Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

The model with the fewest assumptions is probably the correct one, and that one requires many. What accounts for such variability in the tone and intensity of this gap-filling, if hearing loss is permanent? I suspect the signal generation is coming from the cochlea itself, as in the case of otoacoustic emissions or hair cells that are stuck in the "on" position. Obviously damage can occur at any point along the auditory pathway, but for a condition so common, there are likely more common points of failure.

This was discussed already, but the biggest indicator is that in a study on 151 patients that had their auditory nerve cut, 95.4% of patients achieved a favorable outcome. The author of this particular study is now deceased, but if you trust the data it does indicate the signal generation coming from the cochlea. Its entirely possible that all of the neural correlates observed in fNIRS, fMRI, EEG scans of people's brains are just correlates of the psycho-adaptations of tinnitus.

"Hair cells stuck in on" can't be correct because people with diffuse flat epithelial (it's just fibroblasts at that point and no longer has IHC, OHC or even support cells left) in the profound range still have tinnitus, often severe.

I haven't read studies with near a 95% success rate for nerve section. Can you link me the study you are referring to? It's possible, however in some cases the brain stops trying to match perception in those cases.

 

[rid0871]

I really don't think Frequency Therapeutics gives a damn about anyone that is suffering from this nightmare we live... All they do is stall and stall... It's inhumane... All these years... It's just wrong and inhumane...

 

[Tezcatlipoca]

I really don't think Frequency Therapeutics gives a damn about anyone that is suffering from this nightmare we live... All they do is stall and stall... It's inhumane... All these years... It's just wrong and inhumane...

They do care. They have been here for an interview, and are clearly trying to speed the process up as much as they possibly can. But they still need to clear the clinical trials, for everyone's safety and to make sure it does work; If you want to blame someone, blame the FDA.

 

[dd314]

I haven't read studies with near a 95% success rate for nerve section. Can you link me the study you are referring to? It's possible, however in some cases the brain stops trying to match perception in those cases.

Cochlear nerve section for intractable tinnitus

"Hair cells stuck in on" can't be correct because people with diffuse flat epithelial (it's just fibroblasts at that point and no longer has IHC, OHC or even support cells left) in the profound range still have tinnitus, often severe.

Maybe those aren't the cells responsible; it's the damaged cells stuck in "on"? I admittedly don't know very much biology...

 

[FGG]

I really don't think Frequency Therapeutics gives a damn about anyone that is suffering from this nightmare we live... All they do is stall and stall... It's inhumane... All these years... It's just wrong and inhumane...

Even if hypothetically they didn't care (which I don't believe), they still have the incentive to bring their drug to market as quickly as possible.

 

[Zugzug]

Cochlear nerve section for intractable tinnitus

Is it plausible that this works because the brain is no longer struggling for the input? I read that article a while ago. The author says that the location of the sectioning was really important. Something to do with splitting the bipolar spiral ganglion neurons medially.

If the whole problem was hair cells sending signals to the brain, that would stop under any sectioning.

 

[FGG]

Cochlear nerve section for intractable tinnitus

That says only got "complete remission" in 101/151 cases, which is interesting but if the problem is "hair cells stuck in the on position" as your theory goes I would think that would be much higher since you are fully removing input from the ear.

It also doesn't address why people with profound diffuse hearing loss (again no IHCs or OHCs) get tinnitus or why things like hydrops can cause episodic tinnitus (the fluid moves the hair into the "on" switch and then puts it back as it recedes?)

 

[Aaron91]

I really don't think Frequency Therapeutics gives a damn about anyone that is suffering from this nightmare we live... All they do is stall and stall... It's inhumane... All these years... It's just wrong and inhumane...

I know you're frustrated but this really isn't the case. The more I analyse their decisions the more I realise how thorough they have been in making sure there are no slip ups. The first trial passed safety with flying colours. The second trial is now powered for efficacy. They have fast track approval and so the FDA is involved too. They are leaving no stone unturned.

And for what it's worth, Carl LeBel's mother wears hearing aids, if I remember correctly. You can bet he will be doing everything he can so that she doesn't have to wear them anymore, but there is a process to go through and that takes time. The most important thing is not to fail the process.

