Frequency Therapeutics — Hearing Loss Regeneration

[Tweedleman]

FX-322 is the cute girl who sent ambivalent texts after the first date and we are all trying to figure out if there will be a second.

Story of my life, lol.

 

[Diesel]

I miss you. Please come back. I'm a big fat bear holding down the fort. I can handle more weight on my back.

Nice Bear picture... you switching teams on me?

 

[Tezcatlipoca]

I think Phase 2a results are totally salvageable if they eliminate fakers, and by their own press release it sounded like they were soldering on ahead.

Someone even called them this Monday I believe and got told to apply for the Phase 3 trials later this year.

Don't forget that the FDA is very involved in this too.

 

[Zugzug]

Nice Bear picture... you switching teams on me?

All great groups break up. Egos are involved. I wasn't paid generously enough. I wasn't given enough credit.

I did make the Tinnitus Talk Hall of Fame as a bull so some day when they retire my jersey, it will be a Bulls jersey.

For now, we have a rivalry. I want to prove that I can carry a team on my own.

But off the court, we are friends.

 

[Diesel]

All great groups break up. Egos are involved. I wasn't paid generously enough. I wasn't given enough credit.

I did make the Tinnitus Talk Hall of Fame as a bull so some day when they retire my jersey, it will be a Bulls jersey.

For now, we have a rivalry. I want to prove that I can carry a team on my own.

But off the court, we are friends.

I like a good rivalry. May the gods favor you.

 

[Zugzug]

I like a good rivalry. May the gods favor you.

May the gods not favor me so the drug gets through! I'm just doing this to challenge our beliefs.

 

[Jack Straw]

Hmmmm... wrong... both the FDA and the EMA say that a 10 dB improvement is clinically significant:

"With regard to Sonsuvi , the FDA and EMA have indicated that a 10 dB improvement in hearing thresholds is clinically significant, in line with clinical practice. However, no product has been approved for marketing based upon such guidance and we cannot be certain that Sonsuvi will be approved even if it were to demonstrate such result in further Phase 3 trials"

Link: https://ir.aurismedical.com/static-files/8d74fd2e-b09c-4bc5-b2aa-82cc2b4bb1f1

Not sure why you gotta have such a snotty tone when talking to people. I find it very interesting because you, like the rest of us, learned as you went. A little humility would go a long way...

 

[Diesel]

May the gods not favor me so the drug gets through! I'm just doing this to challenge our beliefs.

All you have to do is post "IT DOESN'T WORK" and make dismissive comments without doing any research or engaging other members... am I missing something?

 

[Lucifer]

I think Phase 2a results are totally salvageable if they eliminate fakers, and by their own press release it sounded like they were soldering on ahead.

Someone even called them this Monday I believe and got told to apply for the Phase 3 trials later this year.

Don't forget that the FDA is very involved in this too.

If there were fakers I would assume they would mostly be in the mild hearing loss category and would be best for Frequency Therapeutics to get rid of. The moderately-severe hearing loss category will be less likely to fake their word scores but still possible.

The only way I see Frequency Therapeutics to salvage the Phase 2a results is that either Day 210 results show meaningful word score improvements or to prove that multi dosing does not work. I expect the candidates who had only received one or two doses of FX-322 to show meaningful word score improvements compared to the candidates who got 3 or 4 doses of FX-322.

 

[Zugzug]

All you have to do is post "IT DOESN'T WORK" and make dismissive comments without doing any research or engaging other members... am I missing something?

Yeah. You forgot the part about how mean old Zugzug made you invest thousands of dollars by being so persuasive.

And the part about how if the drug worked, you knew all along.

 

[Diesel]

@Zugzug,

What is the bear thesis on the body selectively regrowing IHC with a single injection with FX-322?

 

[FGG]

Okay, my bear arms are swiping down so fast and so hard that I'm borderline psychopathic (all in fun <3). Let me start with the first half, to give you an idea of what the calculations would involve:

Firstly, before we even get to the math, there's absolutely no way it's 25% fakers. That number is almost conspiratorial to me. I think 10% is actually generous. What is far more likely to me is that there were a few fakers, and by chance, the placebo group performance happened to be closer to the top of the 95% confidence interval. Then the fakers blew it over. In other words, without the fakers, it's a believable, strong performing placebo group. With a faker or two, it became glaring. We'll see.

