Frequency Therapeutics — Hearing Loss Regeneration

[kiki]

I hate to state a truism here but, failure is part of success.

I also think that the writing was on the wall the minute they started looking to hire a scientist to help developing a new delivery method/hydrogel.

The positive is that they'll be able to learn and design both better studies and delivery methods. The negative is the process will take longer than any of us want it to take.

I don't often comment here because I don't have much to offer to the conversation, but I give this thread a quick read everyday and I am very thankful for everyone's contributions. I have learned a lot and over this past year and I've learned to cope much better with my tinnitus largely because of Tinnitus Talk and this thread in particular has served as a wonderful distraction. If we were all standing in line waiting for a hearing/tinnitus drug, I'd let all of you get in line in front of me.

I think so too.

Failure is failure.

However, if we review it from the ground up, I think there is a possibility of a revival.

There are many things to do, such as improving the delivery method and gel, and importantly, reviewing the concentration.

Drugs that are almost ineffective are almost ineffective no matter how many times you take them.

It must be a drug that has a sufficient dB-improving effect that can overwhelm erroneous data in a single dose.

Can they do it?

If I don't think so, I will get depressed.

 

[Zugzug]

Phase 1 indeed had non-responders in both the placebo group and the treatment group. The reason many of us were confident was because we still saw gains in the moderate/severe group. However, on reflection, the bears were right. You can't ignore the fact that there were far more potential responders in the treatment group than the placebo group. The argument being, the placebo group didn't respond the first time round to placebo because their baseline was much higher relatively speaking to the treatment group.

To put it simply: the hearing of the placebo patients was far better overall than of those who received FX-322.

Notice how there is only one circle to the left of the red line, whereas there are 6 diamonds. Many of us here didn't consider that a big deal, but the reality is that it was a very small sample size. It's possible if there were 5 more circles to the left of the red line, we would see some of them improve.

View attachment 44210

Here's the thing though. We can beat it to death and factor in a lot of bear assumptions. It still is the case that if a perfect robot took a WR test twice, there shouldn't be a doubling. It certainly shouldn't happen to multiple ears.

There is that one treated ear that didn't do much of anything. We chalked this up to short duration. Something is fishy. The probabilities of all of those 3 high improvements is extremely low. But conditioned on those 3 high improvements occurring, the probability that the 1 ear didn't do much of anything is also low.

I concede that the drug failed and it's not all test design. But something just feels off. In the Thornton and Raffin paper, all of the data was truly unbiased because there wasn't enrollment for a drug to work. This is why the data looks more robotic and resembles a Binomial Distribution.

Same in the Wilson and McArdle paper, where they looked at WIN stability in veterans.

The delivery is garbage. I thought it may be suboptimal, but I didn't expect garbage.

 

[Tezcatlipoca]

Clearly they're thinking about tweaking things. They hired a drug delivery expert and after this I'm sure they will make their trials even more secure. I think they will also try to reformulate.

 

[spacehunter]

So, who again ridiculed my opinions? Please report back here again.

And that may sound esoteric when I posted yesterday that I have an inspiration, something is coming up...

Yes, yesterday there was a very important 50/50 decision in the private sector (which I could not influence) and it was negative. I had a feeling that this is related to something negative that occurs almost at the same time. Just this bad FX-322 news.

I tied my only hope of living a normal life to the FX-322.

I guess most of us had a hard time believing you since your statements have been very enigmatic and without (solid) proof. May I ask since now all the dust has settled what your sources for your guess have been? Did you kind of had solid proof or was it all just a very sophisticated guess?

Anyways, hope for you and the rest of us that some drug will work in the end. Maybe SPI-1005 or NHPN-1010 will show some unexpected positive results.

Greetings from a fellow German.

 

[FGG]

Isn't this similar to bimodal stimulation?

Not at all. This is talking about implanting something with cochlear implants to give sound a more vibrational quality presumably to give it a little more natural sound.

