20-30 dB shifts in the EHF range, but instead we got none of that.

But, of course I hope, like everyone else, that the tight dose-regiment and the potential "fakers" is what screwed it all up and that longer spaced injections will eventually lead to OHC growth and audiogram improvements.

 

[100Hz]

Many otologists roll their eyes at the notion that hyperacusis patients have auditory damage.

Yeah, and what's funny about that is that they are the same people who give the OAE tests which can indicate damage in a hyperacusis complainant who has good hearing.

My hearing was apparently fine according to my audiologist. My 3 standard tests over the last 3 years also all look well within +-5 dB to me. They were all done on the same machine in the same room by the same guy, and I think this is also important to minimize the margin of discrepancies between testing conditions where possible. But on the same days as the first 2 audiograms he also did OAE tests (all results below). And then he went on to say that I do have damage in my inner ear (indicated by the closing of the gap at 4 - 8 kHz 2018 (L), and 6 - 8 kHz 2019 (L). (Why it seems to get better a year later at 4 kHz I find so weird though! It's a shame because apart from that region I'd say the results are fairly static and this discredits the test quite a lot I think, unless my ear fixed itself which I doubt as I was worse by 2019.)

What OAE tests seem to be very good at picking up though is early onset OHC damage possibly before it shows up on a audiogram (as in typical noxacusis case I guess). But I wonder if sometimes (in the case of noxacusis?) it is actually not measuring true OHC damage but instead measuring a degraded OHC response due to another type of damage, from here take your pick, damage to corresponding IHCs, afferents, efferents, synapses etc. It's also interesting that it seems to be a very noise exposure and tinnitus related test which are regularly discussed along side type II sensitization and IHC synaptopathy etc. as opposed to hearing loss.

I'm surprised this test wasn't used for FX trials because it seems to get described as being a more granular and incremental test than an audiogram and if it can measure damage before it shows up on an audiogram, could it not pick up on those more subtle changes in reverse?

It's only wikipedia but I found quite interesting, I'll do more reading anyway. - https://en.wikipedia.org/wiki/Otoacoustic_emission

I'm neither bear or bull on this by the way. Just looking for some shred of fact. Before this week I didn't really get involved in this thread because it looked like the research and homework was done and it was just a matter of waiting. It feels murky now though as to whether the drug actually works so its worth trying to find out. Being 10 years away from a working drug is infinitely better than being 2 years away from a syringe full of doubts.

 

[Philip83]

The idea of looking for the order of IHC --> OHC, isn't that something they can at least see in vitro?

This is what confuses me as well. If they saw this, why haven't we heard about it from them anywhere?

 

[Gb3]

I have spoken to a patient from the Phase 2 trial. More below.

I think many of you by now know me as a member that often does deep dives and goes down rabbitholes. Ever since I first read the pre-clinical work, there was no doubt in my mind this drug was the real deal, especially after the Phase 1/2 study. For me, it was simply a question of optimising delivery and dosage. However, for the last 72 hours, I have been questioning everything I previously believed to be true. It has been a very unnerving experience to say the least, as I'm sure it has been for others. So I decided to go back and read all the preclinical work again, as well as other literature. This time I wasn't satisfied, because I realised peer-reviewed papers were no longer good enough in face of the current situation. I had planned on taking a break from the forum, but I felt the only way I could settle this one way or another, at least in my mind, was to find someone who took part in the trial.

I can confidently say that I have tracked down two patients from the clinical trial. I am in touch with one of them and waiting to hear back from the other. I went in prepared with questions and made a lot of notes from the conversation with the first patient. I shall summarise them below.

