Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

Oh, come on. I agree with you that PCA is groundbreaking and the long-term outlook is really positive. But there's no conspiracy of audiologists telling people to lie or trying to tank tests. They just failed the trial.

Agree.

Of all the possibilities, I see an audiologist conspiracy as "extremely remote". But this is one that can be fully ruled out to those who really do believe this with unblinding because you can see who got tested where.

But for those unaware, these were the in house audiologists who work at clinical trial sites. One site is doing both FX-322, and PIPE-505 as well as did Phase 1 for both Otonomy drugs. If this was occurring, it would have been known on the analysis after that Phase.

I don't see many people losing their job (and their reputation and maybe even their license) out of worry of the impact of a future product. Since they work at testing sites, especially, they would 100% be fired and reported to the board.

 

[Zugzug]

I know it's a long shot but I wonder if the FDA and Frequency Therapeutics had a similar discussion like that talking about the possibility of completing a pivotal phase on the outcome of the age-related and severe hearing loss trials. I wouldn't be surprised if it happened. Hearing loss is an unmet need and costing the whole world millions each year. Even with a 30-40% improvement it may be enough to get it approved. It doesn't have to be 100% perfect.

That's good enough for me lol, and I think for the FDA as well.

You can hold whatever opinion you would like. My recommendation is to not put any emotional investment into this. If Phase 2a was a mixed bag, where 1x dominated the placebo group in a bunch of tests, but it was obvious that multiple dosing was the issue, maybe this could be valid.

However, they didn't show anything off. They're in a huge funk where they can't transparently create a solid, statistical thesis over the situation. It's really just cherry picking the results that we like.

 

[Diesel]

Discuss:

Now that they've disclosed that they're pushing forward with a single-dose for FX-322 1.0, and the drug seems to be fairly safe, even in cases where cochleas were "overdosed" from the 4x injections...

Would there now be a benefit to treating both ears of severe group with bilateral loss, for example?

 

[FGG]

You can hold whatever opinion you would like. My recommendation is to not put any emotional investment into this. If Phase 2a was a mixed bag, where 1x dominated the placebo group in a bunch of tests, but it was obvious that multiple dosing was the issue, maybe this could be valid.

However, they didn't show anything off. They're in a huge funk where they can't transparently create a solid, statistical thesis over the situation. It's really just cherry picking the results that we like.

I agree that they can't use the data from Phase 2a, even cherry picked. You still have to prove the efficacy in a Phase 2 trial of the single arm. It's not enough just to prove that rapid multi dosing was detrimental and use efficacy from Phase 1.

 

[Philip83]

Discuss:

Now that they've disclosed that they're pushing forward with a single-dose for FX-322 1.0, and the drug seems to be fairly safe, even in cases where cochleas were "overdosed" from the 4x injections...

Would there now be a benefit to treating both ears of severe group with bilateral loss, for example?

I would love to hear just any comment from FREQ about their thoughts on unilateral/bilateral treatment and how that could affect the results.

 

[Diesel]

I would love to hear just any comment from FREQ about their thoughts on unilateral/bilateral treatment and how that could affect the results.

I believe it was on the Tinnitus Talk Podcast, where Carl LeBel said they had thought about doing both ears in the Phase 2A?

 

[Philip83]

I believe it was on the Tinnitus Talk Podcast, where Carl LeBel said they had thought about doing both ears in the Phase 2A?

Oh, really? I must have missed that. That was it though? Nothing about what the implications might be?

 

[Keith Handy]

Oh, really? I must have missed that. That was it though? Nothing about what the implications might be?

I believe the podcast has a searchable transcript, but I've listened to it multiple times and don't recall this.

 

[Guywithapug]

My initial reaction to the results were disbelief and admittedly somewhat denial, rightfully so I believe, as the drug showed early promise.

However, time along with reading the ongoing discussion here and discussing it with my otologist, I agree with those that believe that FX-322 is in fact ineffective, at least as it is currently presented.

People can theorize all they want about what potentially went wrong or how the trial was corrupted but at the end of the day the only way to validate FX-322's efficacy is to show stratified results on the audiogram, which translates to better WR and hearing thresholds.