 

[patorjk]

Just finished read through the thread. After today I may take a break from this site, this news is just a little too much to handle.

I was out on an early morning hike when I saw the email from Frequency Therapeutics. I was initially excited - I figured pre-market news had to be good news. It was disorienting when I realized that what I was reading was bad news. I felt completely numb. There's nothing else on the horizon. We'll be waiting 5-10 years for OTO-413, and even that may not work.

Leading up to this I was actually having dreams about FX-322. In one dream I went down to Mexico to get a shot. When I woke up I was a little sad, but I was at least comforted by the fact that it was on its way. Now there is no such comfort.

 

[Zugzug]

Why are people with blind pessimism taking victory laps on a support forum? Did you understand the situation better than the bulls? I have no problem with giving smart bears their due. But to not even look at the data and formulate opinions other than "I'm depressed and hate the world" is not really some big milestone.

@Toby1972 I was being serious when I said I enjoyed your contributions. Drink a beer with your victory lap. I hope it helps your tinnitus for a few hours.

 

[Jurger]

The really troubling thing is that even in the new single dose trial they also published today and which wasn't compromised, the improvement in WR scores (which weren't that great) can't be related to improvement in extended high frequency scores.

That seems to suggest that in its current form, this drug won't be able to affect audiogram scores at all.

 

[Kendra]

I think the next/first step in hearing restoration really has to be figuring out an efficient and safe way to deliver drugs deep into the cochlea. At least reaching the mid ranges. I think only then will drugs (at least non oral) be able to work. It could be that FX-322 would work if able to be delivered into the cochlea instead of sitting outside of it hoping some will get through.

 

[spacehunter]

I still have the feeling we have not consolidated on a clear statement what to make out of the results of the Phase 2.

Agreed: it was a disaster compared to our lowest expectations. But what does that mean? Is the whole concept of the drug failed? Is the delivery of the drug failed (even more than we agreed on before the results came out)? Is only the study design failed due to bad recruiting/lying applicants?

Besides what to make out of the study is it at least clear whether there will be a immediate Phase 3 after this Phase 2?

 

[Zugzug]

I still have the feeling we have not consolidated on a clear statement what to make out of the results of the Phase 2.

Agreed: it was a disaster compared to our lowest expectations. But what does that mean? Is the whole concept of the drug failed? Is the delivery of the drug failed (even more than we agreed on before the results came out)? Is only the study design failed due to bad recruiting/lying applicants?

Besides what to make out of the study is it at least clear whether there will be a immediate Phase 3 after this Phase 2?

The very bottom line is hard to understand (unless there was something in the news conference that I can't listen to). I am really interested in all of their data analysis methods. Could be a total flop or could be that at least one injections is somewhat encouraging.

 

[FGG]

I just can't figure out how you can *double* word scores in Phase 1 and have all the pre-clinical findings. Based on historical data that seems literally impossible.

Maybe in vivo conditions preferentially draws binding to IHCs to a great degree. IHC function is linked to both speech and WIN and isn't measured on audiograms.

 

[Zugzug]

I just can't figure out how you can *double* word scores in Phase 1 and have all the pre-clinical findings. Based on historical data that seems literally impossible.

Maybe in vivo conditions preferentially draws binding to IHCs to a great degree. IHC function is linked to both speech and WIN and isn't measured on audiograms.

You and me both.

 

[Paulmanlike]

The really troubling thing is that even in the new single dose trial they also published today and which wasn't compromised, the improvement in WR scores (which weren't that great) can't be related to improvement in extended high frequency scores.

That seems to suggest that in its current form, this drug won't be able to affect audiogram scores at all.

1000% agree. The reality is that it doesn't really increase WR scores.

I questioned this a few months ago when their Phase 1b was released.

The company is worthless (at this moment in time).

It's time for us to let go off Frequency Therapeutics and the whole PCA for hearing loss and move on.

Something we should be used to by now.