 

[Keith Handy]

And for what it's worth, Carl LeBel's mother wears hearing aids, if I remember correctly.

She did want to get her eyes checked first, though.

(Sheepishly raise your hand if you've listened to the interview multiple times.)

 

[Diesel]

I'm bored... let's do a vote for when the Phase 2A 90-Day data is released:

Monday - 22nd - Thumbs Up
Tuesday - 23rd - Agree/Check
Wednesday - 24th - Lightbulb
Thursday - 25th - Hug
Friday - 26th - Question

Later than Friday 26th - Genius/Brain

 

[Street Novelist]

I really don't think Frequency Therapeutics gives a damn about anyone that is suffering from this nightmare we live... All they do is stall and stall... It's inhumane... All these years... It's just wrong and inhumane...

If "they" didn't care, Frequency Therapeutics would not have created a drug that cures hearing loss. You're just tired of waiting like the rest of us. Don't worry; we're almost there. Phase 3, assuming positive results from Phase 2, begins next January/February.

 

[Aaron91]

I'm bored... let's do a vote for when the Phase 2A 90-Day data is released:

Monday - 22nd - Thumbs Up
Tuesday - 23rd - Agree/Check
Wednesday - 24th - Lightbulb
Thursday - 25th - Hug
Friday - 26th - Question

Later than Friday 26th - Genius/Brain

I burnt my fingers last time I predicted an announcement at the hearing conference, which I note was a Wednesday. Realistically though there's only two scenarios left. Early week announcement if good news, Friday after market hours if bad news. So I'd say 22nd/23rd or 29th/30th. If we hear nothing by Thursday I'm going to start getting really nervous.

Edit: I also note their ph1 results were announced on a Tuesday. I'm inclined then to go for 23rd or 30th.

 

[Ali.sy]

They will release the results tomorrow.

 

[rid0871]

I know you're frustrated but this really isn't the case. The more I analyse their decisions the more I realise how thorough they have been in making sure there are no slip ups. The first trial passed safety with flying colours. The second trial is now powered for efficacy. They have fast track approval and so the FDA is involved too. They are leaving no stone unturned.

And for what it's worth, Carl LeBel's mother wears hearing aids, if I remember correctly. You can bet he will be doing everything he can so that she doesn't have to wear them anymore, but there is a process to go through and that takes time. The most important thing is not to fail the process.

I know. Thank you for your kind words. I'm just venting because my ears are getting so much worse... I'm just looking for any HOPE to end this nightmare.

 

[AfroSnowman]

I have been doing some international travel (no mean trick in COVID-19 world), it is amazing how far the emotions swing.

 

[Zugzug]

I burnt my fingers last time I predicted an announcement at the hearing conference, which I note was a Wednesday. Realistically though there's only two scenarios left. Early week announcement if good news, Friday after market hours if bad news. So I'd say 22nd/23rd or 29th/30th. If we hear nothing by Thursday I'm going to start getting really nervous.

Edit: I also note their ph1 results were announced on a Tuesday. I'm inclined then to go for 23rd or 30th.

I'm simultaneously a bull and a market idiot. I went with this Friday for no reason at all other than low IQ. Notice no one hit "question mark" on @Diesel's poll. At least Bobb will join me sooner or later. Besides being a dumb pick, it's not like everyone will be cheering for me if I'm right since it would be bad news.

Alas, I'm buying more stocks tomorrow. My wife and I agreed to it with my spending money. I can't compute the p-value with angular transforms and not invest lol.

 

[FGG]

Cochlear nerve section for intractable tinnitus

Maybe those aren't the cells responsible; it's the damaged cells stuck in "on"? I admittedly don't know very much biology...

I thought about your theory more and i think it's extremely improbable for a few reasons:

1) if damaged hair cells gave off a sound/signal like otoacoustic emissions, this would have been measurable and already known and, in fact, the measuring device is used only to confirm perfectly healthy cells which they confirmed in developing it with animal models/post necropsy.

2) this finding would have been easy to confirm on human autopsy histology studies too. We can image channels in cells now.

