Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

You've mentioned "super responders" quite a bit, but I'm not sure they exist.

During Phase I, a few participants who received FX-322 significantly improved word scores. There was a tremendous amount riding on them, and a great deal of hope, not only among participants but also audiologists evaluating them. It's possible unconscious (and conscious) bias skewed results, along with X factors we can never know. Maybe the participants had better night sleeps before the 2nd evaluation. Maybe they had more coffee. Maybe the evaluators made it easier for them, somehow. Maybe the focus on safety meant results were treated more casually. That doesn't mean participants were liars or the results were fraudulent. It means that it was a Phase I safety study with a handful of humans, evaluated by humans, with a great deal riding on them.

If 50% of the almost 100 participants in Phase II showed meaningful word score increases, that would be huge. But 50% of 6 people during Phase I just doesn't tell us all that much (which is why drug trials proceed to ever larger and more meaningful Phase II and Phase III studies).

I respectfully disagree with the perspective on super responders. Coffee or a good night's sleep doesn't double word score and make someone hear better. If it did, we'd all know about it. The trial, even the experimental outcomes are performed to a standard, the details which is reviewed and accepted, so I doubt a testing site just decided to go easy on participants just because. Finally, these super responders consistently showed improvement at day 15, 30, 60, and 90. It's in that patent document shared a few pages back. No amount of sleep, caffeine, or selective lax testing practices would explain this.

 

[FGG]

Agreed. I'm not sure it's helpful to vilify participants who joined the trial at real risk to themselves, or speculate that they're "liars." It's also possible other factors influenced improvements across both treated and placebo groups. It could be that after receiving the treatments, everyone was just super focused in their post-treatment evaluations, swept up in the potentially life-altering process, with evaluators similarly, subtly, pulling for the participants, all with the expectation scores would improve.

That aside, let's assume, for the sake of argument, some participants artificially deflated pre-treatment word scores. Thing is, I'm not sure that undermines the results.

Since no one knew if they were to receive FX-322 or a placebo, artificially deflated scores would be evenly distributed across both placebo and treatment groups. Subsequent score boosts would therefore also be evenly distributed, rather than aggregate only around the placebos. For example, let's say artificially deflating pre-treatment scores gives you, just to pick a number, an extra 10 points in the end. Those 10 points would occur evenly among all groups (as they actually did – all groups, placebo and treated, showed similar word score improvements).

However, if FX-322 actually worked, the trial design flaw cancels itself out, and you would see an additional response, above and beyond the artificial response, among the treated group (10 fake points across all groups + actual improvements for participants treated with FX-322).

I'm not arguing that FX-322 doesn't work, I'm arguing that the trial design flaw doesn't by itself explain the lack of results.

Frequency Therapeutics has argued that they have evidence that people deflated their word scores and rapid multi-dosing itself was detrimental to outcomes (this was true if you got placebo or drug: fluid overload effect? disturbance effect? But even worse if you got more drug). When they release the full data this should show those stats.

Both of those things need to be true to explain the data and that's at least what the company is claiming.

 

[Zugzug]

I respectfully disagree with the perspective on super responders. Coffee or a good night's sleep doesn't double word score and make someone hear better. If it did, we'd all know about it. The trial, even the experimental outcomes are performed to a standard, the details which is reviewed and accepted, so I doubt a testing site just decided to go easy on participants just because. Finally, these super responders consistently showed improvement at day 15, 30, 60, and 90. It's in that patent document shared a few pages back. No amount of sleep, caffeine, or selective lax testing practices would explain this.

Thank you for putting a finer point on my point.

There's no question that the WR test is flawed. But if really was this totally random test where your word scores could often fly all over the place from 20% to 75% or something, there's no way it would be in clinical practice.

I still maintain my position that we don't know what the something is. If there's a placebo patient in the severe trial that looks like that, we'll know (at the very least) the trial designs are screwed.

Even if the severe trial provides no placebo super improvers, it still doesn't override a Phase 2. I feel like we should be careful about where we were wrong and where we weren't. Make no mistake about it -- those 3 super improvers are not normal findings. Even audiologists agree with that.

 

[Jack V]

I'm a little confused, since I've been saying the same things. When I say "super responders," (at the time this post is written, without more data) I really mean super improvers.

