Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

I'm not going to point fingers here, nor do I hold a grudge. The people who suck are those who went and purposely deflated their baseline scores. You weren't to know that.

However, I'm wondering whether what you're saying does hold some truth, not essentially in respect of you but more generally. Didn't Lucchino say something along the lines that they learned from social media points of enquiry that patients had been sharing the WR entry criteria?

It's easy to imagine gaming word scores but with EHF too there is potentially a huge incentive to lie there, too, to have a lower PTA to qualify (ie you only have a 30db notch at 8khz and everything else is at 5db but you made your EHF seem in the moderate range for insurance of getting in).

Most of the people who applied are probably very knowledgeable about the drug and the requirements considering it wasn't in the mainstream news.

Unblinding at the individual level would answer that better.

I know i keep harping on this but there would be zero reason for the Phase 1 super responders to lie unless the whole company is a fraud and I just can't imagine that.

 

[Jurger]

I don't understand why these companies keep making the same mistake with the delivery method to the cochlea. Frequency Therapeutics, Otonomy, Pipeline.

It is no longer about if the drug works or not, it is about the delivery method to the cochlea.

If they do not work on the delivery method to the cochlea, we will always be in the same situation of failures.

Except that Frequency Therapeutics' German study confirmed delivery of the drug into the cochlea. Their first Australian study confirmed the same.

 

[Zugzug]

I know I keep harping on this but there would be zero reason for the Phase 1 super responders to lie unless the whole company is a fraud and I just can't imagine that.

I don't know about zero. Certainly a lot less. Just intuitively, if I am trying to get picked for a hear regeneration drug, even if the recruiting isn't based on efficacy, there's still sort of a natural inclination to guess the filters and want to be picked. The sample sizes are smaller.

The following is from the Phase 1 Clinical Trials inclusion:

1. Established diagnosis of stable sensorineural hearing loss (no changes of 10 dB or more at any frequency) by standard audiometric measures for >6 months.
2. Documented medical history consistent with hearing loss being caused by noise exposure or sudden sensorineural hearing loss (documented audiogram at least 6 months prior to screening required).

They don't specify the level of hearing loss (other than exclusion of >70 dB thresholds), but there's still motive to demonstrate hearing loss.

 

[Diesel]

It's easy to imagine gaming word scores but with EHF too there is potentially a huge incentive to lie there, too, to have a lower PTA to qualify (ie you only have a 30db notch at 8khz and everything else is at 5db but you made your EHF seem in the moderate range for insurance of getting in).

Most of the people who applied are probably very knowledgeable about the drug and the requirements considering it wasn't in the mainstream news.

Unblinding at the individual level would answer that better.

I know i keep harping on this but there would be zero reason for the Phase 1 super responders to lie unless the whole company is a fraud and I just can't imagine that.

I suspect over the coming weeks, there will be more information released on what happened and the future plan for a parallel dosing plan. David Lucchino started off the call today stating, "There are issues with trial design, NOT FX-322."

Now that they've been explicit on the plan for FX-322 to be a "single dose" drug to product, they may start being more forthcoming on data that backs up efficacy/effectiveness/research at a single dose.

 

[Aaron91]

I know i keep harping on this but there would be zero reason for the Phase 1 super responders to lie unless the whole company is a fraud and I just can't imagine that.

Or maybe the drug - for whatever reason - just doesn't activate progenitor cells in vivo human cochlea. Occam's Razor comes to mind. I hope I'm wrong though and that we find a different answer.

 

[FGG]

I don't know about zero. Certainly a lot less. Just intuitively, if I am trying to get picked for a hear regeneration drug, even if the recruiting isn't based on efficacy, there's still sort of a natural inclination to guess the filters and want to be picked. The sample sizes are smaller.

The following is from the Phase 1 Clinical Trials inclusion:

1. Established diagnosis of stable sensorineural hearing loss (no changes of 10 dB or more at any frequency) by standard audiometric measures for >6 months.
2. Documented medical history consistent with hearing loss being caused by noise exposure or sudden sensorineural hearing loss (documented audiogram at least 6 months prior to screening required).

