Frequency Therapeutics — Hearing Loss Regeneration

[Zugzug]

You know, I really think you should send them an email outlining all this. I don't think it would do any harm.

My guess is that they considered these things, but maybe it would have made recruiting difficult. According to the ClinicalTrials.gov, they started on October 4, 2019, so they can't use the COVID-19 lockdowns as an excuse for this aspect of the trial. I wonder if there was investor pressure to move it along.

 

[FGG]

Common sense beats going down technical rabbit-holes.

Common sense dictates that this project is going back to the drawing board.

Now, you may feel that this move is somehow unfair, but that's what seems most likely.

You were comparing the process of trying to understand why the results look the way they do to worshipping completely fictional entities.

It's a nonsense comparison, regardless of outcome.

 

[Lucifer]

He said all of a sudden.

Thanks for the reply. Day 210 results will be interesting then. If they do a u-turn and say that the Day 210 outcome was positive, it will be because of the 3 positive anecdotes and others who had similar experiences to them after Day 90.

 

[LivingGhost371]

My theory on this all is that restoring hearing isn't going to be enough to immediately knock out tinnitus. Maybe it will take some time for the brain to reset. Maybe the brain will need an extra bump to reset, possibly Lenire (didn't the best responders to this have normal hearing) or the Trobalt replacement or Shore's device or rTMS or whatever.

 

[Lucifer]

My theory on this all is that restoring hearing isn't going to be enough to immediately knock out tinnitus. Maybe it will take some time for the brain to reset. Maybe the brain will need an extra bump to reset, possibly Lenire (didn't the best responders to this have normal hearing) or the Trobalt replacement or Shore's device or rTMS or whatever.

I believe Lenire will be relevant once they get FX-322 all sorted. To get rid of tinnitus completely I reckon you need both but FX-322 will need to do most of the work.

They need to fix the physical damage first before Lenire can be useful.

 

[Tezcatlipoca]

My theory on this all is that restoring hearing isn't going to be enough to immediately knock out tinnitus. Maybe it will take some time for the brain to reset. Maybe the brain will need an extra bump to reset, possibly Lenire (didn't the best responders to this have normal hearing) or the Trobalt replacement or Shore's device or rTMS or whatever.

Maybe even a little impoverishment in IHC is enough to reverse plasticity.

 

[Aaron91]

It's still surreal to me this has happened.

I just want to say something to all those pointing fingers, the I-told-you-so's, the naysayers, the conspiracy theorists and so on.

I mentioned this shortly before the readout, but there's a biotech hedgefund called Perceptive Advisors who have a brilliant track record of picking winners. They are considered the best in the business in this area. They have a small investment team made up of molecular biology PhDs, former academics, doctors, biomedical engineers - the whole shebang. Super bright and intelligent people. They bet on Frequency Therapeutics, so much so that they took a 10% position in the company. Out of their 166 open positions, Frequency Therapeutics is 23rd on their list in terms of size - that's top 14%. This is a bull if you've ever seen one.

So for those of us who were expecting good news and gave good reasons for doing so and are trying to make sense of what's happened here, at least we've gone down with some pretty respectable minds who are far more qualified than most of us on this forum.

 

[Gb3]

Their latest tweet mentions "medicines" to treat hearing loss. What is that all about?

 

[Lucifer]

Maybe even a little impoverishment in IHC is enough to reverse plasticity.

That's what I believe with the single dosing of FX-322. The tinnitus may not go away instantly but should reduce in time as long as hair cells are still regrowing. I expect the same thing to happen with hyperacusis.

 

[Tezcatlipoca]

It's still surreal to me this has happened.

I just want to say something to all those pointing fingers, the I-told-you-so's, the naysayers, the conspiracy theorists and so on.

I mentioned this shortly before the readout, but there's a biotech hedgefund called Perceptive Advisors who have a brilliant track record of picking winners. They are considered the best in the business in this area. They have a small investment team made up of molecular biology PhDs, former academics, doctors, biomedical engineers - the whole shebang. Super bright and intelligent people. They bet on Frequency Therapeutics, so much so that they took a 10% position in the company. Out of their 166 open positions, Frequency Therapeutics is 23rd on their list in terms of size - that's top 14%. This is a bull if you've ever seen one.

So for those of us who were expecting good news and gave good reasons for doing so and are trying to make sense of what's happened here, at least we've gone down with some pretty respectable minds who are far more qualified than most of us on this forum.

