Frequency Therapeutics — Hearing Loss Regeneration

[Lucifer]

I refuse to believe that after all the years it took to design FX-322, test it in vitro, and now in vivo, it doesn't work. That would mean either,

a: FX-322 is a failure and Frequency Therapeutics just wasted their time, or

b: the science behind all of this is false and it's not possible to regenerate hearing.

It does work, but only with one dose of FX-322 in Phase 1b trials and it may only work for mild-moderate hearing loss sufferers. They also have age-related hearing loss and severe hearing loss trials to go. If at least age-related hearing loss show meaningful improvements I can see the FDA allowing them to go to the pivotal phase. They can always work out the delivery method after FX-322 is out. They can also get more of a sample of a population and see if people get the same results as in the clinical trial.

They also stated they may run two or more trials at one time so they may test out monthly doses of FX-322 instead to see if monthly doses is enough to stop the steeping on the lawn issue.

 

[Lucifer]

@Gb3, does the positive anecdote consider his hearing loss to be mild, moderate or severe?

 

[wwtsai]

I was in both Phases (1 & 2) of the trial for SPI-1005.

I'm also very curious on how the Phase 1 worked out for you.

 

[FGG]

Having trouble clearing the time to scan through so many posts.

Could someone encapsulate what happened so I can bookmark the post?

I am hoping the Tinnitus Talk Podcast goes over it at least.

It's a lot to parse through but my take:

--Frequency Therapeutics said in Phase 2a all groups improved word scores (including placebo). They attribute this, after reviewing records, to serious discrepancies between historical word scores and the pre-treatment baselines they got. It was widespread enough to include all groups. They suspect social media was used to pool data so people could figure out what was needed but also Frequency Therapeutics themselves publicly announced that they didn't want great word scores to eliminate the ceiling effect from Phase 1.

So, as far as word scores go, someone lied:

1) Phase 1 super responders
2) Frequency Therapeutics
3) The Phase 2a participants (as Frequency Therapeutics has now claimed).

-- The individual data has not been made available and so far the trial is still blinded.

-- As far as EHF audiogram results, there was no significant changes. This is very odd considering the word score changes in Phase 1 especially (unless you think those were the fakers).

Some possibilities here are (if you assume that Frequency Therapeutics isn't a fraud or that Phase 1 participants lied about word scores without the incentive to get into the trial which wasn't a requirement then):

-- People in Phase 2, maybe the same people, artificially depressed their EHF (which most people got right before the trial) to lower their PTA .
-- The drug didn't regrow OHCs but affected some other aspect of hearing (synapses-- unlikely imo, or IHCs, etc). Of these, IHCs actually makes sense embryologically since they develop first. It's not IT injections in general or "cleaning the round window" otherwise IT steroid injections would work chronically.
-- Some other obscure technical problem (e.g., EHF not uniformly calibrated across different centers).

Something else that just occurred to me too is that sudden hearing loss (except for ototoxicity) is less likely to produce as much EHF loss vs age-related hearing loss. Might be an interesting data point from the age-related arm.

-- Historically, you can't double word scores with placebo so I would say that's not happening here (again unless Phase 1 participants lied).

-- The fact that the "super responders" (genuine ones assumed) had minimal audiogram changes leads me to believe that something odd is happening like IHCs are regenerated first. It would actually make sense for people with genuinely terrible word scores to have more IHC loss because most often (except for certain ototoxic drugs, you lose OHCs first and then IHCs). The hypothetical solution to this would be to treat the IHCs first and then follow up with another treatment a bigger interval later (again assuming this is the case).

-- Frequency Therapeutics said rapidly repeating injections actually hurt the efficacy ("you don't walk on a seeded lawn"...) They will continue with single injections only they have said for now. The more doses, the less of an effect.

Personally, I'm most interested in the severe hearing loss group now because 1) they get one injection, 2) they have genuinely awful hearing.