My belief is that clearly something is describing these doublings. All of the points you made are valid considerations. I've been insisting that Phase 2 efficacy matters so much more because the recruiting is biased towards finding responders.

Do I think it's possible that at least 1 of those 3 people had a super response to the drug? Absolutely. Do I think the "evidence is there," so everyone should invest their soul into this drug? Absolutely not.

I think you are misrepresenting my positions. I have admitted that my assumption, prior to the Phase 2 results, that the something was definitely the drug, has not been proven.

Thanks for clarifying. And if I may clarify, you are a "super responder" because your responses in this thread have been super!

What I'm saying is this: far too many big conclusions have been drawn by the almost meaningless positive responses from Phase I. Lost in the language of "Phase I, Phase II, Phase III" is what these processes actually are, how the numbers grow exponentially from almost nothing to potentially millions of people, and how easy it is to get carried away by what could easily be an anomaly among 3 people – three! the number of fingers on one hand (of a Simpson) – explained away by all too human explanations.

After all, AM-101 advanced from Phase I (positive results) to Phase II (positive results) to Phase III where, in light of greater, more meaningful numbers, crashed and burned.

 

[Tezcatlipoca]

You've mentioned "super responders" quite a bit, but I'm not sure they exist.

During Phase I, a few participants who received FX-322 significantly improved word scores. There was a tremendous amount riding on them, and a great deal of hope, not only among participants but also audiologists evaluating them. It's possible unconscious (and conscious) bias skewed results, along with X factors we can never know. Maybe the participants had better night sleeps before the 2nd evaluation. Maybe they had more coffee. Maybe the evaluators made it easier for them, somehow. Maybe the focus on safety meant results were treated more casually. That doesn't mean participants were liars or the results were fraudulent. It means that it was a Phase I safety study with a handful of humans, evaluated by humans, with a great deal riding on them.

If 50% of the almost 100 participants in Phase II showed meaningful word score increases, that would be huge. But 50% of 6 people during Phase I just doesn't tell us all that much (which is why drug trials proceed to ever larger and more meaningful Phase II and Phase III studies).

That would be one hell of a good night sleep/cup of coffee, because word scores had never been doubled before.

 

[MrCrybaby]

Humans have different SGNs than rodents and ours do not degrade for decades to maybe even never. Neuronal damage in humans is usually more immune mediated (MS, GBS etc) and I believe that's Rinri Therapeutics' target population as well.

Oh good to know! When reading up of this I'd always find vague figures, like saying the nerves degrade "over months or possibly years" so I assumed there would be a smaller window to intervene.

 

[Zugzug]

Thanks for clarifying. And if I may clarify, you are a "super responder" because your responses in this thread have been super!

What I'm saying is this: far too many big conclusions have been drawn by the almost meaningless positive responses from Phase I. Lost in the language of "Phase I, Phase II, Phase III" is what these processes actually are, how the numbers grow exponentially from almost nothing to potentially millions of people, and how easy it is to get carried away by what could easily be an anomaly among 3 people – three! the number of fingers on one hand (of a Simpson) – explained away by all too human explanations.

After all, AM-101 advanced from Phase I (positive results) to Phase II (positive results) to Phase III where, in light of greater, more meaningful numbers, crashed and burned.

I'm 100% with you in terms of the drug demonstrating efficacy, certainly three people is not nearly enough.

However, I will throw this out there. And I don't want to make this point repeatedly. Not all placebo effects are the same. Now of course, in terms of a proof, we have to assume that they are. In other words, no matter how painful it is, the clinical trials have to assume that anything at all can happen from a placebo effect.

In reality though, they are not all the same. For example, if a placebo is used to treat anxiety, just believing in the drug can reduce anxiety at least some. I'm not saying anti-anxiety drugs are just a placebo effect, but it's a more reasonable thing.

To take an extreme position, if someone is paralyzed, there's no placebo they can take to undo that.

Hence, I think you are misunderstanding our position on the three number. It's not that it's a big, convincing number, but rather that the degree of difficulty to pull it off at all is very high.

To offer another analogy, if you saw someone squat 700 lbs once, would you suspect that they aren't strong because you only saw it one time?