Patient X Background

Age: 55-65 (I'm avoiding giving the exact number as not to dox the patient)
Presentation: Unilateral hearing loss and bilateral tinnitus
Cause: Unknown
Treatment history: 30 injections of ITT steroids and HBO treatment
Time of onset: 2 years
Hearing aid: Yes

Patient X - FX-322 trial

Baseline WR score: 40%
Post-treatment WR score: 50%
Post-treatment audiogram: 10 dB gains in three frequency bands - two in the extended audiogram and one in the standard audiogram
Post-treatment tinnitus: 90% improvement in both ears (despite only one ear being treated) after 3.5 months

Summary

As you will infer from the above, the patient had a sudden onset of hearing loss in a single ear. This was preceded by tinnitus two weeks before onset. Following 30 injections of ITT steroids and HBO treatment, they were able to go from, for all intents and purposes, deaf to a 40% WR score baseline in the affected ear. They describe their hearing pre ITT steroids and HBO treatment as garbled and sounding like chipmunks. Although this helped regain some hearing, they still required the use of hearing aids moving forward. This was their presentation going into the trial.

Following participation in the trial, the patient saw a 10 point gain in their WR score from baseline and 10 dB gains across three different frequency bands. They started to notice their hearing improvements one month after their last injection. Interestingly, the reduction in bilateral tinnitus, came 3.5 months after the last injection - outside the scope of the interim study. They describe their stress levels induced by tinnitus as having been dramatically reduced and that their general hearing in noisier environments is "better but not perfect". Examples of sounds they say are now easier to discern include the chime on the dryer when the laundry is dry, hearing a waitress's voice in a restaurant (higher pitched female voices), soft and squeaky toys. They also have a better sense of directionality. They still, however, require the use of a hearing aid.

The patient remains blinded and unaware as to whether they received placebo or FX-322 at this moment in time, although they have kindly agreed to letting me know once they know. Similar to another anecdotal experience posted here, they described a burning sensation during 2 of the four injections. They experienced no other discomfort associated with the regularity of the injections.

When asked whether they were surprised the trial had failed, the patient said they were "shocked".

Conclusion

I'm sure some of you have questions as to how I was able to track down a patient from the trial. The answer is I can never know for sure whether this really is a patient from the trial, but what I can confirm, for whatever my word is worth on here, is that Patient X has a publicly documented history of hearing loss and a publicly documented declaration of having applied to (and entered) the trial. I don't wish to say much more than that, but I think if you read between the lines here you'll be able to figure out what I've done and I'm saying. I'm already mindful of the fact that this person has been bombarded with a lot of questions from a complete stranger (yours truly), so if there is something you want to ask, I think the best course of action would be for me to get back in touch with them directly.

I'm about to sleep so won't be able to answer any questions until tomorrow at the earliest, although I still intend to take a break for a week or so from the forum (although I am keeping general tabs on discussions). I will report back if and when I hear from the second patient.

I am almost positive this is the same patient I have been in communication with. The thing that bothers me is that they told me that they have no more follow-ups with the clinic. This is a little confusing to me. Wouldn't they be in contact with the patient going forward before the end of the readout? I agree this person does have a documented history of being on an online forum related to hearing loss going back a couple of years. They told me in a private message that the tinnitus had faded unprompted.

 

[FGG]

Maybe it's just me, but my suspicion is that if the theory is correct that IHC are what's being regenerated in word responders only, I think they will come up with a better delivery (maybe even new formulation) before they make sense of the process of regrow IHC to capacity --> regrow OHC.

Who knows, maybe even with full IHC, the drug just doesn't work well with in vivo OHC.

The idea of looking for the order of IHC --> OHC, isn't that something they can at least see in vitro?

In culture, they grew equal amounts of both in histology at the end of study. Those are very different conditions, though. And it's possible at day 1, day 2, day 3, etc they skewed IHC first but at the end of the study, it was equivalent.

Maybe that's why they focused on clarity also (IHCs)?

I think there may be a weaker effect on OHCs in vivo also for sure (they have way less LGR5+ cells around them in vivo for one) so even single pass in vivo, assuming intact IHCs, there is likely going to be a less robust effect with one dose.

Hypothetically, multi dosing would be the way to tackle that but there needs to be a bigger interval between doses obviously.

I should add that I don't think Frequency Therapeutics should chase this without yet knowing the best interval. I think they should stick to single injection and find a way to ensure better accuracy with word score baselines and worry about multi dosing later.

Ideally, a second Phase 2 would include a more severe group with longer term genuinely depressed baseline word score results.