Also, there's no way the distribution of fakers (assume 25%) is close to split evenly between mild, moderate, and severe. Also, it's highly doubtful that their n=96 consisted of close to an even split across mild, moderate, and severe. You have alluded to this, but it's a really important part of this.

Okay. Regarding the mathematical approach, there's a couple of big problems. Let's use the same numbers you used for illustration. While the expected value of the distributions that you calculated is correct, really you would want to put some confidence intervals around those numbers. Conceptually, we would want to consider the sum of a bunch of probabilities, conditioned on distributions close to 8, 8 ,8 (mild, moderate, moderate-severe). For example, 7, 7, 10 or 7, 8, 9, etc. and all permutations of those numbers (i.e. there's one way to have 8, 8, 8, but three ways 7, 7, 10 can be arranged, etc.). It's a long and tedious process, but all of these probabilities can be calculated.

Then, for each one individually, you would multiply by the probabilities involved in all of your calculations, conditioned on the group distributions. Even then, you really should condition again on distributions entering the 4 cohorts respectively. Trust me, this is really, really difficult to the point where you won't get the satisfaction that you're looking for. Even if you did roll through all of the calculations, there would still be a ton of speculation in the assumptions.

Okay, next order of business. Statistical significance of the placebo group. This is nontrivial because it requires a MMRM (Mixed Model for Repeated Measures). There are various choices for this approach. For the life of me, I'm not sure what they did. From Phase 1/2, the only statistical inference I couldn't make sense of from the paper is the group wide percentage (ratio) improvements across time periods. The reason why this is nontrivial is because there' a correlation between time periods in all of the calculations. I would have to see their details, and I'm not privy to those details, unfortunately.

Anyways, you're sort of right that you're comparing some average to 10% (assuming that's the number), but the comparison is far more complicated than just seeing if it clears 10%. It has to clear some upper threshold U > 10%, where I don't know how they calculated U.

Another point is that I don't even like the 10% number (assuming you mean 10% absolute WR improvement). I think the Thornton Raffin confidence intervals (harder to clear) are much more conservative (and correctly so). This is why I was so bullish on the 3 big responders in Phase 1/2 because they sky rocketed over these confidence intervals, which aren't super easy to clear. Clearing them by a lot is not realistic for just a placebo effect.

Re seeding: I think this is mostly PR currently. I say currently because it could end up being something, but has to be proven. Didn't they say (can't listen to the webcast) that the improvements overlapped? In other words, all treatment groups sort of looked similar? I guess the thought here is that maybe the FX-322 over 4 doses was balanced out by the lawn effect. There is so much conjecture here. Occam's Razor: Multiple doses does nothing, delivery sucks, and maybe there's some lawn effect too. This is just positive spin.

There is no way this goes to Phase 3 from the Phase 2 results. Think of it this way. If you are right that the numbers are 25% fakers, there's a downside to this. As I've outlined, it's embarrassing for the company. They didn't even calculate confidence intervals comparing WR >=6 month to screening (as far as we know). Are they really going to tell the FDA that they are so incompetent that their whole trial is messed up? But magically, this same company did everything else perfectly?

It's a horrible look to mess something so simple up. Maybe if the Phase 1b trials are successful, they save some face with the actual drug. This is going to repeat Phase 2.

I'm sorry if I seem harsh here, I'm actually trying to be kind by killing false hope. If I'm wrong, I will change my avatar to the words "Aaron91 is a god." lol.

A few points:

-- if their trial criteria was "bad word scores, but below severe loss on audiogram" that's a relatively narrow group of real patients vs the potential for the fakers. It's not conspiratorial to think 25% is a genuine possibility. As I have mentioned they inadvertently seem to have selected preferentially for the fake baselines.

-- with my own interview I can confirm stability was determined by audiogram only as I only had one word score measurement.

I do fully agree they will need to repeat Phase 2 but I definitely think the drug has a genuine hearing effect. I guess that puts me in the middle of the bear-bull divide.

 

[Olive27]

All you have to do is post "IT DOESN'T WORK" and make dismissive comments without doing any research or engaging other members... am I missing something?

And what is your research based on exactly? Lies, lies, and statistics...

The only solid proof we have is from the trials themselves which clearly state the drug doesn't currently work!

You can do 10 page posts and try and boggle people but none of it is based on facts, just speculative garbage you've dreamed up to cling onto hope this works!

 

[Stefaniie]

I don't like how final this sounds... Have they given up on FX-322?