What makes more sense to me is that researchers like Will Sedley and Thanos Tzounopoulos are correct but if you cut out 100% of "actual" input, the mismatch between predictive and actual input might cause less neuroplastic hyperexcitability in the form of the brain eventually not trying to "push" the signal through with more glutamate (which transmits sound at both the IHC/synapse level as well as centrally).

That's an interesting thought actually but you'd hate to do something like that in a severe case and then not be able to mask anymore if you had an especially hyperexcited brain that didn't settle.

 

[Chetan]

Cherry picking patients to prove there is a statistically significant difference between placebo and treatment is good science as someone else said. Nothing sinister.

All of the trials this year are intended to identify the broadest widest set of participants that will be responders and be eligible for Phase 3 and likely merit approval of FX-322 in its current form .

They also need data to learn and identify what endpoints are best to set for that registrational trial.

Nothing sketchy here.

For folks that are mad and annoyed that this trial is taking so long to complete, in all honesty going from 2018 Phase 1 to a 2022 Phase 3 is pretty fast when you consider we're talking about a novel mechanism of action that isn't well understood at all (prior to all the clinical data these folks have been gathering to assuage both regular and patient concerns of safety and efficacy).

It took over a decade to get checkpoint inhibitors to be approved and they are the current standard of care in oncology and seem so obvious now.

This is a paradigm shifting process. Taking it slow now is crucial. Look at how gene therapy is going where so many companies went hard and fast and there are side effects. Unknown if related to the gene therapy, but FDA don't care, they still will slap 3 years worth of holds on trials til they learn more.

This is better than taking the really fast route and being stopped because they cut corners

I'm hopeful we see some benefit to audiogram in standard hearing range given we saw 8 kHz benefit for the responders, but I don't hold significant hope of it penetrating deep unless multiple doses works out like some theorize with rolling deeper.

Just hoping we get data this week. I want to take the day off when data comes out to really analyze and process it all.

As far as investors. Honestly even if Frequency Therapeutics can benefit 1% of the hearing loss population at $3,000 a year, this company is worth easily 4-5x the current value, so I'd be happy even then. I'm expecting it to be more than double digits when all is said and done of the market that benefits.

 

[Zugzug]

I thought about your theory more and i think it's extremely improbable for a few reasons:

1) if damaged hair cells gave off a sound/signal like otoacoustic emissions, this would have been measurable and already known and, in fact, the measuring device is used only to confirm perfectly healthy cells which they confirmed in developing it with animal models/post necropsy.

2) this finding would have been easy to confirm on human autopsy histology studies too. We can image channels in cells now.

What makes more sense to me is that researchers like Will Sedley and Thanos Tzounopoulos are correct but if you cut out 100% of "actual" input, the mismatch between predictive and actual input might cause less neuroplastic hyperexcitability in the form of the brain eventually not trying to "push" the signal through with more glutamate (which transmits sound at both the IHC/synapse level as well as centrally).

That's an interesting thought actually but you'd hate to do something like that in a severe case and then not be able to mask anymore if you had an especially hyperexcited brain that didn't settle.

I wonder. What are your thoughts on the role of efferent nerves in this process? I wonder what sectioning the afferents from IHC does to efferents acting on OHC. Do they get excited, but ultimately it doesn't matter because it's never relayed to the brain?

I would imagine the efferents don't do much if there's no tinnitus, and therefore, no effort to figure out the signal.

 

[FGG]

As far as investors. Honestly even if Frequency Therapeutics can benefit 1% of the hearing loss population at $3,000 a year, this company is worth easily 4-5x the current value, so I'd be happy even then.

Investors would be thrilled even if only 1% benefited but sufferers would be absolutely crushed no matter how much money they made as investors. Luckily, I don't think it's the case and I can see you don't either.

But that's one reason I hope non-suffering investors (not you, I find your posts helpful) don't start flocking to this board after positive Phase 2 results, because it will be a huge biotech story and that could happen.

 

[Gb3]

I have been doing some international travel (no mean trick in COVID-19 world), it is amazing how far the emotions swing.

Super spreader.

 

[Chetan]

Wow, I hadn't realized how intensely they blind the studies involved!

This is the first trial I've ever encountered with quadruple blinding (participant, care provider, investigator, and even the outcomes assessor).

