Frequency Therapeutics — Hearing Loss Regeneration

[Diesel]

Same. I also noticed that the popular understanding of IHC and OHC changed. Until the Phase 2 results were released, everyone was saying that the OHC were for higher frequencies while the IHC were for lower frequencies and found deeper in the cochlea. The theory was the OHC were reached while the IHC were not, which was why the word scores and higher frequencies improved. Like "inner" and "outer" referred to their physical location in the cochlea as it spiraled. Suddenly overnight, the uses of these terms flipped and IHC is what apparently is fixed by FX-322 and that's why the word scores get better without audiograms.

Maybe I missed something but it seemed like overnight someone redefined these terms and everyone just jumped on board.

You def missed something. IHC and OHC span the length of the cochlea from high to low frequencies. They have different jobs in terms of hearing. That part of the biology has been agreed upon.

 

[HootOwl]

Until the Phase 2 results were released, everyone was saying that the OHC were for higher frequencies while the IHC were for lower frequencies and found deeper in the cochlea.

Say what now

The theory was the OHC were reached while the IHC were not, which was why the word scores and higher frequencies improved. Like "inner" and "outer" referred to their physical location in the cochlea as it spiraled.

Lol no.

Maybe I missed something

I think you missed 99% of the thread tbh.

 

[Zugzug]

Same. I also noticed that the popular understanding of IHC and OHC changed. Until the Phase 2 results were released, everyone was saying that the OHC were for higher frequencies while the IHC were for lower frequencies and found deeper in the cochlea. The theory was the OHC were reached while the IHC were not, which was why the word scores and higher frequencies improved. Like "inner" and "outer" referred to their physical location in the cochlea as it spiraled. Suddenly overnight, the uses of these terms flipped and IHC is what apparently is fixed by FX-322 and that's why the word scores get better without audiograms.

Maybe I missed something but it seemed like overnight someone redefined these terms and everyone just jumped on board.

This post is nothing short of totally infuriating. Just because you're a moron who thinks outer means high frequencies and inner means low frequencies, doesn't mean that's what everyone else thought. It's funny that you didn't quote anyone because it's slander.

The actual truth, for those curious or confused by the slander from these morons: The entire pre-Phase 2 results discussion was about the depth of inner and outer hair cells simultaneously (because they are obviously both present for a given radial slice of the cochlea, with the exception of no outer hair cells at the helicotrema, which is at the most extreme apex region). Nope, it turns out no one thought outer and inner meant "how deep you go."

Changing gears here, stay with me. The post-Phase 2 discussion is now focusing on the difference between IHC and OHC function at a given slice. Some of us are speculating that it could be the case that some patients are seeing IHC regrowth and little OHC regrowth because their audiogram results are staying within the margin of error, but their word scores improvements are totally unbelievable to occur by chance (see my post about p-values).

"Yeah, but Zugzug is a faux, wanna-be cool kid scientist." Okay, fair enough. Then list to this video from 1:10 until 1:55, where Dr. Cliff Olson explains the difference between OHC and IHC.

No one is in la-la land. I didn't max out my credit cards in FREQ stock with my settlement money as collateral. We are having a grown-up conversation about what could be happening with this drug. That's it.

 

[Tezcatlipoca]

Thank you @HootOwl and @Zugzug. Lots of people talking out of their ass as if it were gospel recently.

 

[Greg Sacramento]

I won't be posting much any more, just too many physical problems and God the pain. I can barely talk never mind writing thoughts. I'm old at 69 and my hearing loss is off the audiogram. Having to take pain meds doesn't help hearing loss or the pain even when I pile them on.

I wrote many posts on the physical causes of tinnitus and pulsatile tinnitus. Some can be addressed, but when hearing loss also has involvement of any fashions, or when one ailment leads to another either emotionally or thru physical transfer, then testing/treatment can be darn if you do and darn if you don't.

So I mentioned before that I talked by email to an old college classmate, now retired, who was one of the MIT researchers that had involvement with study association here. Beyond all the study information referenced by the company, he also provided many other articles of research. We then went round and round from over dosing to audiograms. Yep, I know nothing in comparison to him on this topic matter, but I was pretty stubborn with other equations - physicals and stress and how nerve travel to the ears can associate with tinnitus. This is not a subject of just hair cells or the brain which is just software using data from other functions.

