Frequency Therapeutics — Hearing Loss Regeneration

[Tau]

More information --> Additional information link

https://www.clarahealth.com/studies/hearing-study

Another thing

Exclusion Criteria: Evidence of or previous diagnosis of auditory neuropathy, traumatic brain injury, "central" hearing loss, or "genetic hearing loss".

Is that not incredibly vague? How can you even confirm if you have genetic hearing loss? Pretty much all of us have probably been exposed to loud music/noise, probably certain drugs, or just the effect of aging on hearing.

Interesting that auditory neuropathy is a criterion for exclusion; I thought the drug ideally would regrow IHCs which would then reconnect to the SGNs, thus fixing synaptopathy (one of the subtypes of auditory neuropathy).

 

[Chad Lawton]

in light of a rigorous Phase II evaluation of almost 100 people in which the drug showed no signal - no difference from placebo.

You're correct it showed no benefit over placebo but also remember that the placebo group showed a positive response never before documented in history.

For example, one placebo subject had 28 words correct at baseline and 47 words correct at day 90. When comparing the drug group versus the placebo group, they couldn't tell them apart; which tells us the drug group also saw similar improvements.

It then boils down to the question of which is more likely:

The drug group had a positive response but the trial was designed poorly and also allowed the placebo group to respond to an equal degree.

OR

FX-322 has no effect and sugar water injections to the middle ear improve hearing to a degree never before documented in history.

 

[Street Novelist]

New candidate = New / Reformulated drug.

I'm confused. So, they are rolling out a brand new drug, separate from FX-322?

 

[Diesel]

The Phase I results have been consistently overblown in this thread. Calling a handful of people "super responders" who appeared to do well in an initial safety test is meaningless in light of a rigorous Phase II evaluation of almost 100 people in which the drug showed no signal - no difference from placebo.

Actually, if you had been reading the PR from Frequency Therapeutics, the reason the Phase 2 failed wasn't because the drug group showed NO signal. It was that the placebo group ALSO improved, which made them indistinguishable from the drug group who also showed improvement. This unexpected improvement from the placebo group was not what had been seen in prior validated trials.

When you miss this detail: that placebo improved AND drug improved in Phase 2A, it leads to mis-information, and emotional response about the drug and firm's position.

 

[Diesel]

I'm confused. So, they are rolling out a brand new drug, separate from FX-322?

We'll find out. The way that I read it, they are planning to discuss a new development / improved version of FX-322.

 

[Street Novelist]

We'll find out. The way that I read it, they are planning to discuss a new development / improved version of FX-322.

If they are rolling out a new version of FX-322, I don't know why anyone would want to sign up for their current trial.

 

[Jack V]

You're correct it showed no benefit over placebo but also remember that the placebo group showed a positive response never before documented in history.

For example, one placebo subject had 28 words correct at baseline and 47 words correct at day 90. When comparing the drug group versus the placebo group, they couldn't tell them apart; which tells us the drug group also saw similar improvements.

It then boils down to the question of which is more likely:

The drug group had a positive response but the trial was designed poorly and also allowed the placebo group to respond to an equal degree.

OR

FX-322 has no effect and sugar water injections to the middle ear improve hearing to a degree never before documented in history.

Because bias, and the word score boost attributed to bias, was equally distributed between participants who received the drug and participants who received the placebo, if the drug worked, the group that received the drug would still score higher than the group that didn't because their scores would combine the bias boost with an actual drug boost.

In other words, let's say the boost from bias, or poor design, or lying, is X. And let's say the boost from the drug is Y.

In the trial, X is evenly distributed between drug recipients and placebo recipients.

If the drug worked, the group that got the drug would score even higher, X + Y, because they would get a boost from the drug on top of the boost from bias. But that didn't happen. Everyone showed the same boost, the boost from poor trial design, bias, lying, however you describe it, with no advantage for participants who received the drug.

Therefore, it doesn't really boil down to your two options because they don't take into account the fact that no one knew which group they were in. Poor trial design boosted everyone, and what we're left with is a drug that failed to produce a signal on top of that.

 

[Jack V]

Actually, if you had been reading the PR from Frequency Therapeutics, the reason the Phase 2 failed wasn't because the drug group showed NO signal. It was that the placebo group ALSO improved, which made them indistinguishable from the drug group who also showed improvement. This unexpected improvement from the placebo group was not what had been seen in prior validated trials.