 

[Street Novelist]

I don't know what all of this means. Is Phase 3 still going to start early next year? Or are they going to change the delivery method first?

Where do we go from here? Just wait until May/June when they release the full results?

 

[Zugzug]

Hey @Aaron91 (and whoever else interacts with the bears):

This group would really benefit from having more analytical bears.

@Ed209 seems to be a good one, but has been, unfortunately, suffering with COVID-19. I'm not interested in blind bears who are too lazy to look into it or whatever. I mean legit, analytical, bears that can challenge my arguments.

I'm a mathematician by trade, not a statistician. The problem is that I am capable of studying the data, but I have a lack of experience in understanding the human natures involved in controlled experiments. Even though we don't have evidence, the hypothesis that people consciously or subconsciously exaggerated their hearing to get in is something that literally never crossed my mind. If a bear would have pointed it out, I probably would have shot it down, to be fair and honest though.

I'm not surprised at all that multiple dosing wasn't a raging success, as I predicted as such. I am simply blown away that the people in the Phase 1 study had sky rocketed word scores by chance. I read the Thornton and Raffin paper carefully, and challenged every assumption. It's practically impossible for me to believe that I obtained even an approximation of those p-values by chance. There is something about study design that I just don't understand.

 

[Dirtworks]

Very discouraging. Can someone please clear a couple of things up for me?

I thought I recalled somewhere seeing an of image showing FX-322 before and after cochlear hair cells. Is there even a way to image human cochlear hair cells?

Am I correct in stating that the majority of hearing loss and tinnitus is due to a lack of or damage to cochlear hair cells?

If the above is true, it would certainly seem that they are researching in the right area.

What other research looks promising? I need some hope please.

 

[Matchbox]

Obsession with audiograms is a large part of the issue, it's an archaic test.

 

[ActorFred]

Although the results are incredibly disappointing, I'm weirdly still not giving up on hearing restoration as a whole. It does seem like something to be eventually cracked.

Still not quite giving up on Frequency Therapeutics, it has some great names to the company aka Bob Langer

 

[Aaron91]

I'm starting to cool off and forcing myself to think more critically here.

I think I'm going to ignore the biased sample population argument for now because clearly that wasn't the case in the supplementary Phase 1b (111) study as those patients had been made known about the same WR score criteria ahead of time. That trial went on to see stat sig improvements that were not observed in the Phase 2 trial. So I think that's a red herring and we should focus our attention elsewhere, although I don't deny that trial design is critical moving forward.

I posted this some time ago, but I do remember reading somewhere that the cochlea, being a very delicate membrane, has physical limitations to what can be injected into it before it breaks. Chris Loose also said today that they hadn't trialed multiple doses in animals before because the cochlea would be overwhelmed/break. I'm wondering then whether that analogy - that when you re-seed the lawn you must stay off the grass - does carry some weight. Because regardless of whether someone received 1 dose or 4 doses, EVERYONE received 4 doses of the carrier gel, regardless of whether it was carrying the small molecules or not. I also recall reading in Will McLean's paper that a colony took 12 days to form, which begs the question: why the hell did they only give it one week in between each dose? Even two weeks would be pushing it.

Is it possible, for example, that 4 doses of FX-322 was actually equivalent to 1 dose, because each previous dose washed away the other? On this point, do we have any historical data to glean from regarding multiple dosing for any ear-related condition? For example, is there a study out there that looked at multiple weekly injections of intratympanic steroids against placebo? I'm pretty sure this is a discussion some of us had over on the Otonomy thread about Meniere's and I don't remember finding anything other than maybe one study. In any case, if the lawn analogy is true, this could explain why they didn't see differences between 1x, x2 and x4 FX-322 groups. Unfortunately, this still doesn't explain the lack of difference between placebo within each category. The only explanation we have for that is the failed trial design.