The eight cervical nerve is involved in the pathogenesis of tinnitus:

The eight cervical nerves and its role in Tinnitus (tinnitusjournal.com)

Then you got these nerves for many to consider:

Cervical Nerve Projections to the Auditory Pathway in Tinnitus (tinnitusjournal.com)

When getting older, physicals play more of a role with tinnitus including somatic and pulsatile tinnitus.

I hope that this company can someday help some younger within a subgroup of noise or medication induced hearing loss.

 

[GBB]

I won't be posting much any more, just too many physical problems and God the pain. I can barely talk never mind writing thoughts. I'm old at 69 and my hearing loss is off the audiogram. Having to take pain meds doesn't help hearing loss or the pain even when I pile them on.

I wrote many posts on the physical causes of tinnitus and pulsatile tinnitus. Some can be addressed, but when hearing loss also has involvement of any fashions, or when one ailment leads to another either emotionally or thru physical transfer, then testing/treatment can be darn if you do and darn if you don't.

So I mentioned before that I talked by email to an old college classmate, now retired, who was one of the MIT researchers that had involvement with study association here. Beyond all the study information referenced by the company, he also provided many other articles of research. We then went round and round from over dosing to audiograms. Yep, I know nothing in comparison to him on this topic matter, but I was pretty stubborn with other equations - physicals and stress and how nerve travel to the ears can associate with tinnitus. This is not a subject of just hair cells or the brain which is just software using data from other functions.

The eight cervical nerve is involved in the pathogenesis of tinnitus:

The eight cervical nerves and its role in Tinnitus (tinnitusjournal.com)

Then you got these nerves for many to consider:

Cervical Nerve Projections to the Auditory Pathway in Tinnitus (tinnitusjournal.com)

When getting older, physicals play more of a role with tinnitus including somatic and pulsatile tinnitus.

I hope that this company can someday help some younger within a subgroup of noise or medication induced hearing loss.

Many have undoubtedly benefitted from your contributions and you've made a tangible difference in people's lives, if that carries meaning for you.

 

[Jazzer]

I won't be posting much any more, just too many physical problems and God the pain. I can barely talk never mind writing thoughts. I'm old at 69 and my hearing loss is off the audiogram. Having to take pain meds doesn't help hearing loss or the pain even when I pile them on.

I wrote many posts on the physical causes of tinnitus and pulsatile tinnitus. Some can be addressed, but when hearing loss also has involvement of any fashions, or when one ailment leads to another either emotionally or thru physical transfer, then testing/treatment can be darn if you do and darn if you don't.

So I mentioned before that I talked by email to an old college classmate, now retired, who was one of the MIT researchers that had involvement with study association here. Beyond all the study information referenced by the company, he also provided many other articles of research. We then went round and round from over dosing to audiograms. Yep, I know nothing in comparison to him on this topic matter, but I was pretty stubborn with other equations - physicals and stress and how nerve travel to the ears can associate with tinnitus. This is not a subject of just hair cells or the brain which is just software using data from other functions.

The eight cervical nerve is involved in the pathogenesis of tinnitus:

The eight cervical nerves and its role in Tinnitus (tinnitusjournal.com)

Then you got these nerves for many to consider:

Cervical Nerve Projections to the Auditory Pathway in Tinnitus (tinnitusjournal.com)

When getting older, physicals play more of a role with tinnitus including somatic and pulsatile tinnitus.

I hope that this company can someday help some younger within a subgroup of noise or medication induced hearing loss.

Dear Greg,

I would just like to thank you for your constant friendship and support for me. Even through our occasional disagreements we have both recognised qualities in each other that were more important. This doesn't always happen when people are less mature or more neurotic.

Your advice for me has been of great value, and I feel sure that many on Tinnitus Talk must have experienced something similar.

Tinnitus severity can obviously vary from something which is little more than a mild disappointment, to a truly hateful condition.

I am aware that you have had to suffer this, and much much more. For some of us life itself has become nothing more than a survival course, which, with our depleted resources, we have little or no appetite for.

I wish you peace and comfort Greg, if only that could become a reality. I hope the whole of this community will accord you the love, respect, and recognition you deserve, my friend.

Dave xx
Jazzer

 

[kiki]

Speculation is just speculation. Moreover, our knowledge is inferred from limited information, no matter how hard we try.

It may be completely off the mark.

I'm looking forward to FREQ's report organized from the data.

We are always speculating because their reports are slow and unsatisfactory.

Conversely, they are more cautious. Are they too careful?