They don't specify the level of hearing loss (other than exclusion of >70 dB thresholds), but there's still motive to demonstrate hearing loss.

Of course there is but they wouldn't be believable candidates to have abysmal (CI range in some cases) word scores without much more substantial audiogram widespread changes.

 

[Tezcatlipoca]

I suspect over the coming weeks, there will be more information released on what happened and the future plan for a parallel dosing plan. David Lucchino started off the call today stating, "There are issues with trial design, NOT FX-322."

Now that they've been explicit on the plan for FX-322 to be a "single dose" drug to product, they may start being more forthcoming on data that backs up efficacy/effectiveness/research at a single dose.

Do you think the results would have been different under a different, better designed trial?

 

[FGG]

Or maybe the drug - for whatever reason - just doesn't activate progenitor cells in vivo human cochlea. Occam's Razor comes to mind. I hope I'm wrong though and that we find a different answer.

I get that it's a possibility for sure but I asked multiple Audiologists and an Otologist if you could ever double word score with placebo. All said "Never ever. Absolutely not." It's unheard of. So that would mean they (Phase 1 super responders) lied for literally no reason or the entire company is a fraud unless the drug works.

 

[Lucifer]

@Gb3, it doesn't make sense how she had her last injection 5 months ago and had improvements in her hearing and also got rid of her tinnitus. It doesn't make sense how Phase 2a failed. It should have succeeded with the results she got.

I'm hoping to see positive results up to Day 210 but this is less likely to happen. It would take a miracle to happen.

I just hope with their other trials, the severe category shows substantial improvements in their hearing with one dose so they get a chance at going to the pivotal phase early next year as the likelihood of them faking their hearing test is low.

 

[Xojo]

Except that Frequency Therapeutics' German study confirmed delivery of the drug into the cochlea. Their first Australian study confirmed the same.

Sounds like it's pretty much proven that it doesn't work. At this point, in the best case, it has extremely minimal effects. I wonder if the in vitro study was faked or if there's just something that makes FX-322 not work in vivo.

 

[r34d1ng]

I suspect over the coming weeks, there will be more information released on what happened and the future plan for a parallel dosing plan. David Lucchino started off the call today stating, "There are issues with trial design, NOT FX-322."

Now that they've been explicit on the plan for FX-322 to be a "single dose" drug to product, they may start being more forthcoming on data that backs up efficacy/effectiveness/research at a single dose.

Agreed. I guess they could rebuild investor confidence by providing more information on Phase 2a and what exactly failed... if what was flawed was the trial and not FX-322, of course.

 

[Zugzug]

Or maybe the drug - for whatever reason - just doesn't activate progenitor cells in vivo human cochlea. Occam's Razor comes to mind. I hope I'm wrong though and that we find a different answer.

All I want for Christmas is for someone to explain to me how those 3 treated patients destroyed the WR test the second time around.

 

[Diesel]

Do you think the results would have been different under a different, better designed trial?

Since they immediately pointed to improvements like:

- A lead-in period for repeat measures to eliminate faking on tests
- Potentially spreading out multi-dosing to a month or quarter

Then, yes... I think if they had done these things, it might have helped. Lessons learned.

 

[FGG]

Do you think the results would have been different under a different, better designed trial?

It's hard to say but it's impossible to get good results if participants are lying...

 

[Tezcatlipoca]

It's hard to say but it's impossible to get good results if participants are lying...

Thankfully the FDA already sees their potential, let's hope they take into account the Phase 1 data in their decision making to grant approval for a pivotal phase 3. If FREQ is talking about "next phase" it's because they have had this conversation with the FDA, right?

 

[Gb3]

I listened to the conference call; they tend to believe that a single dose spread out may be beneficial.

 

[mrbrightside614]

Just read the news after a horrible night of sleep. The best case scenario here is that the trial design was so multi-factorily busted that you must take literally all of the results and throw them in the trash. You can take supposed secondhand anecdotes alluded to earlier in this thread to heart and hope that a single injection with a possibly higher concentration/better surfactant will foster better results than they had in phase one.