I've literally never encountered this in my time before, most trials stick to single or double blind (participant or participant + care provider).

This is extremely legit. They are really going all out to ensure no accusations of bias can occur nor will any bias actually mess with the trial.

Btw I forgot to add one even bigger factor that is incredible about this company's progress. We got hit by COVID-19 over the last 12 months and yet the company was only delayed 6 months on their day 90 readout (I think it was originally slated for September and it's now March).

I'm so glad to be a part of this movement and effort!

Here are my guesses for trial outcomes.

Primary Endpoints:

WR quiet: statistically significant improvement, 15-40% absolute improvement. Most obvious endpoint to succeed and with large magnitude in my opinion.

WR noise: potentially statistically significant, 10-15% absolute improvement. Second most likely endpoint to succeed in primary. However, I'm unsure if we will get low frequency penetration to resolve hair cell loss there or if synaptopathy issues are unaffected by drug. EHF should still benefit this endpoint but unsure statistical significance.

Standard audiometry: likely limited improvement here, depends how good drug penetration is especially with repeat dosing, likely 6-8 kHz improvement ranges at best since we did see in patent data that some patients saw improvement at 6 kHz-8 kHz on audiometry indicating drug penetration is possible here. However, if repeat dosing improves penetration deeper than I will be very excited to see the full potential.

Safety: No major adverse events, transient minor events.

Secondary Endpoints:

EHF audiometry: statistically significant improvements. 8 kHz-16 kHz.

TFI improvement: statistically significant dependent on how balanced populations are. Generally expecting improvement, unclear what magnitude or p value to expect.

QoL: statistically significant major improvements anticipated.

Generally unclear how repeat dosing changes things, like penetration of drug beyond 8 kHz-6 kHz and how it enhances WR/TFI/Audiometry.

This week will feel so slow til we have data in hand.

 

[athan86]

I am sure you didn't think about it. Here in Greece we celebrate 200 years after our national revolution on 25th March 2021. They may want to celebrate their revolution with our national celebration and show the parallelism.

I vote 25/3/2021.

P.S.: If FX-322 works properly and is successful, it will be a real medical revolution!

 

[Aaron91]

I wonder. What are your thoughts on the role of efferent nerves in this process? I wonder what sectioning the afferents from IHC does to efferents acting on OHC. Do they get excited, but ultimately it doesn't matter because it's never relayed to the brain?

I would imagine the efferents don't do much if there's no tinnitus, and therefore, no effort to figure out the signal.

Not exactly answering your question, but I thought it would be interesting to know that the efferent fibres play a huge role in regulating noise damage. I only learned this recently from a webcast Paul Fuchs did (maybe @serendipity1996 has the link), but basically the efferent neurons to the cochlea are inhibitory - they turn down our sensitivity to sound, which can in turn protect us from noise trauma. To test this, they genetically engineered some mice to have a different efferent system than normal and then exposed the mice to loud sounds. When they did some tests after, the mice had no hearing loss.

 

[Aaron91]

Wow, I hadn't realized how intensely they blind the studies involved!

This is the first trial I've ever encountered with quadruple blinding (participant, care provider, investigator, and even the outcomes assessor).

I've literally never encountered this in my time before, most trials stick to single or double blind (participant or participant + care provider).

This is extremely legit. They are really going all out to ensure no accusations of bias can occur nor will any bias actually mess with the trial.

Btw I forgot to add one even bigger factor that is incredible about this company's progress. We got hit by COVID-19 over the last 12 months and yet the company was only delayed 6 months on their day 90 readout (I think it was originally slated for September and it's now March).

I'm so glad to be a part of this movement and effort!

Here are my guesses for trial outcomes.

Primary Endpoints:

WR quiet: statistically significant improvement, 15-40% absolute improvement. Most obvious endpoint to succeed and with large magnitude in my opinion.

WR noise: potentially statistically significant, 10-15% absolute improvement. Second most likely endpoint to succeed in primary. However, I'm unsure if we will get low frequency penetration to resolve hair cell loss there or if synaptopathy issues are unaffected by drug. EHF should still benefit this endpoint but unsure statistical significance.