The point has been made that "there couldn't be that many fakers, right?" and if Frequency Therapeutics is seeing it in all groups at a significant level as claimed then yes, there are. If the company is telling the truth. Also, I feel strongly that having a requirement of bad word scores but not severe hearing loss actually preferentially selects for fakers. But the severe hearing loss group should have genuinely bad word scores. So, I await those results the most.

 

[lymebite]

@FGG, when seeding the lawn a single time, and then not walking on it, is it possible for them to use more grass seed? That is, include more of the FX-322 molecules in the single dose of "goop" as people in the thread are calling it?

 

[FGG]

@FGG, when seeding the lawn a single time, and then not walking on it, is it possible for them to use more grass seed? That is, include more of the FX-322 molecules in the single dose of "goop" as people in the thread are calling it?

Maybe different goop (extended release?)

 

[GlennS]

As far as EHF audiogram results, there was no significant changes.

That means that hearing did not in fact improve or that the originally claimed improvement remains the same?

 

[Tezcatlipoca]

Maybe different goop (extended release?)

Extended release is one of Otonomy's specialties I believe.

 

[FGG]

That means that hearing did not in fact improve or that the originally claimed improvement remains the same?

Word score hearing did above a range that can't be reasonably attributed to placebo but no significant audiogram changes at the group level at least (which measure OHCs only).

 

[Tezcatlipoca]

Anyone think there should be an Otonomy + FREQ merger? I think they could do amazing things together.

Word score hearing did above a range that can't be reasonably attributed to placebo but no significant audiogram changes at the group level at least (which measure OHCs only).

Do you think the FDA can take that into account? there was some improvement, even if there weren't significant audiogram changes.

 

[FGG]

Do you think the FDA can take that into account? there was some improvement, even if there weren't significant audiogram changes.

If they could prove the word scores were reliable, yes imo. But how do you do that?

In addition to better trial design, I think they need to figure out why they were seeing the results in Phase 1 that they did (i.e. amazing word score results without corresponding audiogram changes). The assumption was that it must be due to the EHF OHCs, which makes total sense as the drug is concentrated there and it is important for speech in a compensatory way when the lower frequencies are damaged, since there is speech information there.

If unblinded, when they can weed out the "discrepancy cases" especially, they see no EHF effect whatsoever (even mild), then there is some other hearing effect. And before the next trial, they need to figure out what it is. I would guess IHCs since they have more LGR5+ cells around them and develop first in utero.

They have more work to do. This is why I see a repeat of Phase 2 with better design and understanding as likely, personally.

 

[Zugzug]

Word score hearing did above a range that can't be reasonably attributed to placebo but no significant audiogram changes at the group level at least (which measure OHCs only).

So wait. Are we saying patients deflated their scores at screening and at baseline because they were paranoid that they would come off inconsistent? I thought the patients had higher baselines than screens so everyone pushed into the ceiling effect range. Is that incorrect?

 

[Gb3]

@Gb3, does the positive anecdote consider his hearing loss to be mild, moderate or severe?

They were in the Phase 2 study so whatever the inclusion criteria was. I know they had suffered sudden hearing loss.

 

[FGG]

So wait. Are we saying patients deflated their scores at screening and at baseline because they were paranoid that they would come off inconsistent? I thought the patients had higher baselines than screens so everyone pushed into the ceiling effect range. Is that incorrect?

For Phase 2a screenings, you could not have high word scores to get in. They would definitely likely also have low word scores at baseline because I'm not sure the same people were coached on the blinding aspect but the numbers wouldn't have to be an exact match.

 

[andreimatei]

Anyone think there should be an Otonomy + FREQ merger? I think they could do amazing things together.

I think that would indeed be amazing and would help both companies out substantially. Now after each having failed studies and tanked stock prices, joining forces I think would be ideal. Or at the very least, maybe they could license each other's technology?

