Frequency Therapeutics — Hearing Loss Regeneration

[d'Wooluf]

Sure. I always taught that a p-value only measures the validity of an outcome against a statistical model. Not against the real world. This is one of the primary gripes of Bayesian statistics against frequentist.

lol. Thanks for that. I found and bookmarked a 'beginner's' page that compares the two. One day - when I'm confident my head won't explode - I'll read it.

 

[d'Wooluf]

Why else would Astella pony up another $540mil upon successful endpoints? They would have to have serious reason to write up a contract for an additional $540mil.

They pay the full $540 million on full FDA approval I guess, and that makes it a bona fide goldmine. The $80 million is educated speculation. Every payment after that is because risk is reduced with each endpoint reached. If they were totally confident in the success of the product, they might have offered Frequency Therapeutics a single payment of considerably less than the $620 million.

 

[FGG]

They pay the full $540 million on full FDA approval I guess, and that makes it a bona fide goldmine. The $80 million is educated speculation. Every payment after that is because risk is reduced with each endpoint reached. If they were totally confident in the success of the product, they might have offered Frequency Therapeutics a single payment of considerably less than the $620 million.

I put Astellas' payment as they are cautious but optimistic. That data (and any other unknown data they might have) clearly didn't say "the drug doesn't work" to them, though.

 

[FGG]

@JohnAdams, you made me look into how investigational drugs are named .

Apparently, a big factor is how many drugs are being tested at the same trial center(s). You need a unique number. So you couldn't have FX-322 and Avi-322 (fictional drug) at the same center even with the different prefixes. The prefix is obviously just the company name and the two added together further ensures no mix up.

So it's not the "322nd" attempt and possibly (probably?) not a conspiracy.

 

[Mr Mister]

Sure, happy to. The p value is the chance that the results were due to a chance occurance rather than an effect in the hypothesis. So the smaller the p value, the less likely observations were due to chance.

P value takes into account sample size, so the smaller the sample size, the greater the effect has to be to get a small p value.

What this means is, though it's not impossible for the differences between placebo and the drug groups to be due to chance, it's unlikely because of the small p value. So if we are going by odds, it's much more statistically likely there were significant meaningful differences in word scores before and after the drug vs differences in placebo.

It looks like you copied and pasted p-value definition from somewhere so I am still not sure you really understand it. Many statisticians view the small sample size (e.g. 20) is not large enough to test statistical assumptions. The deletion of a single patient's data can reverse the statistically significant conclusion which makes results very unreliable. It makes sense, think about rolling dice a couple of times and then 200 times and compare the averages. And statistical significance does not mean biological significance. It doesn't mean there is a significant effect.

I believe it's because they didn't have a baseline (before injection) of the very high frequemcy measurements because they were just testing safety.

A safety study just requires your hearing not to get worse on a standard audiogram to not report an adverse event. They happened to get an improvement in word score on the safety study, which is exciting so they published. They probably also hoped it would diffuse further but the full dose has potential to diffuse a lot further.

Phase 2 is where efficacy is tested and up to 16000 Hz is included in Frequency's exploratory arm of phase 2. That's not a coincidence. I suspect they believe improvements will be seen there based on the lack of "standard" audiogram changes yet having the increased word score and speech in noise.

Interestingly they are also including THI as well as up to 16000 Hz audiogram. This will be a full efficacy study.

We both know very well that the reason Frequency Therapeutics used pure tone audiometry between 250 Hz and 8000 Hz is that it is a standard for measuring hearing function. Thousands of hearing specialists around the world use it for testing hearing function and it has been verified also on this thread that it is quite commonly used. 250 Hz to 8000 Hz covers the frequencies that are needed for normal hearing in everyday life.

Think about it another way: If frequencies from 8000 Hz to 16000 Hz were crucial to hearing speech then surely Frequency Therapeutics would have been required to test those frequencies for safety. But they were not. Not required by FDA. So please don't confuse people with these ideas that 8000 Hz to 16000 Hz range is crucial to hearing speech because it just isn't.

And since you probably don't believe me, you will believe what Frequency Therapeutics says about it in the IPO document: "Patients are most often tested using pure tone audiometry, in which a tone is played at a particular frequency and patients are asked to indicate whether they can hear the tone at varying levels of loudness. Loudness is recorded in dB. Frequency is recorded in Hertz, or Hz, and is generally measured in the range of 250 to 8000 Hz."
These disclosures are well planned marketing materials prepared by managers who will become millionaires after completion of the IPO. They are cherry picking information and talking about promising word scores when the key point is that there is no change in audiogram which is the golden standard for measuring hearing loss.

 

[JohnAdams]

Is this right?

When we lose input from the cochlea the nerves reattach from places that were giving impulses to other places of activity and that's tinnitus, which explain why some people's tinnitus modulates with what they are looking at.