 

[Ed209]

Lenire's testimonials were garbage though, to the point where I didn't even understand why they released them, and nothing even close to the anecdotes we've seen from FX-322, "90% gone", etc.

There was a girl on here that claimed Lenire completely cured her tinnitus. This is the nature of anecdotes.

I'm still on the fence in all of this. I need to see something that makes me believe.

 

[Zugzug]

In culture, they grew equal amounts of both in histology at the end of study. Those are very different conditions, though. And it's possible at day 1, day 2, day 3, etc they skewed IHC first but at the end of the study, it was equivalent.

Maybe that's why they focused on clarity also (IHCs)?

I think there may be a weaker effect on OHCs in vivo also for sure (they have way less LGR5+ cells around them in vivo for one) so even single pass in vivo, assuming intact IHCs, there is likely going to be a less robust effect with one dose.

Hypothetically, multi dosing would be the way to tackle that but there needs to be a bigger interval between doses obviously.

I guess, hypothetically, this might sound obvious to the point of stupid, but I feel good about this drug if there was a way to safely achieve some sort of slow-release exposure. This sounds so easy, but it's not because the cochlea is so small and delicate. Safety (rightfully so) needs to be prioritized. Any method that leads to inflating the perilymph with the gel risks are sorts of pressure problems. Even harder in vivo.

 

[Zugzug]

There was a girl on here that claimed Lenire completely cured her tinnitus. This is the nature of anecdotes.

I'm still on the fence in all of this. I need to see something that makes me believe.

Even as a bear, I don't view FX-322 and Lenire similarly at all. The former met an obvious roadblock in scientific breakthrough. The latter is not the way of the future.

 

[Diesel]

Ok guys... you know the rules... mention my name 3 times in a page and I re-appear...

I haven't read much more back than the past few pages, and don't plan to... But I'd like to make a comment to all those established Tinnitus Talk readers here that have recently chimed after the Phase 2A flop that have been great about sharing their finger-wagging, told-ya-so's, accusations of bargaining, and 'goal-post-moving.'

What I see with @FGG, @Zugzug, @Aaron91, @100Hz and several others posting here, is what I see regularly in my profession with colleagues in a technical role who are engineers, programmers, data analysts, etc... They're assimilating new evidence to more clearly understand the endpoints to the FX-322 "Project."

A lot of new information was learned in the past week, good and bad... some want to understand deeply what that means for the drug and the expectations. In some cases, that means re-assessing what the Minimum Viable Product will end up being, if at all.

Anyway, have to run to a meeting... but I will follow-up with a few thoughts in the IHC thing, and an opinion on where Frequency Therapeutics should go next with the trials.

 

[Philip83]

There was a girl on here that claimed Lenire completely cured her tinnitus. This is the nature of anecdotes.

I'm still on the fence in all of this. I need to see something that makes me believe.

Oh ok, I must have missed her. But yeah, I'm also on the fence at this point.

 

[attheedgeofscience]

Look at the dates and then look at the difference at various frequencies. This could be construed as an improvement, but I didn't have a treatment of any sort. I took various vitamins and that's about it.

The example you provide compares two different pieces of equipment (it is quite obvious from the readout that the testing was done in different places). This is a separate case.

It's because the test itself is not accurate enough to be certain within that window. It's the standard +- margin of error. Audiologists do not pay attention to jumps of this magnitude because they are meaningless. Have a look at my post above.

There's no other way I can view this. I need to see hard data that proves beyond doubt that FX-322 is doing something inside the ear.

Even if there is a margin of error of ±10 dB, testing done using the same equipment will still have the capability of demonstrating an improvement within the margin of error (provided enough data points are collected). Suppose a person gets a treatment such as FX-322 and experience a threshold shift – that improvement will be picked up by audiometry as a set of data points distributed around a new average:

The chance of not demonstrating an improvement (when in fact there was one) is indicated by the four red "X"-marks. The more data points you have (from the combined number of patients in a trial) makes it increasingly unlikely that everyone would end up scoring red "X"-marks in a situation where the treatment worked. It's similar to flipping a coin and expecting a head (vs. tails). In a one toss scenario, the probability of heads is 1/2. Expecting 4 consecutive heads is (1/2)^4 = 1/16 = 6.25%. The chance of 10 consecutive heads = 0,1%. The probability of landing a specific scenario when there are many data points collected quickly moves towards zero.