 

[Zugzug]

A few points:

-- if their trial criteria was "bad word scores, but below severe loss on audiogram" that's a relatively narrow group of real patients vs the potential for the fakers. It's not conspiratorial to think 25% is a genuine possibility. As I have mentioned they inadvertently seem to have selected preferentially for the fake baselines.

-- with my own interview I can confirm stability was determined by audiogram only as I only had one word score measurement.

I do fully agree they will need to repeat Phase 2 but I definitely think the drug has a genuine hearing effect. I guess that puts me in the middle of the bear-bull divide.

It's hard for me to believe it's that high. I just can't picture sitting there, having a word said to me, and pretending like I didn't hear it. If it's 25% or more, I will live in greater solitude than I do now, which isn't possible.

Humans do suck, but the burden is on the data to prove something like that.

 

[Zugzug]

And what is your research based on exactly? Lies, lies, and statistics...

The only solid proof we have is from the trials themselves which clearly state the drug doesn't currently work!

You can do 10 page posts and try and boggle people but none of it is based on facts, just speculative garbage you've dreamed up to cling onto hope this works!

You clearly have never done science before if you think a failure means the whole thing is trash.

 

[Johan001]

Trying to stay positive... I believe every failed attempt is still a progress. It is very disappointing, but who knows, Frequency Therapeutics or someone else will build upon these results to develop something that eventually will work. At least they're doing something.

 

[Olive27]

You clearly have never done science before if you think a failure means the whole thing is trash.

Aren't you meant to be a bear? Look, you, FGG, Aaron91, Zugzug might do these complicated posts about all the science etc, but don't you think the actual scientists at Frequency Therapeutics have done the same but with the actual data?

FX-322 doesn't work, and the science points to anything positive being from the placebo effect! Face the facts and move on guys!

 

[Lucifer]

Trying to stay positive... I believe every failed attempt is still a progress. It is very disappointing, but who knows, Frequency Therapeutics or someone else will build upon these results to develop something that eventually will work. At least they're doing something.

The multi dosing in weekly succession was most likely the problem. Single dosing of FX-322 showed meaningful improvements and I expect the age-related and severe hearing loss trial to show meaningful improvements with one dose of FX-322. If they get positive results from these two trials, I expect the share price to go back up to $30-$40.

 

[FGG]

I don't like how final this sounds... Have they given up on FX-322?

View attachment 44309

They haven't halted the ongoing trials and are still recruiting for the severe group currently.

It seems odd that they would make a major announcement in a vague Twitter post (i.e. "we are halting all trials and reformulating") vs a press release so I guess it depends on what they mean by "developing".

It also says "medicines" plural for hearing loss which would also be a huge announcement. Very odd tweet.

 

[Diesel]

I don't like how final this sounds... Have they given up on FX-322?

View attachment 44309

They had a ton of bad press after the Phase 2A. They blamed participants for cheating. Their stock just shit the bed. They're on damage control. But it also does sound sort of final.

 

[Tezcatlipoca]

I don't like how final this sounds... Have they given up on FX-322?

View attachment 44309

"As we continue our work," "we remain deeply commited." That's the opposite of them saying "we give up."

 

[Johan001]

The multi dosing in weekly succession was most likely the problem. Single dosing of FX-322 showed meaningful improvements and I expect the age-related and severe hearing loss trial to show meaningful improvements with one dose of FX-322. If they get positive results from these two trials, I expect the share price to go back up to $30-$40.

Fingers crossed. Also, no one mentioned anything about tinnitus scores in this trial... I bet the majority of us are interested exactly in this aspect of the drug?

 

[Zugzug]

Aren't you meant to be a bear? Look, you, FGG, Aaron91, Zugzug might do these complicated posts about all the science etc, but don't you think the actual scientists at Frequency Therapeutics have done the same but with the actual data?

FX-322 doesn't work, and the science points to anything positive being from the placebo effect! Face the facts and move on guys!

This is why no one wants to be a bear. Bear is synonymous with blind critic.

And actually, as I alluded to yesterday, I don't think they computed the p-values by reading the Thornton and Raffin paper in detail and understanding how it would be done. The reason I suspect this is because they do an excellent job of quantifying what clearing the 95% CI means from the 3 superstar responders from Phase 1/2.

I also suspect they didn't take the time to understand the theory because if they did, they would have easily computed lower percentage confidence intervals to detect inconsistencies at the screening.

Besides, none of us think we are better than Will McLean, Robert Langer, or anyone there, really (it's kind of funny to think otherwise). We are mostly having a a fun, educational discussion.