When you miss this detail: that placebo improved AND drug improved in Phase 2A, it leads to mis-information, and emotional response about the drug and firm's position.

What you describe (what happened) is exactly a drug showing no signal at all.

If there's no advantage for the group receiving the drug above and beyond the bias boost impacting everyone, the drug has shown no signal.

 

[tommyd87]

What you describe (what happened) is exactly a drug showing no signal at all.

If there's no advantage for the group receiving the drug above and beyond the bias boost impacting everyone, the drug has shown no signal at all.

So if no one benefitted from the medicine then, explain why those who received it subsequently demonstrated improvement?

I think that @Chad Lawton summed things up quite well with his comment.

 

[UHPTS]

Congratulations @Jack V, you are the 20th person to start this subject all over again! Yeah.

 

[Diesel]

If they are rolling out a new version of FX-322, I don't know why anyone would want to sign up for their current trial.

They believe the drug can still provide a benefit to a specific population. The new candidate could be years away, and require a whole new series of trials. Therefore, it would be beneficial to the business and patient population to have a drug that works okay for a small group, than wait many many more years for one that works better for a larger group.

 

[Diesel]

What you describe (what happened) is exactly a drug showing no signal at all.

If there's no advantage for the group receiving the drug above and beyond the bias boost impacting everyone, the drug has shown no signal.

This has been discussed so many times. If that is the case, then how would we explain in the Phase 2A having the placebo group see improvements AND the drug group see improvements. While in the other Phase 1/2 and 1b, the placebo group DID NOT see improvements, but the drug group DID.

This points to a trial design problem, not a drug problem. Hence the Phase 2B that is active and recruiting right now.

 

[Chad Lawton]

This has been discussed so many times. If that is the case, then how would we explain in the Phase 2A having the placebo group see improvements AND the drug group see improvements. While in the other Phase 1/2 and 1b, the placebo group DID NOT see improvements, but the drug group DID.

This points to a trial design problem, not a drug problem. Hence the Phase 2B that is active and recruiting right now.

Agreed. If the improvements we have been seeing were one giant placebo effect across all the trials, regardless of if the drug works or not, you would expect to see about 33% of patients respond in the presbycusis trial but no one responded in either the drug arm or placebo arm.

If there's no advantage for the group receiving the drug above and beyond the bias boost impacting everyone

But if the bias is in the form of some subjects lying out of desperation to get into the trial, that is not a bias boost that is impacting everyone.

 

[Jack V]

Congratulations @Jack V, you are the 20th person to start this subject all over again! Yeah.

Thread's like a car, bro. Got to start it up from time to time or the battery dies.

 

[Jack V]

So if no one benefitted from the medicine then, explain why those who received it subsequently demonstrated improvement?

I think that @Chad Lawton summed things up quite well with his comment.

There's a great deal of conjecture in this thread about what that "improvement" actually was, and I'm not sure there's anything productive about diving down that rabbit hole again.

Drug trials often show early promise only to flame out in later, more rigorous trials. That's where we are with FX-322. It showed early promise and flamed out in its most rigorous, definitive study.

Hopefully - hopefully - this failure is simply a stepping stone to future success.

 

[Jack V]

This has been discussed so many times. If that is the case, then how would we explain in the Phase 2A having the placebo group see improvements AND the drug group see improvements. While in the other Phase 1/2 and 1b, the placebo group DID NOT see improvements, but the drug group DID.

Phase 2A drug and placebo groups saw improvements, and the same improvements, because they were both equally benefiting from the same flawed trial design. If the drug worked, you would expect to see improvements above and beyond the improvement experienced by everyone. It's the fact that everyone experienced the same improvement that is so damning.

There are other explanations why a handful of participants in early trials seemed to have demonstrated improvements, some we might guess at, some we might not, but that becomes irrelevant in light of a larger, more rigorous study.

If there was something promising demonstrated in early trials with a handful people, something real, let's hope they discover and develop what that was.

 

[Diesel]

Phase 2A drug and placebo groups saw improvements, and the same improvements, because they were both equally benefiting from the same flawed trial design. If the drug worked, you would expect to see improvements above and beyond the improvement experienced by everyone. It's the fact that everyone experienced the same improvement that is so damning.