So we have some plausible explanations given the above, but how does one still reconcile this with the failed EHF audiogram in the Phase 1 study which showed no placebo effect? The only explanation we seem to have, as @FGG and @Diesel have pointed out, is that there is preferential IHC regeneration over OHCs in vivo - the idea being that IHC regeneration will not appear on an audiogram. But again, if IHCs restore clarity, why have we not found statistically significant results in the WIN scores? The only answer again is design error and a biased sample of patients.

To put things simply, for this Phase 2 outcome to have happened, it would have taken a catalogue of errors and unique set of circumstances. So I'm going from "this drug doesn't work" to more of a "perfect storm" take on this. Is it possible this was the perfect storm? We just don't know yet, but obviously things don't look too good right now.

This may seem like a tangent, but I have an interest in air crash investigations. What you find in almost all cases of air crashes is that there is almost never just one cause. You find that there are a catalogue of errors, one after the other, usually combined with a unique set of circumstances, that all together lead to the crash. Perhaps this is one of those occasions.

 

[FGG]

Obsession with audiograms is a large part of the issue, it's an archaic test.

Here is another weird thought, what if is more scattered at the high end. I.e. drugs hit 13750 Hz, 15780 Hz etc.

Would the hearing handicap index be more useful for that in the full readout in that case? Of course you do rely on patient feedback there too...

 

[HootOwl]

Is there even a way to image human cochlear hair cells?

Not in vivo. If we had that kind of diagnostic tool we wouldn't be working solely around audiograms.

 

[FGG]

Why does it still sound like they are proceeding to the next phase in the press releases too?

 

[Jurger]

Obsession with audiograms is a large part of the issue, it's an archaic test.

Except that it isn't. Ask anyone with significant hearing loss. That's not to say that a perfect audiogram means that person has perfect hearing. But improvement on the audiogram as a result of this drug would've been huge.

 

[Tezcatlipoca]

I'm starting to cool off and forcing myself to think more critically here.

I think I'm going to ignore the biased sample population argument for now because clearly that wasn't the case in the supplementary Phase 1b (111) study as those patients had made known about the same WR score criteria ahead of time. That trial went on to see stat sig improvements that were not observed in the Phase 2 trial. So I think that's a red herring and we should focus our attention elsewhere, although I don't deny that trial design is critical moving forward.

I posted this some time ago, but I do remember reading somewhere that the cochlea, being a very delicate membrane, has physical limitations to what can be injected into it before it breaks. Chris Loose also said today that they hadn't trialed multiple doses in animals before because the cochlea would be overwhelmed/break. I'm wondering then whether that analogy - that when you re-seed the lawn you must stay off the grass - does carry some weight. Because regardless of whether someone received 1 dose or 4 doses, EVERYONE received 4 doses of the carrier gel, regardless of whether it was carrying the small molecules or not. I also recall reading in Will McLean's paper that a colony took 12 days to form, which begs the question: why the hell did they only give it one week in between each dose? Even two weeks would be pushing it.

Is it possible, for example, that 4 doses of FX-322 was actually equivalent to 1 dose, because each previous dose washed away the other? On this point, do we have any historical data to glean from regarding multiple dosing for any ear-related condition? For example, is there a study out there that looked at multiple weekly injections of intratympanic steroids against placebo? I'm pretty sure this is a discussion some of us had over on the Otonomy thread about Meniere's and I don't remember finding anything other than maybe one study. In any case, if the lawn analogy is true, this could explain why they didn't see differences between 1x, x2 and x4 FX-322 groups. Unfortunately, this still doesn't explain the lack of difference between placebo within each category. The only explanation we have for that is the failed trial design.

So we have some plausible explanations given the above, but how does one still reconcile this with the failed EHF audiogram in the Phase 1 study which showed no placebo effect? The only explanation we seem to have, as @FGG and @Diesel have pointed out, is that there is preferential IHC regeneration over OHCs in vivo - the idea being that IHC regeneration will not appear on an audiogram. But again, if IHCs restore clarity, why have we not found statistically significant results in the WIN scores? The only answer again is design error and a biased sample of patients.