Have they sold their shares? Or are they still backing FREQ?

 

[Aaron91]

Their latest tweet mentions "medicines" to treat hearing loss. What is that all about?

Semantics. I think everyone is overthinking this tweet.

 

[Lucifer]

It's still surreal to me this has happened.

I just want to say something to all those pointing fingers, the I-told-you-so's, the naysayers, the conspiracy theorists and so on.

I mentioned this shortly before the readout, but there's a biotech hedgefund called Perceptive Advisors who have a brilliant track record of picking winners. They are considered the best in the business in this area. They have a small investment team made up of molecular biology PhDs, former academics, doctors, biomedical engineers - the whole shebang. Super bright and intelligent people. They bet on Frequency Therapeutics, so much so that they took a 10% position in the company. Out of their 166 open positions, Frequency Therapeutics is 23rd on their list in terms of size - that's top 14%. This is a bull if you've ever seen one.

So for those of us who were expecting good news and gave good reasons for doing so and are trying to make sense of what's happened here, at least we've gone down with some pretty respectable minds who are far more qualified than most of us on this forum.

Assuming those word score improvements from Phase 1b weren't fake, how can someone double their word scores? I still have faith with FX-322 but the single dosing is going to be key here.

I think monthly doses would have been a better option but from the trials so far it seems the maximum benefit from one dose of FX-322 is 90 days so maybe the dosage needs to be every 90 days.

If Frequency Therapeutics can somehow improve their delivery method where one dose of FX-322 can reach the end of the round window then this will save time and money. We wouldn't need to worry about multiple dosing of FX-322 as one dose will be enough for almost everyone.

 

[Aaron91]

Have they sold their shares? Or are they still backing FREQ?

Good question, I actually made the post as I happened to go check this. I can't see any evidence of them having closed their position but there could be a lag/time delay - I will keep an eye out though in the coming weeks/months. I imagine they might also be doing what we're doing right now.

 

[FGG]

Semantics. I think everyone is overthinking this tweet.

Lol. It look me an hour or two but I'm there too.

 

[Diesel]

Good question, I actually made the post as I happened to go check this. I can't see any evidence of them having closed their position but there could be a lag/time delay - I will keep an eye out though in the coming weeks/months. I imagine they might also be doing what we're doing right now.

I believe institutions report their holdings quarterly. A change would be visible in April.

 

[Tezcatlipoca]

I believe institutions report their holdings quarterly. A change would be visible in April.

Let's put a pin in that then. We should know in a couple of weeks.

 

[Zugzug]

It's still surreal to me this has happened.

I just want to say something to all those pointing fingers, the I-told-you-so's, the naysayers, the conspiracy theorists and so on.

I mentioned this shortly before the readout, but there's a biotech hedgefund called Perceptive Advisors who have a brilliant track record of picking winners. They are considered the best in the business in this area. They have a small investment team made up of molecular biology PhDs, former academics, doctors, biomedical engineers - the whole shebang. Super bright and intelligent people. They bet on Frequency Therapeutics, so much so that they took a 10% position in the company. Out of their 166 open positions, Frequency Therapeutics is 23rd on their list in terms of size - that's top 14%. This is a bull if you've ever seen one.

So for those of us who were expecting good news and gave good reasons for doing so and are trying to make sense of what's happened here, at least we've gone down with some pretty respectable minds who are far more qualified than most of us on this forum.

Thinking this wasn't supposed to be a success is completely unreasonable. Could we have tempered our expectations a little? Maybe. But really not by much. I think we all sort of know when we're in rabbit-hole land and having fun with some speculation versus hard facts.

The hard facts were: Works in a lab, cures mice, works ex vivo in human cochlea, makes its way into the perilymph, had super responders in Phase 1/2 that weren't seen in the placebo group, and most importantly, has a team of expert scientists.

The thing I've learned (and why I'm now a bear) is by default, assume the conjecture stuff has to be totally proven. This is how hypothesis testing is set up; the scientists think they know what will happen (and this information is actually used to calculate sample sizes, etc.), but they have to operate under the painful assumption that absolutely anything can happen.

The only thing I'm learning from last time is not getting too invested in the lawn theory, beyond an academic curiosity. Until they prove this idea, I will go into the next trial as if it's not true (not that it matters because they are doing single dosing, but that's the idea).