Absent the stratified effect, all we're doing is pissing in the wind looking at marginal dB gains which most likely comes down to test variance and accuracy when fitting the equipment and people being able to guess better when determining repetitive words.

Sorry for the pessimist coming out but I think that any further emotional investment in this is futile, fueled by desperation, understandably.

I sincerely hope that Frequency Therapeutics can deliver a drug in the future that penetrates well below 8 kHz, shows substantial dB gains and tinnitus improvement as a by product! But that is probably at least decade away, I hope I'm wrong.

 

[Zugzug]

My initial reaction to the results were disbelief and admittedly somewhat denial, rightfully so I believe, as the drug showed early promise.

However, time along with reading the ongoing discussion here and discussing it with my otologist, I agree with those that believe that FX-322 is in fact ineffective, at least as it is currently presented.

People can theorize all they want about what potentially went wrong or how the trial was corrupted but at the end of the day the only way to validate FX-322's efficacy is to show stratified results on the audiogram, which translates to better WR and hearing thresholds.

Absent the stratified effect, all we're doing is pissing in the wind looking at marginal dB gains which most likely comes down to test variance and accuracy when fitting the equipment and people being able to guess better when determining repetitive words.

Sorry for the pessimist coming out but I think that any further emotional investment in this is futile, fueled by desperation, understandably.

I sincerely hope that Frequency Therapeutics can deliver a drug in the future that penetrates well below 8 kHz, shows substantial dB gains and tinnitus improvement as a by product! But that is probably at least decade away, I hope I'm wrong.

I agree with just about everything you've said and have written about these things at length. The drug failed Phase 2.

Where I disagree with you though, is I don't think doubling word scores is easily explained by unconscious bias/guessing/etc.

I believe something is going on. That something could be the drug working, horrible trial design, the person somehow studying the words and knowing which words are correct in a multiple choice scenario, etc. I don't think this happens just from your every day Joe getting a placebo and innocently guessing a few times, watching his score go from 40% to 86%.

The benchmarks for determining test-retest stability, however flawed, have been in practice for many decades for a reason. If it was a reasonably common occurrence for someone's score to be that all over the map, they wouldn't even administer the test. Granted, they should consider other tests regardless.

 

[FGG]

My initial reaction to the results were disbelief and admittedly somewhat denial, rightfully so I believe, as the drug showed early promise.

However, time along with reading the ongoing discussion here and discussing it with my otologist, I agree with those that believe that FX-322 is in fact ineffective, at least as it is currently presented.

People can theorize all they want about what potentially went wrong or how the trial was corrupted but at the end of the day the only way to validate FX-322's efficacy is to show stratified results on the audiogram, which translates to better WR and hearing thresholds.

Absent the stratified effect, all we're doing is pissing in the wind looking at marginal dB gains which most likely comes down to test variance and accuracy when fitting the equipment and people being able to guess better when determining repetitive words.

Sorry for the pessimist coming out but I think that any further emotional investment in this is futile, fueled by desperation, understandably.

I sincerely hope that Frequency Therapeutics can deliver a drug in the future that penetrates well below 8 kHz, shows substantial dB gains and tinnitus improvement as a by product! But that is probably at least decade away, I hope I'm wrong.

What are his/her thoughts on the Phase 1 word scores out of curiosity? Because at the time of release, I asked my otologists and 2 audiologists and both said that's not a chance or placebo result.

Is your otologist going by the multi dose results?

What are their theories on the Phase 1 results? Do they think it's fraud?

 

[ThomasRobert]

As for the upcoming severe hearing loss trial, is there any chance that a candidate is not really severe but just moderate in order to get in the trial? And then results of the word score would appear to increase?

 

[Billy_Shears]

Oh, come on. I agree with you that PCA is groundbreaking and the long-term outlook is really positive. But there's no conspiracy of audiologists telling people to lie or trying to tank tests. They just failed the trial.

You may have misunderstood me pertaining to audiologists. There is currently an unknown reason for the bias that occurred in Phase 2a. As well, it's well known that any success with FX-322 could effect the hearing aid industry in a negative way - and audiologists are basically the middle-man in this industry.

I did not imply a 'conspiracy' or 'telling people to lie'. What I meant was an 'off the cuff' mannerism at audiologists influencing the data. Seriously, I don't buy into it much either but I do remain perplexed at the source of the bias.