To put things simply, for this Phase 2 outcome to have happened, it would have taken a catalogue of errors and unique set of circumstances. So I'm going from "this drug doesn't work" to more of a "perfect storm" take on this. Is it possible this was the perfect storm? We just don't know yet, but obviously things don't look too good right now.

This may seem like a tangent, but I have an interest in air crash investigations. What you find in almost all cases of air crashes is that there is almost never just one cause. You find that there are a catalogue of errors, one after the other, usually combined with a unique set of circumstances, that all together lead to the crash. Perhaps this is one of those occasions.

So it takes about two weeks to work but they gave it half the time, that's moronic.

This could explain it.

 

[Diesel]

I'd hate to say it, but I hope there's a chance that someone that got FX-322 in-vivo during the trials dies so that Frequency Therapeutics can harvest their cochleas. I mean... some of these people are 65+ in the ARHL trial...

Not to be morbid... because it's for science.

 

[FGG]

I'm starting to cool off and forcing myself to think more critically here.

I think I'm going to ignore the biased sample population argument for now because clearly that wasn't the case in the supplementary Phase 1b (111) study as those patients had made known about the same WR score criteria ahead of time. That trial went on to see stat sig improvements that were not observed in the Phase 2 trial. So I think that's a red herring and we should focus our attention elsewhere, although I don't deny that trial design is critical moving forward.

I posted this some time ago, but I do remember reading somewhere that the cochlea, being a very delicate membrane, has physical limitations to what can be injected into it before it breaks. Chris Loose also said today that they hadn't trialed multiple doses in animals before because the cochlea would be overwhelmed/break. I'm wondering then whether that analogy - that when you re-seed the lawn you must stay off the grass - does carry some weight. Because regardless of whether someone received 1 dose or 4 doses, EVERYONE received 4 doses of the carrier gel, regardless of whether it was carrying the small molecules or not. I also recall reading in Will McLean's paper that a colony took 12 days to form, which begs the question: why the hell did they only give it one week in between each dose? Even two weeks would be pushing it.

Is it possible, for example, that 4 doses of FX-322 was actually equivalent to 1 dose, because each previous dose washed away the other? On this point, do we have any historical data to glean from regarding multiple dosing for any ear-related condition? For example, is there a study out there that looked at multiple weekly injections of intratympanic steroids against placebo? I'm pretty sure this is a discussion some of us had over on the Otonomy thread about Meniere's and I don't remember finding anything other than maybe one study. In any case, if the lawn analogy is true, this could explain why they didn't see differences between 1x, x2 and x4 FX-322 groups. Unfortunately, this still doesn't explain the lack of difference between placebo within each category. The only explanation we have for that is the failed trial design.

So we have some plausible explanations given the above, but how does one still reconcile this with the failed EHF audiogram in the Phase 1 study which showed no placebo effect? The only explanation we seem to have, as @FGG and @Diesel have pointed out, is that there is preferential IHC regeneration over OHCs in vivo - the idea being that IHC regeneration will not appear on an audiogram. But again, if IHCs restore clarity, why have we not found statistically significant results in the WIN scores? The only answer again is design error and a biased sample of patients.

To put things simply, for this Phase 2 outcome to have happened, it would have taken a catalogue of errors and unique set of circumstances. So I'm going from "this drug doesn't work" to more of a "perfect storm" take on this. Is it possible this was the perfect storm? We just don't know yet, but obviously things don't look too good right now.

This may seem like a tangent, but I have an interest in air crash investigations. What you find in almost all cases of air crashes is that there is almost never just one cause. You find that there are a catalogue of errors, one after the other, usually combined with a unique set of circumstances, that all together lead to the crash. Perhaps this is one of those occasions.

Oh wow. Interesting. You may be on to something. All groups got 4 shots with variable level of placebo. They could have washed away drug before full effect.