With all of this being said, I am definitely team "at least 1 of the 3 means something." The something is flexible, ranging from drug efficacy to cheating to receiving the same test twice and memorizing it. Something that's off.

 

[FGG]

Oh good to know! When reading up of this I'd always find vague figures, like saying the nerves degrade "over months or possibly years" so I assumed there would be a smaller window to intervene.

That was the thought based on rodent studies but it turns out our SGNs are really different from rodents.

 

[RB2014]

I'm 100% with you in terms of the drug demonstrating efficacy, certainly three people is not nearly enough.

However, I will throw this out there. And I don't want to make this point repeatedly. Not all placebo effects are the same. Now of course, in terms of a proof, we have to assume that they are. In other words, no matter how painful it is, the clinical trials have to assume that anything at all can happen from a placebo effect.

In reality though, they are not all the same. For example, if a placebo is used to treat anxiety, just believing in the drug can reduce anxiety at least some. I'm not saying anti-anxiety drugs are just a placebo effect, but it's a more reasonable thing.

To take an extreme position, if someone is paralyzed, there's no placebo they can take to undo that.

Hence, I think you are misunderstanding our position on the three number. It's not that it's a big, convincing number, but rather that the degree of difficulty to pull it off at all is very high.

To offer another analogy, if you saw someone squat 700 lbs once, would you suspect that they aren't strong because you only saw it one time?

With all of this being said, I am definitely team "at least 1 of the 3 means something." The something is flexible, ranging from drug efficacy to cheating to receiving the same test twice and memorizing it. Something that's off.

When I got tinnitus, I went to the doctor and they prescribed anti-depressants for my severe depression. They said "take these and your depression will go away." I took them. A week later I was my old self again after months after months of feeling horrible. When I checked in a week later with my doctor I told them I was cured. They said... wait a second... it doesn't work like that. The medicine takes time and the earliest I would begin to see a benefit would be two weeks. I had cured myself based on the belief that the anti-depressants would cure me. The placebo effect can work. This was an extreme case, but just the belief that I would get better was enough to cure me.

 

[Jack V]

Frequency Therapeutics has argued that they have evidence that people deflated their word scores and rapid multi-dosing itself was detrimental to outcomes (this was true if you got placebo or drug: fluid overload effect? disturbance effect? But even worse if you got more drug). When they release the full data this should show those stats.

Both of those things need to be true to explain the data and that's at least what the company is claiming.

Regarding deflated word scores, my point is that I just don't see how that impacts results as much as they indicated, given that artificial deflations would be evenly distributed. You'd still expect a bump (above and beyond whatever artificial deflation gives you) among treated participants.

Regarding rapid multi-dosing, we didn't get evidence, we got a metaphor ("walking on a recently seeded lawn"). Hopefully there is actual evidence behind it, because that's easier to fix than the alternatives.

 

[Zugzug]

That aside, let's assume, for the sake of argument, some participants artificially deflated pre-treatment word scores. Thing is, I'm not sure that undermines the results.

Since no one knew if they were to receive FX-322 or a placebo, artificially deflated scores would be evenly distributed across both placebo and treatment groups. Subsequent score boosts would therefore also be evenly distributed, rather than aggregate only around the placebos. For example, let's say artificially deflating pre-treatment scores gives you, just to pick a number, an extra 10 points in the end. Those 10 points would occur evenly among all groups (as they actually did – all groups, placebo and treated, showed similar word score improvements).

However, if FX-322 actually worked, the trial design flaw cancels itself out, and you would see an additional response, above and beyond the artificial response, among the treated group (10 fake points across all groups + actual improvements for participants treated with FX-322).

I'm not arguing that FX-322 doesn't work, I'm arguing that the trial design flaw doesn't by itself explain the lack of results.

I actually agree with most of this.
What I think is going on is the drug really is more disappointing than we were hoping for in live humans. I'm generally with you that there should be some cancelling out going on within the groups. And actually, it was a 3:1 treatment to placebo design so the treatment groups should have received a ton of the word deflaters, if they exist.

My current belief is that the drug does work, but it's for an odd or specific hair cell distribution type. Sadly, it could fail Phase 2 again for this reason.

My low goal for this drug is just some proof of in vivo action at an individual level. Even finding out there are some people that do respond is nice moving forward, as it gives hope that a new formulation and/or delivery could achieve the necessary Phase 2 incremental result.