This is a crushing blow, undoubtedly. What makes no sense to me, and what I was not aware of, was the brief scheduling of follow-up injections. Here, the grass analogy warrants some merit. Speculation on sufferers lying to get their ears on a potentially life-changing drug seems pointless to me — I couldn't blame anyone for taking this path, even though it inevitably would muddy the results of the trial and delay release.

In truth, the drug isn't dead to me for a variety of reasons. I'm very interested in how they will learn from the mistakes of phase 2 going forward — dosing strategies, lengthened follow-ups for primary and secondary endpoints, etc.

Sorry to those whose hopes I got up.

 

[Lucifer]

Thankfully the FDA already sees their potential, let's hope they take into account the Phase 1 data in their decision making to grant approval for a pivotal Phase 3. If FREQ is talking about "next phase" it's because they have had this conversation with the FDA, right?

If the Phase 1b results are positive at the end of the year and the severe patients show substantial improvements in their hearing then they may be able to go through with the pivotal phase early next year.

 

[Diesel]

I get that it's a possibility for sure but I asked multiple Audiologists and an Otologist if you could ever double word score with placebo. All said "Never ever. Absolutely not." It's unheard of. So that would mean they (Phase 1 super responders) lied for literally no reason or the entire company is a fraud unless the drug works.

When it comes to fraud, you have to figure out when the shift to cheat began. There's usually a "gap" in a company's timeline, that looking back should have been obvious; perhaps where they get opaque about information, or remove stuff. I have a hard time finding it. Consider this timeline, even before Frequency Therapeutics was established, and see where you think the fraud shift/gap took place.

- The Presentation on PCA in Mouse Cochleas by Will McClean
- Research publications on website from 2014-2017 (some pre-dating the establishment of the firm)
- Preclinical work using donating human cochlea (this may still be going on)
- Phase 1 "First in human use" trial + FDA review
- Phase 1/2
- Submission of US Patent for FX-322 (May 2019, IIRC)
- Phase 2A (Sept 2019)
- Perilymph Study (Jan-Apr 2020)
- Phase 1Bs (ARL/Severe SNHL) Announced (Sept 2020)
- Int'l Patent Approval — Publishing (Oct 2020)
- Publishing of Study in Oto Journal (Feb 2021)
- Phase 1B — Open Label dosing (Recent?)

I don't see where the shift is in the timeline where they started thinking fraud. Unless it was something nefarious like never actually using human cochlea and claiming it was.

I also see where they may have made a big fuck up. They may have established the dosing schedule BEFORE the perilymph study was complete. So, I often wonder if they didn't realize how easily they can "overdose" the cochlea after observing only a single dose from the perilymph study.

I see an ambitious company, that is running probably a little fast and loose with a ton of confidence, that just got their first kick in the balls. Now they're on damage control, and probably wanting badly to regain some confidence to finish the work and get the product out.

 

[Diesel]

@Gb3, it doesn't make sense how she had her last injection 5 months ago and had improvements in her hearing and also got rid of her tinnitus. It doesn't make sense how Phase 2a failed. It should have succeeded with the results she got.

I'm hoping to see positive results up to Day 210 but this is less likely to happen. It would take a miracle to happen.

I just hope with their other trials, the severe category shows substantial improvements in their hearing with one dose so they get a chance at going to the pivotal phase early next year as the likelihood of them faking their hearing test is low.

We have to assume that many honest people enrolled in the study who wanted to help progress the treatment, and did everything right and proper. It may have only taken 10%-20% of the participants to fake some scores to get in, and that was enough to muddy the outcomes. It's really unfortunate.

 

[Street Novelist]

Hearing loss and eye floaters; will there ever be a cure? God I hope so. I'm too young to have to deal with all of this s!!t.

 

[Xojo]

@Gb3, it doesn't make sense how she had her last injection 5 months ago and had improvements in her hearing and also got rid of her tinnitus. It doesn't make sense how Phase 2a failed. It should have succeeded with the results she got.

It's probably just a placebo effect. I remember that one guy from that study that involved drilling the cochlea from a while back. He kept claiming that he thought he could hear a little better as the weeks passed but in the end, there was no real improvement and he eventually even admitted that he was mistaken.