 

[FGG]

As for the upcoming severe hearing loss trial, is there any chance that a candidate is not really severe but just moderate in order to get in the trial? And then results of the word score would appear to increase?

They are defining severity by a (stable) severe pure tone average audiogram so I would say no.

I can't fully rule out word score depression to get in but it's way less likely as the severe group mostly probably does have genuinely bad word scores.

 

[Aleksandar]

You may have misunderstood me pertaining to audiologists. There is currently an unknown reason for the bias that occurred in Phase 2a. As well, it's well known that any success with FX-322 could effect the hearing aid industry in a negative way - and audiologists are basically the middle-man in this industry.

I did not imply a 'conspiracy' or 'telling people to lie'. What I meant was an 'off the cuff' mannerism at audiologists influencing the data. Seriously, I don't buy into it much either but I do remain perplexed at the source of the bias.

The negative impact of hearing aid companies on finding a regenerative cure is as sure as gravity, all for the damn money. I don't understand people who think otherwise...

 

[PortugalTheMan]

I find it very interesting that FX-332 works and that people can hear perfectly again.

Do not forget that many people have tinnitus induced by noise but they do not have hearing loss. That is, we can have perfect hearing but our real problem remains.

What research is most targeted at tinnitus?

 

[kiki]

A new Phase 2 that includes all designations that have been trialed under the Phase 1Bs. This is the "catch-all" term. Because they're accepting basically all hearing loss classes, there is no incentive to cheat.

Thank you.

I understand that.

The FDA will not accept what I have misunderstood.

 

[Lucifer]

Frequency Therapeutics Provides Business Updates and Reports Fourth Quarter and Full Year 2020 Financial Results

 

[Guywithapug]

What are his/her thoughts on the Phase 1 word scores out of curiosity? Because at the time of release, I asked my otologists and 2 audiologists and both said that's not a chance or placebo result.

Is your otologist going by the multi dose results?

What are their theories on the Phase 1 results? Do they think it's fraud?

Unfortunately the discussion was brief as it was a segment I brought up during a post-op consultation of mine, so time was limited and his primary focus was elsewhere. Much of what I stated in my post was from my own thoughts but I will reiterate what he said in my own words.

When raising the Phase 2a results he did elaborate that while the Phase 1 results were encouraging on paper, the drug would have to continue to demonstrate a clear distinction between itself and placebo moving forward, but failed to achieve that within the trials as defined. They [trials] are not perfect but can provide important indicators in which direction to head and that it was a good starting point for further development based upon the PCA platform.

He embraces the research and development of regen drugs, as he expressed great interest in one day being able to treat his patients for a better quality of life but from a clinical standpoint, the drug is a currently a failure, it did not show any improvement over placebo.

So Frequency Therapeutics needs to continue working on the drug formulation/delivery for future revisions and better demonstrate efficacy within their trials, which is going to take years.

 

[Zugzug]

So I've been thinking about writing/exploring a research project. The point is not to prove that Phase 2 was a success, as I absolutely believe it failed. Before I see where this goes, I want to ask the following question. When one takes the WR test or SIN test, is it acceptable to say "I don't know"?

Based on my own experiences, I'm not sure. I don't remember being told that I had to guess.

 

[FGG]

Frequency Therapeutics Provides Business Updates and Reports Fourth Quarter and Full Year 2020 Financial Results

Tl;dr: Plan to continue with FX-322 with single dosing only (and a better trial design), the results of the severe group and age-related group will help determine patient selection for that trial, they are very well funded for continuing.

 

[Cernuto]

The more word score tests you take, the more proficient you become at taking word score tests? Is this a factor? My point is, if someone has 10+ word score tests under their belt, will they perform better than someone who has zero experience, all other things being equal?

 

[FGG]

The more word score tests you take, the more proficient you become at taking word score tests? Is this a factor? My point is, if someone has 10+ word score tests under their belt, will they perform better than someone who has zero experience, all other things being equal?

Even if that somehow was possible hypothetically (I don't think it is with the improvement seen), you think someone practiced with their audiologist and took 10 tests in between baseline and post drug testing in Phase 1?