 

[Jack V]

I'm 100% with you in terms of the drug demonstrating efficacy, certainly three people is not nearly enough.

However, I will throw this out there. And I don't want to make this point repeatedly. Not all placebo effects are the same. Now of course, in terms of a proof, we have to assume that they are. In other words, no matter how painful it is, the clinical trials have to assume that anything at all can happen from a placebo effect.

In reality though, they are not all the same. For example, if a placebo is used to treat anxiety, just believing in the drug can reduce anxiety at least some. I'm not saying anti-anxiety drugs are just a placebo effect, but it's a more reasonable thing.

To take an extreme position, if someone is paralyzed, there's no placebo they can take to undo that.

Hence, I think you are misunderstanding our position on the three number. It's not that it's a big, convincing number, but rather that the degree of difficulty to pull it off at all is very high.

To offer another analogy, if you saw someone squat 700 lbs once, would you suspect that they aren't strong because you only saw it one time?

With all of this being said, I am definitely team "at least 1 of the 3 means something." The something is flexible, ranging from drug efficacy to cheating to receiving the same test twice and memorizing it. Something that's off.

Fair enough. So how hard is it to double word scores in a small group? How many words were they given? What was the interaction like between audiologist and patient? What were the circumstances? What were the expectations?

Patient: "You are one of the first people on Earth to receive a potentially revolutionary drug that will, for the first time in history, restore hearing!"

Audiologist: "We are building a $1b company with some of the most prestigious scientists in the world to achieve the holy grail of regenerative medicine and alleviate the suffering of millions of people, but we do have this little hurdle to overcome first...."

I don't know about you, but I think I'd be all sorts of focused on my follow-up exam.

 

[Tezcatlipoca]

When I got tinnitus, I went to the doctor and they prescribed anti-depressants for my severe depression. They said "take these and your depression will go away." I took them. A week later I was my old self again after months after months of feeling horrible. When I checked in a week later with my doctor I told them I was cured. They said... wait a second... it doesn't work like that. The medicine takes time and the earliest I would begin to see a benefit would be two weeks. I had cured myself based on the belief that the anti-depressants would cure me. The placebo effect can work. This was an extreme case, but just the belief that I would get better was enough to cure me.

Sorry but I don't think we can even compare placebo in depression vs hearing loss, you just can't suddenly "hear better".

 

[FGG]

Fair enough. So how hard is it to double word scores in a small group? How many words were they given? What was the interaction like between audiologist and patient? What were the circumstances? What were the expectations?

Patient: "You are one of the first people on Earth to receive a potentially revolutionary drug that will, for the first time in history, restore hearing!"

Audiologist: "We are building a $1b company with some of the most prestigious scientists in the world to achieve the holy grail of regenerative medicine and alleviate the suffering of millions of people, but we do have this little hurdle to overcome first...."

I don't know about you, but I think I'd be all sorts of focused on my follow-up exam.

I have said this before but if "focus" could actually double word scores, hearing loss would be treated with motivational speakers and pep talks.

Believe me, no amount of caffeine, sleep or "focus" allows me to unscramble the word jumbles on the TV. Even if I sat right in front of it and give it 100% of my focus.

 

[Zugzug]

Fair enough. So how hard is it to double word scores in a small group? How many words were they given? What was the interaction like between audiologist and patient? What were the circumstances? What were the expectations?

Patient: "You are one of the first people on Earth to receive a potentially revolutionary drug that will, for the first time in history, restore hearing!"

Audiologist: "We are building a $1b company with some of the most prestigious scientists in the world to achieve the holy grail of regenerative medicine and alleviate the suffering of millions of people, but we do have this little hurdle to overcome first...."

I don't know about you, but I think I'd be all sorts of focused on my follow-up exam.

I'll just provide one more thing to think about and I've outlined this in detail in the past. In particular in this post, I talk about the game theory, from the perspective of the participant.

The way I see it, and why I'm not overly concerned with the bias either way, is that there's a balancing effect going on that helps regulate the stuff you talked about.

A test is a quick, 50 word thing, but think about all of the time outside of the testing. I am living with this drug/placebo. I probably have an idea as to which one I think I got.