 

[FGG]

I think that would indeed be amazing and would help both companies out substantially. Now after each having failed studies and tanked stock prices, joining forces I think would be ideal. Or at the very least, maybe they could license each other's technology?

Otonomy have a drug in pre-clinical for hair cell regeneration (OTO-6xx).

There is no way they would do this imo.

 

[Lucifer]

They were in the Phase 2 study so whatever the inclusion criteria was. I know they had suffered sudden hearing loss.

I just checked the criteria and it was mild-moderately severe, so he must have been somewhere between those two.

I wonder what type of sudden hearing loss he had. If he couldn't hear birds before, would that be mild hearing loss?

 

[Zugzug]

For Phase 2a screenings, you could not have high word scores to get in. They would definitely likely also have low word scores at baseline because I'm not sure the same people were coached on the blinding aspect but the numbers wouldn't have to be an exact match.

Wow. So when I outlined to @Aaron91 the game theory as to why it doesn't make sense to fake low at baseline (even if there is incentive to fake at screening), it really is true that human beings could have been that stupid... wow, this just keeps getting worse. I still think it's not that many.

 

[FGG]

Wow. So when I outlined to @Aaron91 the game theory as to why it doesn't make sense to fake low at baseline (even if there is incentive to fake at screening), it really is true that human beings could have been that stupid... wow, this just keeps getting worse. I still think it's not that many.

It's at least enough to be represented in all cohorts and for Frequency Therapeutics to imply it was significant.

Ordinarily, I would say you are right. Surely, most people wouldn't do that but their requirements inadvertently favored people who would (for Phase 2a).

This would be less likely in the severe group, thankfully.

 

[Tezcatlipoca]

I think the severe hearing loss trial will have ideal outcomes, or at least positive enough; all single dose trials have been positive, so why wouldn't this one be?

 

[serendipity1996]

Otonomy have a drug in pre-clinical for hair cell regeneration (OTO-6xx).

There is no way they would do this imo.

Remind me again, do we know anything regarding the method Otonomy will be using for their hair cell drug?

 

[FGG]

Remind me again, do we know anything regarding the method Otonomy will be using for their hair cell drug?

Nope. No info yet. It would be a great thing to ask them though...

 

[Zugzug]

It's at least enough to be represented in all cohorts and for Frequency Therapeutics to imply it was significant.

Ordinarily, I would say you are right. Surely, most people wouldn't do that but their requirements inadvertently favored people who would (for Phase 2a).

This would be less likely in the severe group, thankfully.

In that case, much of my analysis has been off today. All of it was framed from the perspective of both groups started shifted up at baseline (beyond the filter) so both improved together, but the treated group couldn't take off. In other words, everyone behaved normally from baseline to day 90, but not necessarily at screening.

It seems like what really happened is they both improved together, but with artificially low baselines.

As far as motivation to lie at baseline after lying at the screening, is it something along the lines of them being afraid that if they perform different at baseline than screen, it won't stop them from the trial (quadruple blinding), but could impact the passing of the drug after unblinding?

If this is the case, then there is definitely motivation to be consistent from screen to baseline. Although, since people are idiots, they probably didn't consider that they could greatly hurt the drug getting through if they shift up the placebo group (precisely what happened).

 

[FGG]

In that case, much of my analysis has been off today. All of it was framed from the perspective of both groups started shifted up at baseline (beyond the filter) so both improved together, but the treated group couldn't take off. In other words, everyone behaved normally from baseline to day 90, but not necessarily at screening.

It seems like what really happened is they both improved together, but with artificially low baselines.

As far as motivation to lie at baseline after lying at the screening, is it something along the lines of them being afraid that if they perform different at baseline than screen, it won't stop them from the trial (quadruple blinding), but could impact the passing of the drug after unblinding?

If this is the case, then there is definitely motivation to be consistent from screen to baseline. Although, since people are idiots, they probably didn't consider that they could greatly hurt the drug getting through if they shift up the placebo group (precisely what happened).