 

[Cernuto]

I find it very interesting that FX-332 works and that people can hear perfectly again.

Do not forget that many people have tinnitus induced by noise but they do not have hearing loss. That is, we can have perfect hearing but our real problem remains.

What research is most targeted at tinnitus?

I wish this one was. I believe FX-322 as it sits today has a good chance of improving high-frequency tinnitus for some people, which could be a stepping stone to wider applications.

 

[Lucifer]

Tl;dr: Plan to continue with FX-322 with single dosing only (and a better trial design), the results of the severe group and age-related group will help determine patient selection for that trial, they are very well funded for continuing.

I'm glad they stated that in this press release. Maybe that's why they had a vague response on Twitter.

I'm really gutted that this will delay FX-322 from coming out in the market but hopefully with the single dosing of FX-322 the trials will be much quicker as there are only follow-ups up to Day 90.

I'm trying to see the positive side out of this.

 

[GBB]

and discussing it with my otologist

? - can we not invoke medical professionals as if they actually have any useful insight here - you might as well cite your astrology symbol. I've been to 6 or 7 Columbia and NYU doctors and the extent of their knowledge is farcical. They focus on the small fiefdom of medicine that overlaps between treatable, lucrative, and common, anything else you might as well ask a Rabbi, an imaginary friend, or your pet.

 

[Cernuto]

Even if that somehow was possible hypothetically (I don't think it is with the improvement seen), you think someone practiced with their audiologist and took 10 tests in between baseline and post drug testing in Phase 1?

I think that's highly unlikely. However, someone with prior familiarity would be more capable of maybe gaming the system to their 'advantage', maybe even unconsciously. "Yes, take poor me, I have trouble hearing," then after the drug, "Wow, this drug sure works great! I can hear everything now, it's truly amazing!"

There's a degree of test subject subjectivity inherent to the design of the test. Also, the placebo effect has been proven to be real.

 

[Keith Handy]

So I've been thinking about writing/exploring a research project. The point is not to prove that Phase 2 was a success, as I absolutely believe it failed. Before I see where this goes, I want to ask the following question. When one takes the WR test or SIN test, is it acceptable to say "I don't know"?

Based on my own experiences, I'm not sure. I don't remember being told that I had to guess.

I answered every one, there was only one word on the whole list that I thought could have been two different words and said them both... not sure if that counted as a missed word. I don't recall being told I had to guess, either, but doesn't every short word at least sound like something when you haven't heard it clearly? The mind fills in blanks immediately. "S'cuse me while I kiss this guy," etc. Saying "I don't know" for a one syllable word seems odd.

 

[FGG]

I think that's highly unlikely. However, someone with prior familiarity would be more capable of maybe gaming the system to their 'advantage', maybe even unconsciously. "Yes, take poor me, I have trouble hearing," then after the drug, "Wow, this drug sure works great! I can hear everything now, it's truly amazing!"

There's a degree of test subject subjectivity inherent to the design of the test. Also, the placebo effect has been proven to be real.

Of course the placebo effect is real. I just don't see it doing something that has historically not been possible (doubling word scores in chronic hearing loss).

The placebo effect is limited to possible things. E.g., Paraplegic people can't walk due to placebo.

 

[Zugzug]

I answered every one, there was only one word on the whole list that I thought could have been two different words and said them both... not sure if that counted as a missed word. I don't recall being told I had to guess, either, but doesn't every short word at least sound like something when you haven't heard it clearly? The mind fills in blanks immediately. "S'cuse me while I kiss this guy," etc. Saying "I don't know" for a one syllable word seems odd.

Completely agree. I guess I'm thinking about it like this. Let's say you're not a dishonest person, but have varying levels of motivation. For example, if you're motivated to get into a trial with low word scores, are you going to hear the word "cat" and say "bat" or "not sure"? I'm going to assume the percentage of people that would do this is negligible.

But like you say, if you think it could be cat, cap, clap, clack, but you're not sure and getting things right is bad for you, you might subconsciously say "I don't know." There's no moral sting because you aren't doing anything dishonest, but it's also not the way you would answer it if someone had a gun to your head and will only not shoot you if you get it right.

I'm trying to explore test variation for reasons that are innocent.