Say I think I got the placebo. Then my motivation is actually to not score well because by scoring well, I am helping the placebos and reducing the likelihood of me eventually receiving the drug. In other words, the person who goes in gunning for a top score has to believe they got the drug.

Now, granted, there could be a real placebo effect in that they guessed wrong. But given the 3:1 sampling ratio, their likelihood of guessing wrong is a lot lower than in a 1:1 situation. Hence, you are right that there could be more incentive for people who think/did get the drug compared to people who think they didn't, but want to see the drug pass so they can eventually take it.

This is why I argued that the motivation could even favor the treatment group. This is, of course, bad for thee Phase 2 results, as it paints them as even worse on the groupwide level. However, it's confusing at the individual level because if someone is "trying harder" or "studying harder" that also can be correlated with seeing their every day lives improve and want to show it off. Hence, these superstar performances can be a combo effect.

But think about it. If the person doesn't think their life improved at all, why would they want to perform well on the test? Why would the audiologists be "pressuring" them if they are blinded and they could be pressuring a placebo patient, hurting the company? I don't buy this conspiratorial stuff, as it doesn't make sense for a blinded, placebo-controlled study.

Occam's razor is that the drug just isn't that good at a groupwide level, with some individual responders that will play no role in the approval of the drug, but hopefully progress the science in a positive way.

 

[FGG]

I think some people without clarity problems don't get this concept. To them, if you can hear a word, you can understand it as long as you are paying attention, so it's just a function of loudness in their minds.

As an anecdote, I was as motivated to watch Season 2 of The OA as some people would be to advance regenerative medicine. Didn't make any difference, read the captions the whole time.

 

[Diesel]

My low goal for this drug is just some proof of in vivo action at an individual level. Even finding out there are some people that do respond is nice moving forward, as it gives hope that a new formulation and/or delivery could achieve the necessary Phase 2 incremental result.

I actually think the Low Goal is the goal Frequency Therapeutics needs to land on for FX-322, and in hindsight probably should have been trying to figure out immediately after the Phase 1/2. I think trying to cast this wide net of SNHL/NIHL classifications along with ARHL all grouped into a series of trial is simply too broad. I get the incentive to show right away that it works across all of these types, the investors will love access to a huge market.

But really, they should be focusing on where they think the drug will most reliably work; the only evidence is from the Phase 1/2 with the Moderate-Moderately Severe group. Many also think that the Severe-only trial may be promising.

That relatively small group isn't exactly huge, but continued analysis of their condition may help reveal what makes them unique as responders to FX-322.

 

[Zugzug]

I think some people without clarity problems don't get this concept. To them, if you can hear a word, you can understand it as long as you are paying attention, so it's just a function of loudness in their minds.

Definitely. I'll admit that I've struggled with this, and it saddens me, because I know people have to struggle understanding my hyperacusis. I genuinely believe that the biggest thing people are missing about this problem is that the volume is fixed and comfortable. Not understanding this part is where it gets confusing.

Actually, I can sort of relate to this problem, but not in a medically disabled way. I am really, really bad at making out sound lyrics. It doesn't matter how hard I try and how comfortable it is. I often just can't figure out the word. I have to imagine there's a parallel, but with normal words.

 

[roy1159]

Sure! Here is one on temporary threshold shifts and synaptopathy:

Hearing Loss: Reestablish the Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells

But there are a ton of papers on this topic. A lot of cochlear synaptopathy papers mention the temporary audiogram changes despite permanent synapse loss. Just search "cochlear synaptopathy" in PubMed.

Interestingly, it's more established in rodents that cochlear synaptopathy itself can commonly cause tinnitus on its own. A few papers suspect this is "uncommon" for people but temporary thresholds shifts are less common in people so synaptopathy would be the result (usually) of a more gradual and less severe loss than in experimental rodent studies.

Some studies suggest IHC damage itself and not synaptopathy would be the more common cause in normal audiogram people:

Assessment of Hidden Hearing Loss in Normal Hearing Individuals with and Without Tinnitus

I'm not sure where I stand as far as synaptopathy generating tinnitus from the more gradual, cumulative age-related loss but I don't see why we would be different from rodents after a more substantial loss causing a temporary threshold shift, which suggests a lot more synapse damage.