If that is right, then that means everything is functioning correctly and the only way to get the nerve to reconnect is to restore the input.

Right??

 

[FGG]

It looks like you copied and pasted p-value definition from somewhere so I am still not sure you really understand it. Many statisticians view the small sample size (e.g. 20) is not large enough to test statistical assumptions. The deletion of a single patient's data can reverse the statistically significant conclusion which makes results very unreliable. It makes sense, think about rolling dice a couple of times and then 200 times and compare the averages. And statistical significance does not mean biological significance. It doesn't mean there is a significant effect.

We both know very well that the reason Frequency Therapeutics used pure tone audiometry between 250 Hz and 8000 Hz is that it is a standard for measuring hearing function. Thousands of hearing specialists around the world use it for testing hearing function and it has been verified also on this thread that it is quite commonly used. 250 Hz to 8000 Hz covers the frequencies that are needed for normal hearing in everyday life.

Think about it another way: If frequencies from 8000 Hz to 16000 Hz were crucial to hearing speech then surely Frequency Therapeutics would have been required to test those frequencies for safety. But they were not. Not required by FDA. So please don't confuse people with these ideas that 8000 Hz to 16000 Hz range is crucial to hearing speech because it just isn't.

And since you probably don't believe me, you will believe what Frequency Therapeutics says about it in the IPO document: "Patients are most often tested using pure tone audiometry, in which a tone is played at a particular frequency and patients are asked to indicate whether they can hear the tone at varying levels of loudness. Loudness is recorded in dB. Frequency is recorded in Hertz, or Hz, and is generally measured in the range of 250 to 8000 Hz."
These disclosures are well planned marketing materials prepared by managers who will become millionaires after completion of the IPO. They are cherry picking information and talking about promising word scores when the key point is that there is no change in audiogram which is the golden standard for measuring hearing loss.

I didn't copy a paste a thing. What a baseless assumption.

My information of p values in small studies comes from my own background and investing in biotech that dealt with rare diseases so had a small sample size. There were people saying Sarepta had no proof of working because of the small sample size but these kids' moms were posting DMD skiing in the drug.

And no one anywhere in this thread said 8000-16000 Hz was *essential* to speech. Up to 8000 Hz is but the higher frequencies provide further clarity. You definitely need higher than the wiki article numbers you posted though. Ask literally anyone who has been fitted for a hearing aid.

 

[JohnAdams]

Guys and gals, I've said this before, but when they were testing the foundation of this LGR5+ stem cell ear regeneration using the gamma secretase inhibitor ly411575, the first gave it to the rodents orally, but it caused unwanted side effects. Surely the only chemical on the planet that can cause this to occur isn't just man made. Seriously, what if there is a combination of naturally occurring or readily available compounds that can achieve cochlear hair cell regeneration without the unwanted side effects of the gamma secretase inhibitors that they are using? The action of these chemicals is to make LGR5+ supporting cells proliferate. This is done by inhibiting a pathway called notch1 and also activating a pathway called WNT.

Curcumin is a notch1 inhibitor and that's how I got turned on to it, and I was taking large doses to try and regenerated my hair cells but then found out that didn't work, but had other properties that quieted my tinnitus.

I am dead serious, why aren't we all researching a possible substance or group of substances that can achieve this, and possibly cure our SNHL and then be on with our lives?

 

[WickedCarnival]

If you had bought it you would have lost a lot of money. Be realistic. It doesn't work.

Investing ain't a get rich quick scheme: https://www.investopedia.com/investing/dollar-cost-averaging-pays/

I'd like to put smaller amounts of money into companies that I believe in consistently over time, much like any other intelligent investor.

 

[leledany]

Just curious, but in your opinion why would Astrellas partner with them? They gave them a lot of money up front (not for stock in return but for a return on profits after licensing) after reading the same results we did. They are an established pharma company and this isn't their first rodeo.

Government funding could be a good revenue return, just push on the fact that it has not side effects and have demonstrated hair cell regrow in vitro.

 

[FGG]

Government funding could be a good revenue return, just push on the fact that it has not side effects and have demonstrated hair cell regrow in vitro.

Government funding benefits Frequency sure but Astellas doesn't see a dime unless it passes FDA trials, which means it has proven efficacy. So, what is your opinion on them investing 80 million with no expected revenue unless FX-322 is a licensed drug at the end? They clearly see something optimistic in the data provided.

 

[FGG]

To anyone who feels confident this drug doesn't work: buy long term puts that expire Dec 2020. Yeah long term option contracts are pricey but if you are right, you will make a fortune.

 

[JohnAdams]

To anyone who feels confident this drug doesn't work: buy long term puts that expire Dec 2020. Yeah long term option contracts are pricey but if you are right, you will make a fortune.