I'll leave my own two before/after diagrams that actually were done using the same testing equipment and environment 2 months apart (the improvement of 25 dB at 8 kHz was not a coincidence...):

 

[FGG]

I guess, hypothetically, this might sound obvious to the point of stupid, but I feel good about this drug if there was a way to safely achieve some sort of slow-release exposure. This sounds so easy, but it's not because the cochlea is so small and delicate. Safety (rightfully so) needs to be prioritized. Any method that leads to inflating the perilymph with the gel risks are sorts of pressure problems. Even harder in vivo.

Otonomy has a slow release gel. It's very doable. But considering Otonomy has their own hair cell drug in pre-clinical, I doubt they would license theirs, so Frequency Therapeutics would have to develop their own slow release gel.

Regardless, I think monthly injections (for instance) would solve the pressure problem at least.

 

[serendipity1996]

In culture, they grew equal amounts of both in histology at the end of study. Those are very different conditions, though. And it's possible at day 1, day 2, day 3, etc they skewed IHC first but at the end of the study, it was equivalent.

Maybe that's why they focused on clarity also (IHCs)?

I think there may be a weaker effect on OHCs in vivo also for sure (they have way less LGR5+ cells around them in vivo for one) so even single pass in vivo, assuming intact IHCs, there is likely going to be a less robust effect with one dose.

Hypothetically, multi dosing would be the way to tackle that but there needs to be a bigger interval between doses obviously.

I should add that I don't think Frequency Therapeutics should chase this without yet knowing the best interval. I think they should stick to single injection and find a way to ensure better accuracy with word score baselines and worry about multi dosing later.

Ideally, a second Phase 2 would include a more severe group with longer term genuinely depressed baseline word score results.

This is interesting - regarding the relationship between IHCs and LGR5+ cells, does this mean that each IHC has more than 1 corresponding LGR5+ progenitor cell? I'm just going over the Tinnitus Talk Podcast transcript with Carl LeBel again and he states that "Whatever is missing [either OHCs or IHCs], that's how we believe it's sort of programmed, because it tends to be a 1:1 relationship, every hair cell has their sort of partner progenitor cell." But we know that IHCs have more LGR5+ cells surrounding them. I may be completely misinterpreting this.

 

[Ed209]

One trial was bad with biased results that can't be trusted...

Keep your shares, Jack. There's no way of knowing how this will all turn out, and although I may come across like a negative Nancy on here, I am completely neutral and only motivated by what can be proven.

If Phase 2a had shown good/promising results, I would have been cartwheeling around my living room along with everyone else.

I think the blame for any sabotage has to lie with Frequency Therapeutics. They must have known it was a possibility to fake the results if that is indeed what happened.

 

[Zugzug]

Ok guys... you know the rules... mention my name 3 times in a page and I re-appear...

I haven't read much more back than the past few pages, and don't plan to... But I'd like to make a comment to all those established Tinnitus Talk readers here that have recently chimed after the Phase 2A flop that have been great about sharing their finger-wagging, told-ya-so's, accusations of bargaining, and 'goal-post-moving.'

What I see with @FGG, @Zugzug, @Aaron91, @100Hz and several others posting here, is what I see regularly in my profession with colleagues in a technical role who are engineers, programmers, data analysts, etc... They're assimilating new evidence to more clearly understand the endpoints to the FX-322 "Project."

A lot of new information was learned in the past week, good and bad... some want to understand deeply what that means for the drug and the expectations. In some cases, that means re-assessing what the Minimum Viable Product will end up being, if at all.

Anyway, have to run to a meeting... but I will follow-up with a few thoughts in the IHC thing, and an opinion on where Frequency Therapeutics should go next with the trials.

I miss you. Please come back. I'm a big fat bear holding down the fort. I can handle more weight on my back.