 

[ajc]

Trials are cancelled all the time, even ongoing or recruiting ones. Let's see if we hear them terminate FX-322 officially next week...

 

[Keith Handy]

I don't like how final this sounds... Have they given up on FX-322?

View attachment 44309

If "who participated" was instead written as "who have participated" it would sound a lot less final.

 

[serendipity1996]

It kind of sounds like they are doing some damage control to avoid potebtially antagonising patients. Very ambiguous tweet though...Strange that they haven't accompanied it with an official statement or press release. If they were about to make a final decision (e.g. terminating the trial) why would they announce it as a cryptic vague-tweet.

 

[Aaron91]

Firstly, before we even get to the math, there's absolutely no way it's 25% fakers. That number is almost conspiratorial to me. I think 10% is actually generous. What is far more likely to me is that there were a few fakers, and by chance, the placebo group performance happened to be closer to the top of the 95% confidence interval. Then the fakers blew it over. In other words, without the fakers, it's a believable, strong performing placebo group. With a faker or two, it became glaring. We'll see.

On what are you basing this 10% figure though? Granted, I picked 25% somewhat arbitrarily and I am not basing this on anything either, but that was more in the interests of demonstrating an example of how the averages could be affected (I know you have an issue with that too but I just want to take one thing at a time). I'm not saying it wasn't 10%, but I'd like to know what makes you so confident it was unlikely to be anything more than that.

Also, there's no way the distribution of fakers (assume 25%) is close to split evenly between mild, moderate, and severe. Also, it's highly doubtful that their n=96 consisted of close to an even split across mild, moderate, and severe. You have alluded to this, but it's a really important part of this.

Granted, we don't have the numbers on this and this was an assumption of mine, but I don't think it was unreasonable of me to assume that Frequency Therapeutics would at least have attempted to balance the groups during recruiting. Remember, the whole bear thesis the first time round was the fact there were too many patients close to the ceiling in order to make a fair comparison. I'm guessing Frequency Therapeutics would have aimed to have, at the very least, a more equal distribution of baselines across all groups and by default in the placebo group as well, even if they did not actually achieve it, to at least minimise any similar criticisms moving forward. Also, I made a disclaimer that it was for the sake of illustration.

Okay. Regarding the mathematical approach, there's a couple of big problems. Let's use the same numbers you used for illustration. While the expected value of the distributions that you calculated is correct, really you would want to put some confidence intervals around those numbers. Conceptually, we would want to consider the sum of a bunch of probabilities, conditioned on distributions close to 8, 8 ,8 (mild, moderate, moderate-severe). For example, 7, 7, 10 or 7, 8, 9, etc. and all permutations of those numbers (i.e. there's one way to have 8, 8, 8, but three ways 7, 7, 10 can be arranged, etc.). It's a long and tedious process, but all of these probabilities can be calculated.

Then, for each one individually, you would multiply by the probabilities involved in all of your calculations, conditioned on the group distributions. Even then, you really should condition again on distributions entering the 4 cohorts respectively. Trust me, this is really, really difficult to the point where you won't get the satisfaction that you're looking for. Even if you did roll through all of the calculations, there would still be a ton of speculation in the assumptions.

Agreed. Everything was for the purposes of illustration. The point I was trying to get across was that a scenario can exist where things have gone quite wrong and Frequency Therapeutics were just unlucky. For example, I also remember you calculating a situation whereby all fakers ended up in the placebo group and that probability came to circa 4%. As you rightly inferred, that scenario is very unlikely. I don't have the capacity or know-how to crunch the numbers in the example I illustrated, but I'd be interested to know, relatively speaking, how more likely it is that one would end up with a scenario such as the one I described or similar. Would that too be circa 4%? Correct me if I'm wrong here, but 7, 7, 10 or 7, 8, 9 or 9, 10, 7 or 7, 8, 10 split or any other combination you can think of along similar lines doesn't exactly throw out my argument entirely although it does of course affect the overall % averages in each group. Having 1-2 more fakers in the group would strengthen the placebo, whereas 1-2 less fakers would mean that the remaining fakers would need to have even stronger improvements than under the equal split scenario for the group to demonstrate a similar average.

Re seeding: I think this is mostly PR currently. I say currently because it could end up being something, but has to be proven. Didn't they say (can't listen to the webcast) that the improvements overlapped? In other words, all treatment groups sort of looked similar? I guess the thought here is that maybe the FX-322 over 4 doses was balanced out by the lawn effect. There is so much conjecture here. Occam's Razor: Multiple doses does nothing, delivery sucks, and maybe there's some lawn effect too. This is just positive spin.