Standard audiometry: likely limited improvement here, depends how good drug penetration is especially with repeat dosing, likely 6-8 kHz improvement ranges at best since we did see in patent data that some patients saw improvement at 6 kHz-8 kHz on audiometry indicating drug penetration is possible here. However, if repeat dosing improves penetration deeper than I will be very excited to see the full potential.

Safety: No major adverse events, transient minor events.

Secondary Endpoints:

EHF audiometry: statistically significant improvements. 8 kHz-16 kHz.

TFI improvement: statistically significant dependent on how balanced populations are. Generally expecting improvement, unclear what magnitude or p value to expect.

QoL: statistically significant major improvements anticipated.

Generally unclear how repeat dosing changes things, like penetration of drug beyond 8 kHz-6 kHz and how it enhances WR/TFI/Audiometry.

This week will feel so slow til we have data in hand.

Yeah I meant to mention that to you in our chats. Carl LeBel has made a big point about blinding themselves at all levels for the exact reasons you have suggested. And yes, we were all gutted about COVID-19 pushing things back but all credit to them. Just to think that if this readout is good, had it not been for COVID-19, we would have gone from Phase 1 to Phase 3 in less than 5 years.

As for your predictions, I get the feeling you are edging on the conservative side of things. I know it was a small sample, but if you take the average WR scores of the responders' improvement over baseline, you get an average improvement of 62.5%! I'm not sure if your average was for all patients, but if it was for just responders I'd be inclined to say at least 50%. So anyway, here are mine:

Primary Endpoints:

WR: statistically significant improvement, 20-50% absolute improvement in "responders". Strongly agree with you that this is the most obvious primary endpoint to succeed.

WIN: There's obviously a bit of a question mark here as I think we all know this will largely come down to how much synaptic recovery there is in each patient. I'm also expecting minor WIN improvements in all categories along a similar percentage with statistically significant and clinically meaningful improvements at least in the x4 cohort, especially in the severe category which I suspect will have the most synaptic loss.

Standard Audiogram: given the highly selective criteria this time, I think we will definitely see statistically significant results at 8 kHz and possibly 6 kHz, at least in the higher dose cohorts, especially in the mild category if the "absorption" theory holds any weight. I don't think Frequency Therapeutics would be doing multiple doses unless this was informed from somewhere that this really could help. I suspect they may have done some further undisclosed preclinical work. If the drug does penetrate deeper, I would be pleasantly surprised if we got benefits all the way down to 4 kHz.

Safety: no major events, although @FGG's point about links between VPA and dormant herpes viruses has me slightly on edge.

Secondary Endpoints:

EHF Audiometry: I think this will be the endpoint that knocks all others out the park, which is a shame, because it's only a secondary endpoint. I expect to see statistically significant improvements in all groups and a strong relationship between frequency and relative gain. I'm expecting exponential gains in the higher dose cohorts, with an average of 30-40 dB gain at 16 kHz in the x4 cohort for the moderate to severe categories.

TFI Improvement: I don't want to make any predictions here given the subjectivity of tinnitus, but I think this could be a real easter egg. Let's wait and see.

QoL: statistically significant major improvements anticipated as well.

Oh guys, by the way, today is 3/22...

 

[ThomasRobert]

@Frequency Therapeutics

 

[Chetan]

Investors would be thrilled even if only 1% benefited but sufferers would be absolutely crushed no matter how much money they made as investors. Luckily, I don't think it's the case and I can see you don't either.

But that's one reason I hope non-suffering investors (not you, I find your posts helpful) don't start flocking to this board after positive Phase 2 results, because it will be a huge biotech story and that could happen.

It absolutely will be a huge biotech story, and the reason why I'd be happy with even 1% (aside from financial implications) is I view this like a mathematical "existential proof" if you are familiar with the concept.

Such proofs are done to prove QED that there exists a solution to a problem even if the proof cannot describe the solution exactly.

If this can benefit statistically significant in its current incarnation 1% of patients, then the entire BP industry will pivot around this chasing this. Greed is a potentially uncouth motivating factor, but its purity in aligning incentives in biotech/pharma to pursue novel mechanisms of action and breed competition with more and more options for the consumer is crucial in my opinion to advancing the state of the art and ensuring that more companies invest in progenitor approaches to try and find better ways to unlock greater patient benefit (whether it's delivery tech, better molecules for activation, different signaling pathways etc).