 

[Diesel]

The thing I've learned (and why I'm now a bear) is by default, assume the conjecture stuff has to be totally proven. This is how hypothesis testing is set up; the scientists think they know what will happen (and this information is actually used to calculate sample sizes, etc.), but they have to operate under the painful assumption that absolutely anything can happen.

The only thing I'm learning from last time is not getting too invested in the lawn theory, beyond an academic curiosity. Until they prove this idea, I will go into the next trial as if it's not true (not that it matters because they are doing single dosing, but that's the idea).

You have to chuckle in sadness a little that considering all the science and brains behind the clinical trial, they left an exploit in their recruiting method that the average joe herd mind figured out from social media.

I was a little taken back that the lawn analogy was used to explain science on an investor call with biotech analysts. They probably could have gone up a few levels and explain in some scientific terms what they believed they were observing. This makes me think that if/when a multi-dose "parallel" trial takes place, it may be one of many before they get it just right.

Probably better to invest in trialing different extended release formulas.

 

[Koz]

When I initially got attached to FX-322, it wasn't for the notion of "improved word scores" and improvements in the super high frequencies. It was for a potentially effective hearing loss treatment. Like actual restoration that is evident on an audiogram for those of us, like me, have hearing loss that shows on the entire audiogram with potentially being able to improve or outright get rid of tinnitus as a by-product of the drug.

The results from Phase 1 on this thing were really not a big deal and in fact we all acknowledged it wasn't because it was just a safety dose - one safety dose. Now all of a sudden we're all going with the narrative that it was something significant? A 10 dB improvement at 8 kHz is already within the give or take +/- range of a hearing test without any drug injected in your ear and as for the word scores you already have these guys saying there might be bias. I mean come on.

The only few little positives from it would have been worthy of something if they got something out of Phase 2. They did not. Assuming their full ex-vivo restoration was multidose injection which led them to going this route initially and that didn't work in-vivo then literally anything from this point onwards is "well let's hope this other way works".

There is absolutely no guarantee whatever they do from this point matches with the hundreds of hypotheses in here of what went wrong and what will happen moving forward. Has it so far? The only certainty as of now is uncertainty. I say this whilst at the same time applauding the effort and thinking that goes behind some of "what went wrong / what might still happen" hypothesis contributions.

Sorry if I sound like a negative Debbie Downer, but I can't help but feel there's a lot of rationalising based on hope and desperation and I don't blame anyone for it but I can't say I am anywhere near as attached to this product as I was initially.

It's the very reason I am going to take a break from this thread and this forum indefinitely. Months and months of waiting as we sit theorizing which subsequently could flat out be off the mark and pointless in the long run is not how I want to spend my time moving forwards.

Good luck guys, if these guys are the frontrunners of hearing loss treatment then unfortunately we are a bit further off away than we had all hoped for. They could still very well get it right but by this point, putting a time on it or even hypothesizing how it will happen is practically useless. I'm sorry.

 

[Street Novelist]

Extended release formula? I don't even want to think about how long that would take Frequency Therapeutics to develop. After all of these years, to think we might have to wait a few more, Jesus, it's unbearable. Please God, guide them in their quest.

 

[just1morething]

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

It doesn't look good when FREQ stock price broke below the IPO price in a matter of seconds. Confidence has been shaken to the core. Science is one thing but the trials are the only thing that really matters. Maybe it will work better with a single dose.

 

[weab00]

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

It's called corpspeak.

 

[paul mclean]

Do you reckon David Luchinno, Robert Langer and the rest of the team are hurting right now and don't know what to do? Or do you think they know specifically what went wrong and how they are going to fix this?

 

[Lucifer]

Do you reckon David Luchinno, Robert Langer and the rest of the team are hurting right now and don't know what to do? Or do you think they know specifically what went wrong and how they are going to fix this?

They definitely know what went wrong. The weekly dosing of FX-322 was too much for the ear to handle. The single dosing shown in previous trials was more effective than the multi dosing.

From this moment on they will focus with the single dosing treatment but in the future they may try running a simultaneous trial dosing monthly.

 

[Gb3]

It's the very reason I am going to take a break from this thread and this forum indefinitely.

Last seen one minute ago.