So why are they doing a Phase 2B with the same drug and basically the same inclusion/exclusion criteria? Why would they spend the resources on this trial if the drug doesn't work?

You seem confident on the subject, I'd like to know the reason?

 

[Jack V]

But if the bias is in the form of some subjects lying out of desperation to get into the trial, that is not a bias boost that is impacting everyone.

It impacts the whole study. After all, the liars weren't just put in the placebo cohort, they're also in the drug cohort. Therefore, if the drug worked, the liars get doubly boosted: whatever boost they get from the drug on top of the boost they get from the lie. But that didn't happen. There's only an even increase across all groups, and no signal from the drug. No pop, even among liars receiving FX-322 (which you would expect if it worked).

 

[Jack V]

So why are they doing a Phase 2B with the same drug and basically the same inclusion/exclusion criteria? Why would they spend the resources on this trial if the drug doesn't work?

You seem confident on the subject, I'd like to know the reason?

I have no idea why they are doing a Phase 2B trial because I don't know what they know. Maybe they've figured something out and are on the verge of a breakthrough. Maybe they're posturing for their investors. Hopefully the former, not the latter.

 

[Diesel]

I have no idea why they are doing a Phase 2B trial because I don't know what they know. Maybe they've figured something out and are on the verge of a breakthrough. Maybe they're posturing for their investors. Hopefully the former, not the latter.

Ok. It's the same exact drug, delivered the same exact way to basically the same class of patients.

The differences are 1 dose, a 1:1 drug-placebo group size, and the addition of lead-in tests to reduce baseline inconsistencies.

The drug is unchanged. All of those differences point to trial design.

What am I missing?

 

[Sunshine007]

Because bias, and the word score boost attributed to bias, was equally distributed between participants who received the drug and participants who received the placebo, if the drug worked, the group that received the drug would still score higher than the group that didn't because their scores would combine the bias boost with an actual drug boost.

In other words, let's say the boost from bias, or poor design, or lying, is X. And let's say the boost from the drug is Y.

In the trial, X is evenly distributed between drug recipients and placebo recipients.

If the drug worked, the group that got the drug would score even higher, X + Y, because they would get a boost from the drug on top of the boost from bias. But that didn't happen. Everyone showed the same boost, the boost from poor trial design, bias, lying, however you describe it, with no advantage for participants who received the drug.

Therefore, it doesn't really boil down to your two options because they don't take into account the fact that no one knew which group they were in. Poor trial design boosted everyone, and what we're left with is a drug that failed to produce a signal on top of that.

One issue with the X+Y argument is that there might be a ceiling effect to X that dwarfs Y and you don't quite have the candidate profile to observe Y. Let us assume people with true scores of 45 whose baseline was established at 25, we are not going to see a 10 word increase that might have been observed had it been a true score of 25. We should not expect to see a 10 word increase on top of the 45 given the past responder data. Even if we have the true 25s move to 30/35 it will not appear meaningful compares to the explosive jump from 25 to 45.

That we did not see an effect is a fact the reasons on the why range from the drug being a dud to flawed trial design and lawn effect.

 

[d'Wooluf]

I suppose you can draw the same conclusion as if your grandma was not able to have children, then your mother was not able to have children and now it's you in the same situation, well this is clearly genetic. The same goes for hearing. If your grandma was deaf, ...

There's a bit of a problem with your analogy

 

[UHPTS]

There's a bit of a problem with your analogy

Where?

 

[d'Wooluf]

Where?

If your grandma was unable to have children she couldn't be your grandma? Maybe I'm missing something...

Anyway, did anyone else notice that Frequency Therapeutics are now considering speech understanding as the sole measure of efficacy for FX-322. So we can finally stop speculating about how they're going to get their drug all the way through the cochlea. It doesn't matter any more!

 

[sensualmosquito]

Actually, if you had been reading the PR from Frequency Therapeutics, the reason the Phase 2 failed wasn't because the drug group showed NO signal. It was that the placebo group ALSO improved, which made them indistinguishable from the drug group who also showed improvement. This unexpected improvement from the placebo group was not what had been seen in prior validated trials.

When you miss this detail: that placebo improved AND drug improved in Phase 2A, it leads to mis-information, and emotional response about the drug and firm's position.