Apologies for a potentially messy analogy, but it's like being aware of a brand new style of cooking because you ate a new dish at a restaurant and trying to reverse engineer how it was made. You don't know how, but you know it's possible, so you try and try and try and eventually you may succeed

Same here, if you think that FREQ is too slow, wait til they get strong confirmation. If I'm management at that point I start doubling down, diluting to raise a couple hundred million in additional cash and go on a hiring and growth spree because I know I've hit the medical jackpot in terms of treatments and opportunities to advance the state of the art light years.

If drug delivery technology is the issue then I look at acquiring the tech as needed. Perhaps I buy the IP from OTIC, buy OTIC for $500M, license the OTIC assets in a revenue sharing deal etc.

If we need more drug delivery expertise, I open a division for it and have them work on it day and night.

If we need more trial data to identify the optimal tinnitus subset, I kick off a clinical research roadmap revolving around TFI or other endpoints and new trials that aim to recruit more.

Astellas and likely other BP would step up to try and license more assets before valuations go runaway and out of control

So on so forth. This is the way pharma works. Once you identify something works as a major advancement in medical science with commercial opportunity, you iteratively refine and improve upon it, combination studies in cancer are a good idea etc, so you can get more benefit and remain competitive, and over time patients and insurance companies and pharma all benefit from better drugs, reduced cost burden of disease, and increased cash flows to reinvest in R&D.

 

[Diesel]

Just a note to those that are bummed that the EHF endpoint is experimental in the Phase 2A. If it looks as good as many speculate (statistically significant, clinically meaningful), it's 100% possible that the EHF measure can be moved to a primary outcome in the Phase 3.

What that would mean is potentially having EHF loss be "on-label" for FX-322 when it becomes a product. This would be a good addition for treating patients who have "normal" hearing on the standard audiogram + EHF losses.

 

[Keith Handy]

EHF Audiometry: I think this will be the endpoint that knocks all others out the park, which is a shame, because it's only a secondary endpoint. I expect to see statistically significant improvements in all groups and a strong relationship between frequency and relative gain. I'm expecting exponential gains in the higher dose cohorts, with an average of 30-40 dB gain at 16 kHz in the x4 cohort for the moderate to severe categories.

Shame that it's a secondary endpoint, but would show beyond a shadow of a doubt that the drug -- if not the delivery system -- works and works spectacularly.

Oh guys, by the way, today is 3/22...

Whether anything comes out today or not, it shall be the day nerds celebrate.

 

[Chetan]

As for your predictions, I get the feeling you are edging on the conservative side of things. I know it was a small sample, but if you take the average WR scores of the responders' improvement over baseline, you get an average improvement of 62.5%! I'm not sure if your average was for all patients, but if it was for just responders I'd be inclined to say at least 50%. So anyway, here are mine:

Yep, I basically looked at the average improvement seen in the moderate hearing loss responder population in absolute numbers, then I looked at this with a lens of counting all 6 patients vs counting 5 patients.

If I count all 6, you get 82 words improved across 6 people, which amounts to 27% absolute improvement.

If I count all 5, you get 78 words improved across 5 people, which amounts to 30% absolute improvement.

Slide 42:
https://investors.frequencytx.com/static-files/d7d67466-a36c-4b61-9468-a33025f96b30

Now if I consider that there may be patients with milder WR deficits who may see more variance and maybe see 15% benefit, I needed to dilute the low end of my expectations as it averages out.

On the other hand, repeat dosing may show additional benefit or ceiling, or even higher result now that we are getting more patients that fit the profile and we may not have seen peak benefit possible for someone yet.

Hence why I set my range to be 15-45% on WR quiet.

WIN same feeling, I was going through the patent data and there are some remarkable WIN improvements, but I'm unsure how much we can bank on this or being amazing vs good and promising, hence went more conservative. I think it'll average out to be clinically meaningful but unsure if statistically significant (if we hit statistically significant and clinically meaningful on both WR and WIN then it doesn't matter if we see no benefit in standard audiometry, which again I suspect we will see some benefit here).