 

[Aaron91]

They definitely know what went wrong. The weekly dosing of FX-322 was too much for the ear to handle. The single dosing shown in previous trials was more effective than the multi dosing.

From this moment on they will focus with the single dosing treatment but in the future they may try running a simultaneous trial dosing monthly.

During the teleconference call, when pressed by an investor on what mechanical or molecular effect could be causing the multi-dosing to dampen the effect, they had no answer. When subsequently asked whether there was any pre-clinical work to inform what might be happening, or why they pursued multi-dosing in the first place, again they had no answer. In their defence, they said it was impossible to try multi-dosing in vivo in animals as it would be too traumatic to the cochlea. I can only infer from that that any pre-clinical work in ex vivo human cochlea wouldn't serve to inform anything meaningful. Whatever way you look at it, Phase 2 was a giant experiment in multi-dosing that backfired spectacularly.

Anyone listening in to that webcast could see a deer having been caught in the headlights. I think it's fair to say they know multi-dosing screwed things up, but not being able to explain it, let alone not being able to justify why they pursued multi-dosing without any pre-clinical work to inform making that decision the first place, makes for seriously bad optics. Chris Loose and David Lucchino strike me as very confident and the latter made it very clear they were not going to rest on their laurels and just wait for Phase 1b results to come out and see what happens. It sounded to me as if they're already drawing up some kind of contingency plan. The reality is that this is a new company testing a new platform in an area where there is an unmet need. The odds are stacked against them.

 

[RichieTheKid]

Why don't we come up with a delivery method? Any experts here?

 

[GlennS]

You were comparing the process of trying to understand why the results look the way they do to worshipping completely fictional entities.
It's a nonsense comparison, regardless of outcome.

I stand by my assertion that there is a lot of faith-based argumentation going on here, shrouded behind intellectual rationalization as it may be. We obviously want this to work so there's no way for us to be completely objective.

 

[Diesel]

During the teleconference call, when pressed by an investor on what mechanical or molecular effect could be causing the multi-dosing to dampen the effect, they had no answer. When subsequently asked whether there was any pre-clinical work to inform what might be happening, or why they pursued multi-dosing in the first place, again they had no answer. In their defence, they said it was impossible to try multi-dosing in vivo in animals as it would be too traumatic to the cochlea. I can only infer from that that any pre-clinical work in ex vivo human cochlea wouldn't serve to inform anything meaningful. Whatever way you look at it, Phase 2 was a giant experiment in multi-dosing that backfired spectacularly.

Anyone listening in to that webcast could see a deer having been caught in the headlights. I think it's fair to say they know multi-dosing screwed things up, but not being able to explain it, let alone not being able to justify why they pursued multi-dosing without any pre-clinical work to inform making that decision the first place, makes for seriously bad optics. Chris Loose and David Lucchino strike me as very confident and the latter made it very clear they were not going to rest on their laurels and just wait for Phase 1b results to come out and see what happens. It sounded to me as if they're already drawing up some kind of contingency plan. The reality is that this is a new company testing a new platform in an area where there is an unmet need. The odds are stacked against them.

In hindsight, there were a few times in the past where Frequency Therapeutics was interviewed and they said they were unable to validate a multi-dose strategy with an animal model. Probably a bigger red flag than many of us realized.

However, multi-dosing being untested and ultimately needing more research doesn't mean the drug is a 100% flop. Showing those open-label trial results should be more revealing.

I'm curious if they could do a multi-dose open label trial? Just recruit groups into cohorts based on a 2x dose schedule length? Like a 2-week, 1-month, 2-month group?

 

[kiki]

I thought about why multiple short-term intensive injections, once a week, would hinder the effect.

1. Because the division of support cells by HIR99021 and VPA destroys the delicate and growing hair cells that are supported.

2. Because the induction of division by HIR99021 and VPA also acts on growing hair cells and destroys them.

3. Because the pressure of the injected FX-322 gel destroys delicate growing hair cells.

4. After the supporting cell (LGR5+) divides into two, "modification of epigenetic status" by VPA (HDAC) regenerates one into hair cells.
However, the second and subsequent injections adversely affect the "modification of epigenetic status" with each injection, ruining and inhibiting the regeneration of growing hair cells.

5. Caused by multiple 1, 2, 3, and 4.

6. Or something completely different.

I think I have to wait for the cause to be announced by FREQ, but when will it be ...

If anyone is guessing the cause, please let me know.