Interesting advice given on today of all days.

 

[leledany]

To anyone who feels confident this drug doesn't work: buy long term puts that expire Dec 2020. Yeah long term option contracts are pricey but if you are right, you will make a fortune.

For me the best revenue would be if it works but I have less expectations now.
Why haven't they done high-frequency audiograms already? Is it so complicated? Millions of dollars in funding and they cannot upgrade their soundproof cabin. Ah sorry phase I is only a safety test... just wait another year... funny

 

[Mr Mister]

I didn't copy a paste a thing. What a baseless assumption.

My information of p values in small studies comes from my own background and investing in biotech that dealt with rare diseases so had a small sample size. There were people saying Sarepta had no proof of working because of the small sample size but these kids' moms were posting DMD skiing in the drug.

And no one anywhere in this thread said 8000-16000 Hz was *essential* to speech. Up to 8000 Hz is but the higher frequencies provide further clarity. You definitely need higher than the wiki article numbers you posted though. Ask literally anyone who has been fitted for a hearing aid.

You joined a discussion chain in which it was claimed that frequencies up to 16000 Hz are needed to distinguish words like bike, Mike, hike, etc. It was also suggested that word scores in the clinical trials improved due to improved hearing in the frequencies that were not tested ie 10000-16000 Hz. That was the discussion you joined with your "speech bananas" post which was a continuation of the idea that ultra high frequencies are the explanation behind improved word scores. Hopefully someone can come up with a more realistic explanation.

 

[FGG]

You joined a discussion chain in which it was claimed that frequencies up to 16000 Hz are needed to distinguish words like bike, Mike, hike, etc. It was also suggested that word scores in the clinical trials improved due to improved hearing in the frequencies that were not tested ie 10000-16000 Hz. That was the discussion you joined with your "speech bananas" post which was a continuation of the idea that ultra high frequencies are the explanation behind improved word scores. Hopefully someone can come up with a more realistic explanation.

No. Reread what is written. The claim was that up to 8000 Hz is needed. Above that provides further clarity. That "further clarity" isn't needed to hear regular speech if you have otherwise normal hearing up to 8000 Hz but any increase in clarity can make a big difference when you have hearing deficiencies.

Case in point, the 4 who saw an increase in word scores had moderate to severe hearing loss on the standard (up to 8000 Hz) audiogram. For them any boost in clarity would make a big difference in trying to discern speech.

While the bulk of speech info is under 8000 Hz, there is definitely additional info at the higher frequencies. I posted one article from PubMed for you and would be happy to post others. Just let me know.

https://journals.sagepub.com/doi/abs/10.1177/019459987808600125

 

[Mr Mister]

Government funding benefits Frequency sure but Astellas doesn't see a dime unless it passes FDA trials, which means it has proven efficacy. So, what is your opinion on them investing 80 million with no expected revenue unless FX-322 is a licensed drug at the end? They clearly see something optimistic in the data provided.

Or maybe the Japanese quarter is 25 years and they have more time to wait than us here suffering of tinnitus and hearing loss. There is always option value in the technology and no one is saying that it can not work after further development. It's just much more unlikely after their recent disclosure where it was shown that they struggle even with drug delivery which itself might take years to fix. Time is the key here. We know that hearing loss will be cured ultimately but the question is when.

 

[Mr Mister]

No. Reread what is written. The claim was that up to 8000 Hz is needed. Above that provides further clarity. That "further clarity" isn't needed to hear regular speech if you have otherwise normal hearing up to 8000 Hz but any increase in clarity can make a big difference when you have hearing deficiencies.

Case in point, the 4 who saw an increase in word scores had moderate to severe hearing loss on the standard (up to 8000 Hz) audiogram. For them any boost in clarity would make a big difference in trying to discern speech.

While the bulk of speech info is under 8000 Hz, there is definitely additional info at the higher frequencies. I posted one article from PubMed for you and would be happy to post others. Just let me know.

https://journals.sagepub.com/doi/abs/10.1177/019459987808600125

You are not convincing if you are suggesting that word score results were due to improved hearing in ultra high frequencies. Why are you denying the situation? The fact is that there is no change in audiogram in their clinical trials. No one wanted this but it is better to accept the facts.

 

[FGG]

You are not convincing if you are suggesting that word score results were due to improved hearing in ultra high frequencies. Why are you denying the situation? The fact is that there is no change in audiogram in their clinical trials. No one wanted this but it is better to accept the facts.

Please read this and give me your explanation then:

https://journals.sagepub.com/doi/abs/10.1177/019459987808600125

 

[RB2014]

You are not convincing if you are suggesting that word score results were due to improved hearing in ultra high frequencies. Why are you denying the situation? The fact is that there is no change in audiogram in their clinical trials. No one wanted this but it is better to accept the facts.