I think the motivation was less noble than that even. It was "well, I better fake a low baseline too so I don't get kicked out" (not being aware of how the blinding works and only being told via social media how bad the word scores needed to be).

 

[Tezcatlipoca]

In that case, much of my analysis has been off today. All of it was framed from the perspective of both groups started shifted up at baseline (beyond the filter) so both improved together, but the treated group couldn't take off. In other words, everyone behaved normally from baseline to day 90, but not necessarily at screening.

It seems like what really happened is they both improved together, but with artificially low baselines.

As far as motivation to lie at baseline after lying at the screening, is it something along the lines of them being afraid that if they perform different at baseline than screen, it won't stop them from the trial (quadruple blinding), but could impact the passing of the drug after unblinding?

If this is the case, then there is definitely motivation to be consistent from screen to baseline. Although, since people are idiots, they probably didn't consider that they could greatly hurt the drug getting through if they shift up the placebo group (precisely what happened).

Under that assumption it did work but it doesn't appear so at first because some trial participants inflated their baselines and by doing that ruined the "placebo vs drug" comparison of improvement. Is that right?

 

[Zugzug]

Under that assumption it did work but it doesn't appear so at first because some trial participants inflated their baselines and by doing that ruined the "placebo vs drug" comparison of improvement. Is that right?

Now that I understand the issue, there are varying levels of theorizing. Obviously, the big question is "how many cheaters were in the study?"

Then, once you have X cheaters, how were they distributed (drug vs placebo)? Then, how did the individual cheaters happen to behave? Just as a strawman, if the cheaters that landed in the placebo maintained their cheating with low baselines, they will have artificial inflations after treatment. If the cheaters that performed normally at baseline landed in the drug group, they would have a ceiling effect.

Obviously, that's a super bullish way to look at what happened. In my opinion, the most likely situation is that there were a few cheaters, they put very little thought into it, just faked low screens and baselines. At least some landed in the placebo group. Maybe a proportionate number landed in the drug group.

It's very possible that FX-322 is still largely ineffective, with the exception of helping word scores in some super responders.

 

[FGG]

Under that assumption it did work but it doesn't appear so at first because some trial participants inflated their baselines and by doing that ruined the "placebo vs drug" comparison of improvement. Is that right?

If the drug does indeed improve hearing speech but it did not show that in Phase 2a, it's because the Phase 2a group had "inconsistencies" in their numbers, yes vs the Phase 1 participants.

 

[Gb3]

I just checked the criteria and it was mild-moderately severe, so he must have been somewhere between those two.

I wonder what type of sudden hearing loss he had. If he couldn't hear birds before, would that be mild hearing loss?

No, that would be high frequency like me. I can't hear birds chirping.

High frequency on a normal audio gram is like 4,000 Hz and up.

 

[Gb3]

I think the motivation was less noble than that even. It was "well, I better fake a low baseline too so I don't get kicked out" (not being aware of how the blinding works and only being told via social media how bad the word scores needed to be).

It wasn't told via social media. If you read their Phase 1 study you would realize "oh if my word score is high they won't accept me because they want the increase to be clinically significant".

So I do fault Frequency Therapeutics there because it was obvious to me that's what they were looking for.

It's very easy to fake a word score, all you have to do is say I don't understand. I think it's harder to fake an audiogram.

 

[Lucifer]

I think the severe hearing loss trial will have ideal outcomes, or at least positive enough; all single dose trials have been positive, so why wouldn't this one be?

I think the severe hearing loss category will show some improvements. I remember reading the Frequency Therapeutics presentation and it talked about 42% of words are high frequency.

@FGG, for severe hearing loss sufferers, what would be considered a successful trial? Would that be if the improvement in their word scores using one dose of FX-322 is 10% more from their baseline? Would restoring high-mid frequencies for severe hearing loss sufferers do anything to improve their word scores?