 

[Diesel]

Oh man, they must be reading this thread:

#TinnitusTalkTriggered

 

[Damocles]

IHC and OHC span the length of the cochlea from high to low frequencies. They have different jobs in terms of hearing. That part of the biology has been agreed upon.

Thank you for clarifying this @Diesel.

@Chad Lawton's explanation regarding the structure and workings of the inner ear had sounded plausible, but I see now the reasoning behind the IHC/OHC theory isn't quite as simple as the diagram suggests.

In fact, thank you for the ELI3 biology lesson in general (credit to @Zugzug for the identification of the majority of the thread's current proficiency level).

 

[Damocles]

Speculation is just speculation. Moreover, our knowledge is inferred from limited information, no matter how hard we try.

It may be completely off the mark.

I'm looking forward to FREQ's report organized from the data.

We are always speculating because their reports are slow and unsatisfactory.

Conversely, they are more cautious. Are they too careful?

THIS, basically.

Not sure what exactly either side of the debate are arguing for; unless the benefactors have got some money invested in Frequency Therapeutics that I wasn't aware of (?)

 

[Jurger]

This post is nothing short of totally infuriating. Just because you're a moron who thinks outer means high frequencies and inner means low frequencies, doesn't mean that's what everyone else thought. It's funny that you didn't quote anyone because it's slander.

The actual truth, for those curious or confused by the slander from these morons: The entire pre-Phase 2 results discussion was about the depth of inner and outer hair cells simultaneously (because they are obviously both present for a given radial slice of the cochlea, with the exception of no outer hair cells at the helicotrema, which is at the most extreme apex region). Nope, it turns out no one thought outer and inner meant "how deep you go."

Changing gears here, stay with me. The post-Phase 2 discussion is now focusing on the difference between IHC and OHC function at a given slice. Some of us are speculating that it could be the case that some patients are seeing IHC regrowth and little OHC regrowth because their audiogram results are staying within the margin of error, but their word scores improvements are totally unbelievable to occur by chance (see my post about p-values).

"Yeah, but Zugzug is a faux, wanna-be cool kid scientist." Okay, fair enough. Then list to this video from 1:10 until 1:55, where Dr. Cliff Olson explains the difference between OHC and IHC.

No one is in la-la land. I didn't max out my credit cards in FREQ stock with my settlement money as collateral. We are having a grown-up conversation about what could be happening with this drug. That's it.

What still concerns me is the low response rate (around 35% in Phase 1/2) and that the presbycusis trial showed no statistical significant improvements, including word scores. Sure, these were older patients, but no statistical significant improvement at all...? I'm afraid Frequency Therapeutics has to go back to the drawing board, but we'll see what happens with the 'severe trial'.

 

[Damocles]

Oh man, they must be reading this thread:

View attachment 45337

#TinnitusTalkTriggered

What? they couldn't just "@" @GlennS?

I hate when scientific research companies talk about you like you're not in the room.

 

[Zugzug]

What still concerns me is the low response rate (around 35% in Phase 1/2) and that the presbycusis trial showed no statistical significant improvements, including word scores. Sure, these were older patients, but no statistical significant improvement at all...? I'm afraid Frequency Therapeutics has to go back to the drawing board, but we'll see what happens with the 'severe trial'.

Yeah, don't get me wrong, the drug has issues. I'd love to talk about them, honestly.

The 34% that scored absolutely WR improvement of >=10% in the Open Label study 111 does very little for me. I also don't see the Phase 1/2 results (in totality, not individuals) as riveting because audiograms were weak and the WR test had a (by chance) bias in favor of the treatment because they had less ceiling effect.

For me, my attitude will change a lot if I see a placebo patient double word scores because then that will cast doubt into what's happening with the super responders. Are they recalling patterns from the first test? Are they guessing better on the second test because of extra motivation? I don't believe fraud is likely at all.

My take on the "cheaters" speculation is much more moderate: I don't think there were many people (if any) that flat out lied (as in, they heard "cat" clear as day and said "cap"), but rather that they gave themselves a moral pass to not try if they weren't 100% sure, due to a bias to get in. In other words, exactly as the company says, a bias. I know they are also using this language for PR, but I think it also speaks to the real truth to some degree.

I definitely think this drug is really getting somewhere though. Abandoning it is beyond stupid.

 

[Diesel]

What still concerns me is the low response rate (around 35% in Phase 1/2) and that the presbycusis trial showed no statistical significant improvements, including word scores. Sure, these were older patients, but no statistical significant improvement at all...? I'm afraid Frequency Therapeutics has to go back to the drawing board, but we'll see what happens with the 'severe trial'.