We were only trying to come up with some reasoning for the better word scores. I don't think it is possible without a better audiogram either, but I stated that we really don't understand the human ear as well as we should. I'm pretty sure we are all on the same page, and disappointed in the results, and just trying to interpret the data as best as we can.

10 dB is nothing. I bet any hearing test can easily have a 10 dB margin of error. When you throw tinnitus into it, having a good day or bad day could easily cause a 10 dB variance either way.

There are so many problems with this trial, the first being the incredibly small sample size. No testing up to 16 kHz. No explanation of how impartial the tests were. Dosages are still in question. Drug delivery is in question. But hey, we have an IPO on the way...

We really need more information before we start going back and forth and you are right, there are many challenges ahead.

 

[lobbypolice]

Your entire argument for the standard audiogram is that it's the current standard.

And at this point I don't think it's any big secret that high frequency hearing above 8 kHz helps with hearing in noise.

 

[Daniel Lion]

Thanks for your advice everybody.

I have profound hearing loss as you all know, but my word scores are 92% in my right ear and 96% in my left ear. My right ear sustained the most damage. What does that mean? I don't know how to read these charts.

I have decided to pursue hearing aids on the advice of my colleagues here.

Should I go to a center that specializes in hearing aids or to a hospital? My inclination says go to to a center that distributes hearing aids and has many options, any advice? This is all new to me... any thoughts are welcome. Since nothing is happening with Fox until the 5 minute shpeel on the 17th I don't mind asking as I don't think it will distract from the general circuitous conjecture.

Thanks everybody, you're basically my ENT since I don't have one

 

[JohnAdams]

 

[d'Wooluf]

I put Astellas' payment as they are cautious but optimistic. That data (and any other unknown data they might have) clearly didn't say "the drug doesn't work" to them, though.

Yes. You don't just throw away $80 million. Cautious but optimistic is the note that Frequency Therapeutics should have been aiming for in their public communications. What we got was relentless promotion. I prefer the Regain Project's approach. Keep it low-key and just get on with it.

 

[Earing]

Did Frequency Therapeutics do the press release, other than the information already found on the internet?

 

[Fabrikat]

This may have been stated before, but I guess it helps to be mindful that Progenitor Cell Activation is a groundbreaking technology that is in its embryonic stages.

Frequency Therapeutics has decided to choose hearing loss as its first target, but the technology is aimed at many different illnesses.

It may explain why companies such as Astellas are prepared to invest and play the long game with the company.

It may not necessarily work on ears, though we hope that it does, but it may turn out to be very effective on other conditions such as Multiple Sclerosis or intestinal disorders for example. All very lucrative for any Biotech investor.

 

[Daniel Lion]

Just curious, but in your opinion why would Astrellas partner with them? They gave them a lot of money up front (not for stock in return but for a return on profits after licensing) after reading the same results we did. They are an established pharma company and this isn't their first rodeo.

FGG, I really respect you so much.

My ears are shot and really wanted this to work.

To be honest 65,000,000 or 85,000,000 is chump change. Freaking athletes and movie stars have that kind of cash. I'm on a three day drug binge. Between losing my best friend and my audiogram I just said fuck it. I'll regroup soon.

Frequency Therapeutics and the hype machine, I should have known Lucchino was a skilled bullshit artist.

Time will tell, god willing we get help, and just maybe we get lucky.

 

[Aleksa Uzunovic]

Ey guys, pay attention to Audion's Regain trial. We will have info whether their thing cures hearing loss next year. They are going with this much more efficiently and if their thing works we will have our treatment most probably next year. I feel like they are genuinely working to get the cure as fast as possible to the patients.

Forget about Frequency Therapeutics, they are bunch of corporate pricks and they are irrelevant, screw 'em.

 

[Daniel Lion]

Ey guys, pay attention to Audion's Regain trial. We will have info whether their thing cures hearing loss next year. They are going with this much more efficiently and if their thing works we will have our treatment most probably next year. I feel like they are genuinely working to get the cure as fast as possible to the patients.

Forget about Frequency Therapeutics, they are bunch of corporate pricks and they are irrelevant, screw 'em.

Aleksa that's how people speak where I grew up in Boston. No bullshit, no flowery crap. Like your style man. You may well be right. Thanks for weighing in...

 

[Jukka]

Ey guys, pay attention to Audion's Regain trial. We will have info whether their thing cures hearing loss next year. They are going with this much more efficiently and if their thing works we will have our treatment most probably next year. I feel like they are genuinely working to get the cure as fast as possible to the patients.

Forget about Frequency Therapeutics, they are bunch of corporate pricks and they are irrelevant, screw 'em.

Right. And how about OTO-413 and/or CGF166?