From what I was able to infer (thanks a lot brain fog!), abnormal WAVE I amplitude in ABR test in rodents was indicative of cochlear synaptopathy (without threshold changes). In humans the results weren't as conclusive (I didn't fully understand why).

Do you think if our ABR test is normal (especially WAVE I), it's enough to rule out cochlear synaptopathy? Mine is normal but a 70-year-old understands speech better than I do lol...

 

[FGG]

From what I was able to infer (thanks a lot brain fog!), abnormal WAVE I amplitude in ABR test in rodents was indicative of cochlear synaptopathy (without threshold changes). In humans the results weren't as conclusive (I didn't fully understand why).

Do you think if our ABR test is normal (especially WAVE I), it's enough to rule out cochlear synaptopathy? Mine is normal but a 70-year-old understands speech better than I do lol...

Personally, I don't think synaptopathy is my problem. I think it's a combination EHF and LF (100 Hz and below, I have problems hearing thunder) OHC loss and scattered IHC loss. Insurance didn't cover ABR testing for me. It wouldn't have changed anything so I didn't get it.

Synaptopathy is also usually gradual unless you had a temporary threshold shift (or even permanent one).

 

[serendipity1996]

Definitely. I'll admit that I've struggled with this, and it saddens me, because I know people have to struggle understanding my hyperacusis. I genuinely believe that the biggest thing people are missing about this problem is that the volume is fixed and comfortable. Not understanding this part is where it gets confusing.

Actually, I can sort of relate to this problem, but not in a medically disabled way. I am really, really bad at making out sound lyrics. It doesn't matter how hard I try and how comfortable it is. I often just can't figure out the word. I have to imagine there's a parallel, but with normal words.

Yeah I imagine this is why mental fatigue and exhaustion are so commonly cited with hearing loss as your brain is having to work exceptionally hard to figure out what people are saying. It's not like you can just put your mind to it and succeed.

 

[RingingBrother]

I wonder what's the new timeline now for Frequency Therapeutics to repeat Phase 2a with single dosing?

 

[d'Wooluf]

You've mentioned "super responders" quite a bit, but I'm not sure they exist.

During Phase I, a few participants who received FX-322 significantly improved word scores. There was a tremendous amount riding on them, and a great deal of hope, not only among participants but also audiologists evaluating them.

What gives me a little bit of hope is the follow-up study they did on those super-responders. And the thing that gives me hope is the way most of them were declining off their 90 day scores. It's the consistency of that decline across participants which makes me think that the 90 day scores were possibly reliable.

I still think FX-322 was over-hyped by a group that was more interested in entrepreneurship than science. Anyway, I'm still following along.

Fair enough. So how hard is it to double word scores in a small group? How many words were they given? What was the interaction like between audiologist and patient? What were the circumstances? What were the expectations?

Wasn't this study blinded? And even if it wasn't, the audiologists were employed by a company that was paid to conduct the study. They would have had no great motivation for padding the results.

 

[Street Novelist]

I wonder what's the new timeline now for Frequency Therapeutics to repeat Phase 2a with single dosing?

I think we're going to have to wait until June, when they release the results of their current trials (age-related hearing loss and severe hearing loss).

I wouldn't expect anything before then.

 

[Lucifer]

I think we're going to have to wait until June, when they release the results of their current trials (age-related hearing loss and severe hearing loss).

I wouldn't expect anything before then.

I really hope we hear some good news from the age-relared and severe hearing loss trials.

 

[Tezcatlipoca]

FREQ is back to double digits! $10.06 as of writing this message.

 

[tarmaced]

Checking in for the first time in months.

The news didn't do me any good, but the ongoing analysis is super appreciated.

Feeling informed feels better, even if the info is for the better or otherwise.

June does not seem too long a wait.

Cheers guys and girls.

 

[JRC1]

Why in the world is the FREQ stock up 14% today?

 

[Keith Handy]

Why in the world is the FREQ stock up 14% today?

IDK. Yesterday they tweeted about people over the age of 65. That's all I can spot.

 

[FGG]

IDK. Yesterday they tweeted about people over the age of 65. That's all I can spot.

Sorta but not exactly. They retweeted an AARP tweet and then emphasized clarity again.