The response rate depends on the recruiting in the trial. It's all a numbers game.

In the Phase 1/2, that 35% response rate included participants with mild to moderately severe hearing loss. And it turns out, the moderate - moderately severe participants responded in a significant way. It makes sense that they took this shotgun approach for an early trial, they simply didn't know.

In the later "open label" trial, they recruited mild to severe hearing loss patients. And again, claim to have observed about the same results.

So, one might conclude, if they did another Phase 1 trial where they only recruited patients with moderate or worse hearing loss, what would that response % look like based on what has been observed above?

Based on the Q&A from the Goldman Sachs Webinar, Lucchino alluded to the best responders from their two most significant trials (above) having NIHL/SNHL and Moderate or worse hearing loss.

This is why the severe trial carries some interest. We know that in the "open-label" study, they included severe patients, which were not included in the Phase 1/2. Lucchino seemed confident that the severe trial should produce favorable outcomes as well. Further, if from these three trials moderate-severe hearing loss NIHL/SNHL participants show consistent outcomes, it stands to reason that level of hearing loss is where hair cells are indeed damaged/dead.

 

[grate_biff]

The theory was the OHC were reached while the IHC were not, which was why the word scores and higher frequencies improved. Like "inner" and "outer" referred to their physical location in the cochlea as it spiraled.

We should maybe call it left and right cells, that what they really are. IHC are the sensorical part, OHC are the amplifier part.

 

[Chinmoku]

I won't be posting much any more, just too many physical problems and God the pain. I can barely talk never mind writing thoughts. I'm old at 69 and my hearing loss is off the audiogram. Having to take pain meds doesn't help hearing loss or the pain even when I pile them on.

So sorry the pain is so bad, Greg. We do miss you. You have positively impacted so many lives in and outside the forum. I really hope you can get some relief and some peace.

 

[anotherforumuser]

I won't be posting much any more, just too many physical problems and God the pain. I can barely talk never mind writing thoughts. I'm old at 69 and my hearing loss is off the audiogram. Having to take pain meds doesn't help hearing loss or the pain even when I pile them on.

Hi @Greg Sacramento. I am new here but I have been reading your posts a lot with the searcher for the weekend, because your points on spine/neck/TMJ really gave me ideas for my ear pain as it could be related. You are a great person, who even under the current conditions still has just taken an effort to type us once more some ideas. Thanks a lot for your input. I wish you as much health as possible.

 

[weab00]

Some pretty mega cope in this thread.

 

[Zugzug]

What? they couldn't just "@" @GlennS?

I hate when scientific research companies talk about you like you're not in the room.

But if you had normal, sexually appetizing audiograms and low WR scores, you wouldn't know what they were saying even if you were in the room. At least they are saving you the frustration of being humiliating without even understanding why... that sounds like quite the bargain. Bargaining sounds pretty cool, actually.

 

[Lucifer]

We have to remember that there may have been some improvements in word scores for mild hearing loss sufferers but due to the ceiling effect they can't be recorded as FX-322 improving their word scores.

Hopefully with the severe hearing loss patients it shows some word score improvements and audiogram improvements at the highest frequency.

 

[GlennS]

This post is nothing short of totally infuriating.

In any thread like this there is usually one or two people who function like unpaid evangelists. All one has to do is look at some of the emotionally charged back and forth that occurred in the Lenire thread when results seemed similarly ambiguous and inkblot-like. It's eerily similar. Funny how the drama just quietly died back over there once the hype train finally went off the rails. Point being is that things are gonna play out regardless of how any of us on the sidelines spin it, declare faith in it, play armchair scientist, square off in camp optimist vs. pessimist, etc...

Is hair cell regeneration promising in general? Yes. Is FX-322 in particular really a breakthrough? The burden is decidedly on them at this point.

 

[Chinmoku]

If we have to use memes...

I think the discussion has been good and intelligent with the information we have so far.

I think Frequency Therapeutics has very competent people and they will work hard at getting as much as they can from the drug. How much, we have to wait to see, but we should look at this as a beginning.

Lenire is a beginning too, and we may see more refined and effective bimodal neuromodulation devices come out later.