 

[FGG]

The hire of Kevin Franck now appears to be because they were looking at preliminary data and were surprised by the results, not just audiology educating. Kevin was the one who did an audiologic post mortem on the population data and said "looking at these results, the word scores don't match the medical records..."

He can't do this at an individual level until he is unblinded but it's possible to separate out the suspect individuals when it's unblinded and maybe that's part of the reason he was hired.

 

[serendipity1996]

I don't know if I'm just clutching at straws here but I still have faith in the PCA platform. For what it's worth, I think Frequency Therapeutics' approach to hair-cell regeneration is still far more promising than a transdifferentiation approach. There's no way to get around it — today was disappointing. But I don't think they're going to abandon this drug. I don't know whether it's the trial design, the delivery system, or in vivo factors (perhaps a combination of all three, a perfect storm) but I am hoping we will get more clarity in the near future about where they are going from here.

 

[Greg Sacramento]

Or maybe the drug - for whatever reason - just doesn't activate progenitor cells in vivo human cochlea.

There's lots of clinical studies on this — biology 102.

lied for literally no reason or the entire company is a fraud unless the drug works.

The company favors professional investment and not retail. Options are set up for protection of professional fund investment. There was study leakage or convention talk, signaling hit the exit. Pointed out on 19th March of a 477,000 stock sale and several million dollar sales.

So by corporate and investor relations playing a dirty investment game — then they probably had no problems with playing the obvious medical hype game.

In the months to come, headlines for FREQ will probably be securities law firm litigation.

Future dilution of shares to raise funds may also happen and hedge funds would want an extremely low offering price because of readouts today which will pressure share price even more. This is very bothersome.

 

[Cernuto]

The smarter way would be to do an injection, monitor for improvement, then if improvement is shown do another. A test process like this probably would confuse the FDA though.

 

[Tezcatlipoca]

I think we may have been too pessimistic, sounds like the results would have been positive if they spaced out the injections and weeded out the liars.

FX-322 is NOT dead.

 

[Lucifer]

The hire of Kevin Franck now appears to be because they were looking at preliminary data and were surprised by the results, not just audiology educating. Kevin was the one who did an audiologic post mortem on the population data and said "looking at these results, the word scores don't match the medical records..."

He can't do this at an individual level until he is unblinded but it's possible to separate out the suspect individuals when it's unblinded and maybe that's part of the reason he was hired.

Is that still possible to do, get rid of the people that lied about their hearing results and then reassess the data? Could reassessing the data show that there were actually substantial improvements?

 

[Keith Handy]

The smarter way would be to do an injection, monitor for improvement, then if improvement is shown do another. A test process like this probably would confuse the FDA though.

This assumes that the 2x and 1x groups got their real injections before the placebo injections. For keeping the end result times aligned, they might have started with placebos.

 

[Aaron91]

The hire of Kevin Franck now appears to be because they were looking at preliminary data and were surprised by the results, not just audiology educating. Kevin was the one who did an audiologic post mortem on the population data and said "looking at these results, the word scores don't match the medical records..."

He can't do this at an individual level until he is unblinded but it's possible to separate out the suspect individuals when it's unblinded and maybe that's part of the reason he was hired.

You beat me to it, I had been thinking about this too. Let's hope they're able to figure this one out and see who the suspects were.

The thing that's still nagging me is that lack of EHF audiogram performance in both studies, especially the Phase 1 study which had stat sig WR scores. Like @Zugzug, I just can't for the life of me reconcile this with the pharmacokinetic models where we know the drug is concentrated. Even if we go with the preferential IHC thesis, that hardly bodes well for most of us moving forward, let alone the commercialisation of the drug.

I'm just finding it really difficult to spin this. Even if you have a population bias issue, I'm not sure you can still explain what's happened here.

@FGG Back to your point on audiologists saying ears don't do this (which I fundamentally agree with), are we aware of any previous study where something similar has occurred i.e. where both placebo and the drug have shown efficacy? Frequency said it's unprecedented but I want to know if there's evidence in the literature to the contrary. If there is I'm certainly not aware of it. Also, is there anything in the literature to suggest that the process of an intratympanic injection could have some kind of positive effect on hearing?