But it would also mean repeat injections may have disturbed the lawn too much too otherwise 4 injections should have an effect but that group may need more time.

 

[Brian Newman]

I think we all knew deep down it was too good to be true. We just wanted to have hope.

I wish I was a billionaire. If I had money and resources I could have the cure in a few years.

These companies are all lazy.

I bet if somebody slapped 100 million on the table, they would have the cure in a year.

 

[Jurger]

I'm starting to cool off and forcing myself to think more critically here.

I think I'm going to ignore the biased sample population argument for now because clearly that wasn't the case in the supplementary Phase 1b (111) study as those patients had made known about the same WR score criteria ahead of time. That trial went on to see stat sig improvements that were not observed in the Phase 2 trial. So I think that's a red herring and we should focus our attention elsewhere, although I don't deny that trial design is critical moving forward.

I posted this some time ago, but I do remember reading somewhere that the cochlea, being a very delicate membrane, has physical limitations to what can be injected into it before it breaks. Chris Loose also said today that they hadn't trialed multiple doses in animals before because the cochlea would be overwhelmed/break. I'm wondering then whether that analogy - that when you re-seed the lawn you must stay off the grass - does carry some weight. Because regardless of whether someone received 1 dose or 4 doses, EVERYONE received 4 doses of the carrier gel, regardless of whether it was carrying the small molecules or not. I also recall reading in Will McLean's paper that a colony took 12 days to form, which begs the question: why the hell did they only give it one week in between each dose? Even two weeks would be pushing it.

Is it possible, for example, that 4 doses of FX-322 was actually equivalent to 1 dose, because each previous dose washed away the other? On this point, do we have any historical data to glean from regarding multiple dosing for any ear-related condition? For example, is there a study out there that looked at multiple weekly injections of intratympanic steroids against placebo? I'm pretty sure this is a discussion some of us had over on the Otonomy thread about Meniere's and I don't remember finding anything other than maybe one study. In any case, if the lawn analogy is true, this could explain why they didn't see differences between 1x, x2 and x4 FX-322 groups. Unfortunately, this still doesn't explain the lack of difference between placebo within each category. The only explanation we have for that is the failed trial design.

So we have some plausible explanations given the above, but how does one still reconcile this with the failed EHF audiogram in the Phase 1 study which showed no placebo effect? The only explanation we seem to have, as @FGG and @Diesel have pointed out, is that there is preferential IHC regeneration over OHCs in vivo - the idea being that IHC regeneration will not appear on an audiogram. But again, if IHCs restore clarity, why have we not found statistically significant results in the WIN scores? The only answer again is design error and a biased sample of patients.

To put things simply, for this Phase 2 outcome to have happened, it would have taken a catalogue of errors and unique set of circumstances. So I'm going from "this drug doesn't work" to more of a "perfect storm" take on this. Is it possible this was the perfect storm? We just don't know yet, but obviously things don't look too good right now.

This may seem like a tangent, but I have an interest in air crash investigations. What you find in almost all cases of air crashes is that there is almost never just one cause. You find that there are a catalogue of errors, one after the other, usually combined with a unique set of circumstances, that all together lead to the crash. Perhaps this is one of those occasions.

"that when you re-seed the lawn you must stay off the grass"

They weren't entirely clear on that in their investor conference today. LeBel said something probably happens in the middle ear ear as a result of four injections, and Lucchino said something happens in the ear. If it's a middle ear thing it at the very least means that IT injections aren't as harmless as they made it out to be, but that it could be fixed with intracochlear injections or some other type of direct drug delivery. If it's an inner ear issue, you would have to wait for some time after an injection before you get another shot.

 

[FGG]

I'd hate to say it, but I hope there's a chance that someone that got FX-322 in-vivo during the trials dies so that Frequency Therapeutics can harvest their cochleas. I mean... some of these people are 65+ in the ARHL trial...

Not to be morbid... because it's for science.

If they will take volunteers, I will do this.