However, I wouldn't compare Lenire with FX-322, mostly because with FX-322 we had more reasons to be enthusiastic. Lenire only had a trial with an unpublished paper and some improbabile testimonials. FX-322 worked in explanted cochleas, the science looked sound, Phase 1 looked promising and the objective is very ambitious. If you read the thread, the technical depth of the comments here from several intelligent contributors don't have an analog in the Lenire thread. I liked @PeterPan's analysis, that was a great service, but if Minnesota were ongoing I think that would lend itself to a deeper discussion, and Dr. Shore's device might too, but Lenire was too simple, fitted based on a 8 kHz audiogram, too much of a "one size fits it all" approach. It certainly benefited from being touted as the first science-based treatment with results, which may explain the somewhat exaggerated initial enthusiasm.

For FX-322 the story is not finished, we need to wait and see more data. I don't see the previous discussion as biased towards optimism, if you read the past posts the discussion is quite nuanced. Sure, here and there some people may have over optimist or over pessimist attitudes, but we are only human.

 

[Zugzug]

In any thread like this there is usually one or two people who function like unpaid evangelists

I know, it's an injustice that I'm not paid. I agree.

 

[Koz]

View attachment 45363

In any thread like this there is usually one or two people who function like unpaid evangelists. All one has to do is look at some of the emotionally charged back and forth that occurred in the Lenire thread when results seemed similarly ambiguous and inkblot-like. It's eerily similar. Funny how the drama just quietly died back over there once the hype train finally went off the rails. Point being is that things are gonna play out regardless of how any of us on the sidelines spin it, declare faith in it, play armchair scientist, square off in camp optimist vs. pessimist, etc...

Is hair cell regeneration promising in general? Yes. Is FX-322 in particular really a breakthrough? The burden is decidedly on them at this point.

I don't regularly post on here anymore by the way because it doesn't really bring on anything and I can't be bothered reading walls of texts by people, who despite their best intentions, have nothing to do with the development of the drug or the trials whatsoever nor do they have any qualified/certified medical background. I check from time to time because I care and I do want things to work out for me and everyone, but I have found it counterproductive to obsessively do it day in day out as well as even hypothesising about anything at this point. Nobody really knows, certainly not anyone on a message board, what's going to happen, that's why the scientists are doing trials.

Anyway, TL;DR, drifted away from what I was planning to say - I have agreed with you on practically every single occasion. Your arguments, points and reminders are reasonable and realistic (for a large reason I feel because of how long you've had tinnitus and I can relate to this too, I was also super positive a decade ago, now I'm more realistic and pragmatic), unfortunately many a time dampened by those who mostly cling on hope, faith and the breadcrumbs of positive science at this current stage of this drug imo.

Good for you @GlennS.

 

[GlennS]

Lenire only had a...

Hindsight is 20/20. The entire site (including me) piled in and huddled within the Lenire thread during the whole hype-cycle with the user experience thread, etc... Sure, that was justified, but it did also result in inflated levels of optimism which was then resistant to conceding reality.

 

[Zugzug]

 

[Chinmoku]

View attachment 45369

A good geometric summary from one of our resident nuanced bears.

Hindsight is 20/20. The entire site (including me) piled in and huddled within the Lenire thread during the whole hype-cycle with the user experience thread, etc... Sure, that was justified, but it did also result in inflated levels of optimism which was then resistant to conceding reality.

I'm saying that the level of sophistication of that debate and the type of discussion and disillusionment occurring there have little to do with the level of sophistication and the current situation in this thread. The history of the two products is very different, the discussion in this thread was much more nuanced than "it works/it doesn't work". We had both bullish and bearish attitudes represented, discussed at length and defended. The posts are still there. I wouldn't throw everything into a blender and do a FX-322 thread smoothie I would compare with a Lenire thread smoothie, not least because the ramifications of the two products are very different, as I tried to illustrate. It's like comparing a 10-dimensional manifold to a cube.

You perceive an analogy by seeing an exaggerated optimism in both threads but even if the bears and the nuance were not there in this thread, those are very restricted lens through which one can compare the two.

Will FX-322 help our hearing loss/tinnitus or not? I understand this is the only question that matters to many, or perhaps the question is even simpler, will it improve my audiogram or not, and I don't know the answer to that, but hair cells regeneration has just begun and we need more data. The bears have been and are still there and will continue the discussions critically as new data come out.

 

[Zugzug]

It's like comparing a 10-dimensional manifold to a cube.

I've tried. Man I fold

 

[Pharz]

View attachment 45369

Was this a scam by the way? I mean this whole electricity through the tongue while the headphones are outputting random noises? I emailed Neuromod once asking for some proof, and now they are just bombarding me with emails in German language which I can't even understand.