I appreciate your input here, as you break things down in a less emotional light. With so many of us (particularly on this website) emotionally invested in a potential solution to our problems it is only natural to take a side one way or another, to believe it's perfect or that it will never work and never will. I, of course, hope that it works very well as I also have an emotional investment in this working. However, I also understand that this field is very new, and many unknown variables at play, and this drug may not work as intended or as well as were all hoping. Or, maybe it will, time will tell.

I am in some ways lucky that my tinnitus is moderate, not severe. My right ear may sound like a broken microphone but at least I have my left ear. I can wait years upon years for something to come out (provided my situation doesn't deteriorate significantly) while perhaps some of us are desperate for freedom from this terrible affliction.

I noticed you take the known information and look at it in a systematic way which I appreciate. We all just need to take a deep breath, and do the best we can given our situations, as difficult or seemingly impossible as that may be.

 

[tommyd87]

If your grandma was unable to have children she couldn't be your grandma? Maybe I'm missing something...

Anyway, did anyone else notice that Frequency Therapeutics are now considering speech understanding as the sole measure of efficacy for FX-322. So we can finally stop speculating about how they're going to get their drug all the way through the cochlea. It doesn't matter any more!

Why would that stop speculation about how they can get the medicine the whole way through the cochlea? Can't improve one's understanding of speech if this is not doable...

 

[d'Wooluf]

Why would that stop speculation about how they can get the medicine the whole way through the cochlea? Can't improve one's understanding of speech if this is not doable...

It won't. Ninety percent of this thread is pure speculation based on almost nothing. My comment was mostly meant as tongue-in-cheek. But seriously, the pages and pages we spent discussion the minutiae of cochlea drug delivery because we all thought thresholds were important. Now it's just about improving speech understanding. Presumably that involves improving at least some aspect of hearing. Exactly what aspect? It's kind of a black box at this point.

 

[RB2014]

If your grandma was unable to have children she couldn't be your grandma? Maybe I'm missing something...

Anyway, did anyone else notice that Frequency Therapeutics are now considering speech understanding as the sole measure of efficacy for FX-322. So we can finally stop speculating about how they're going to get their drug all the way through the cochlea. It doesn't matter any more!

This makes sense then. They are going to keep going with the existing formulation and see if they can get it approved as a speech understanding drug. This would allow them to start making money to keep the company going and continue research.

The new drug candidate could be what they have developed after additional research and information received from the existing trials. So there is still hope that they will get something out there that could help with hearing loss.

The concerning part is that the announcement diydnt even dent the stock price, so people are now skeptical that they have developed something that will truly work. It also seems like they can't issue additional stock to keep the company running to continue the research into the new formulation as their stock price is still declining.

 

[Diesel]

This makes sense then. They are going to keep going with the existing formulation and see if they can get it approved as a speech understanding drug. This would allow them to start making money to keep the company going and continue research.

The new drug candidate could be what they have developed after additional research and information received from the existing trials. So there is still hope that they will get something out there that could help with hearing loss.

The concerning part is that the announcement diydnt even dent the stock price, so people are now skeptical that they have developed something that will truly work. It also seems like they can't issue additional stock to keep the company running to continue the research into the new formulation as their stock price is still declining.

You're on the money with the strategy in the first 2 paragraphs.

As far as stock price. It's not live or die for them based on price. They have $200MM in the bank to keep them operating through 2023. They also have next to no debt, so that's an option if they really need to fund operations. My guess is that after the Phase 2A debacle, investors are looking for tangible positive outcomes: IE: trials that show improvements. Everything else is just talk now.

 

[tommyd87]

This makes sense then. They are going to keep going with the existing formulation and see if they can get it approved as a speech understanding drug. This would allow them to start making money to keep the company going and continue research.

The new drug candidate could be what they have developed after additional research and information received from the existing trials. So there is still hope that they will get something out there that could help with hearing loss.

The concerning part is that the announcement diydnt even dent the stock price, so people are now skeptical that they have developed something that will truly work. It also seems like they can't issue additional stock to keep the company running to continue the research into the new formulation as their stock price is still declining.

Even if it is developed as a speech understanding drug, this is still helping with hearing loss even if there is no improvement on the audiogram. One such argument is that it is triggering the inner hair cells which deal with this.