The delivery does suck, I don't think anyone here disagrees with that. I think it's a bit unfair to say multiple dosing does nothing, although I think it is fair to say multiple dosing does nothing when administered weekly. We can't categorically state the effect of multiple dosing without more data, but I accept the only data we have so far to glean anything from isn't promising. The literature though suggests there still may be grounds for trying it and it's interesting Chris Loose said they're going to try a multi-dose trial again in parallel to whatever future single dose trial they do. Lawn effect remains unknown, but again, I was just trying to illustrate a situation whereby, assuming what Frequency Therapeutics are saying is true - and given how much trust has been lost I accept that is a big stretch for many, myself included - it's possible this has an effect too. The reality is we don't know. Occam's Razor: multiple dosing does nothing (if not detrimental) in weekly doses, delivery sucks, lawn effect currently unknown.

There is no way this goes to Phase 3 from the Phase 2 results. Think of it this way. If you are right that the numbers are 25% fakers, there's a downside to this. As I've outlined, it's embarrassing for the company. They didn't even calculate confidence intervals comparing WR >=6 month to screening (as far as we know). Are they really going to tell the FDA that they are so incompetent that their whole trial is messed up? But magically, this same company did everything else perfectly?

It's a horrible look to mess something so simple up. Maybe if the Phase 1b trials are successful, they save some face with the actual drug. This is going to repeat Phase 2.

You are almost certainly right. I'm not trying to give myself or others false hope, but I don't think the FDA will care too much about reputation here. There are clearly several reasons as to why patient selection has gone wrong, but had Frequency Therapeutics not blinded themselves they would have caught their own oversight. That's not an excuse for not being more careful in the first place, but it is worth considering. Clinical trials communicate the minimum requirements to enter the trial all the time, but how many biotechs end up getting their fingers burnt this badly for this exact reason? The thing about hearing loss is that it's not something like cancer, where you either have it or you don't - there are various degrees and levels to it. Cancer diagnostics are also far superior than diagnostics for hearing loss. There are multiple body scan options to determine how far a cancer has spread (MRI, X-ray, CT scan etc), as well as various blood tests. We have no equivalent for hearing loss. We have the shitty audiogram and a WR test. I think we all agree neither are perfect. I think my point here is that you can't fake your way into a cancer treatment trial, whereas even someone with perfect hearing could probably fake their way into a hearing loss trial if they knew what to do.

It's also worth mentioning that some Phase 2 trials use historical controls. It's interesting to me that Frequency Therapeutics have communicated that the placebo effect observed is not in keeping with well-established standards and previous clinical trials in regards to hearing loss.

I'm sorry if I seem harsh here, I'm actually trying to be kind by killing false hope. If I'm wrong, I will change my avatar to the words "Aaron91 is a god." lol.

Unlikely I'll have to keep you to this, but I'm screenshotting it for good measure just in case lol.

 

[Johan001]

Aren't you meant to be a bear? Look, you, FGG, Aaron91, Zugzug might do these complicated posts about all the science etc, but don't you think the actual scientists at Frequency Therapeutics have done the same but with the actual data?

FX-322 doesn't work, and the science points to anything positive being from the placebo effect! Face the facts and move on guys!

Science is still massively unexplored in the hearing/tinnitus field. So, at some point there definitely will be something that actually does work, one way or another. The fact is that for the time being we just need to soldier on and find a way to live our lives regardless.

 

[Olive27]

This is why no one wants to be a bear. Bear is synonymous with blind critic.

And actually, as I alluded to yesterday, I don't think they computed the p-values by reading the Thornton and Raffin paper in detail and understanding how it would be done. The reason I suspect this is because they do an excellent job of quantifying what clearing the 95% CI means from the 3 superstar responders from Phase 1/2.

I also suspect they didn't take the time to understand the theory because if they did, they would have easily computed lower percentage confidence intervals to detect inconsistencies at the screening.

Besides, none of us think we are better than Will McLean, Robert Langer, or anyone there, really (it's kind of funny to think otherwise). We are mostly having a a fun, educational discussion.

But you are then being a blind patriot towards Frequency Therapeutics if you think a multi million dollar company in a clinical trial didn't compute their p values correctly because it doesn't match the outcome you wanted!

Wow I have even less respect now!