Frequency Therapeutics — Hearing Loss Regeneration

[Jurger]

SSHL in just one ear?

It almost always is in just one ear.

 

[FGG]

This assuming it doesn't reach a point of diminishing returns.

I think an important component of "diminishing returns" will definitely be what proportion of damage is hair cell loss vs say synaptopathy. Liberman proposed that synapses are often damaged first before hair cells are lost.

 

[Diesel]

I guess one important point will be the ENT's ability to inject the liquid as far as possible too. Not sure if it's as simple as injecting the liquid right behind the eardrum or if it's way more technical.

It's injected behind the eardrum and absorbed into the cochlea. Source:
https://investors.frequencytx.com/static-files/4ac687f2-04b5-4d23-ab23-daa7826cd1b0

Since the cochlea is essentially liquid-filled, the assumption by Frequency Therapeutics is that liquid diffusion may be a factor in additional injections getting deeper into the cochlea. Each new injection pushes the prior drug injection further in. Think about dropping dye in a glass of water, for example.

https://en.wikipedia.org/wiki/Diffusion

 

[serendipity1996]

I found a participant on Reddit.
Looks like FX-322 is ineffective.
Statistically speaking, a participant has only 20% chance to receive 4/4 placebo doses.
This guy had 80% chance of receiving minimal 1 shot of the real drug. He said that he doesn't feel any benefit.

View attachment 42005
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Except we know that FX-322 has at least some level of efficacy based on the Phase 1/2 results.

Also, how can you determine whether you got a placebo or not based on whether the injection is painful lmao?

 

[Ozwel]

I think an important component of "diminishing returns" will definitely be what proportion of damage is hair cell loss vs say synaptopathy. Liberman proposed that synapses are often damaged first before hair cells are lost.

Oh... well! So now do we have another ongoing trial targeting synapses?

What an adventure

 

[patorjk]

This guy had 80% chance of receiving minimal 1 shot of the real drug. He said that he doesn't feel any benefit.

I did some internet sleuthing and this is the same exact person that was talked about back in August (see page 341 of this thread for more info). Based on other things I've seen, I'm noticing that people who have negative reactions are much more likely to talk about them.

The positive case we've seen - in every instance someone had to ask that person for an update for them to say anything. The only original thing they said was that that they were applying for the trial, and then later updating that they'd gotten in.

 

[FGG]

It almost always is in just one ear.

SSHL due to very loud noise tends to be bilateral. Idiopathic or viral SSHL is unilateral.

Though, it is much more common for people with localization issues to be unilateral so it would make sense in this case.

People with unilateral loss and localization issues usually have at least moderately severe loss.

From this, my guess is he/she still has some loss in the bands tested but they are greatly improved. I bet they would benefit (in terms of tinnitus) from more injections.

If it's caused by noise especially, there is likely to be some synaptopathy too.

 

[GBB]

Presumably, there is a threshold for damage below which we don't perceive any tinnitus, therefore it's probable we don't need to get our ears back to virgin condition, just good enough to cross back over that threshold. I know from prior hearing tests I had hearing damage years before my tinnitus became evident; it was only a problem once I crossed over a certain boundary line.

 

[Jurger]

This guy had 80% chance of receiving minimal 1 shot of the real drug. He said that he doesn't feel any benefit.

View attachment 42005
View attachment 42006

I doubt FX-322 would 'burn' whereas placebo wouldn't. The entire idea behind a double blind study is that both the doctor and the patient don't know what they administer/get.

Lack of results could also be explained by the fact this patient only has some hearing loss in the mid-frequencies.

 

[tommyd87]

I am so confused on what to do. I do want to help out but I need help too and I'm afraid I won't get it. I do not know man. I'm just really down after reading through here this am.

Either way we need people like you to please participate so the trials turn out the required participation to prove the medicine's effectiveness. Even if the medicine doesn't get injected into your ear we still need proof that the placebo doesn't work and the medicine hopefully works in order to get it through the trials.

The fact of the matter is you might get unlucky if you'll get given the placebo during the trial, though you won't be in any worse position than you are now and will actually be helping with the progression of the medicine to a point hopefully where it is working well enough to get released and it is available. As a result if the trials are not completed then there will be no available treatment so you will be benefiting us all and benefiting yourself regardless just by taking part.

 

[serendipity1996]

Oh... well! So now do we have another ongoing trial targeting synapses?

What an adventure

Yes - Pipeline Therapeutics, Otonomy, and Hough Ear Institute (although they're not in trials yet and we're kind of unsure of the current status of their proposed drug).

In fact, Otonomy is set to release the results of their synapse drug, OTO-413, this month - Phase 1/2 results.

 

[Bill Arsenault]

We desperately want this company to somehow go well out of their way to allow and implement compassionate use of their product to this community.
We want special designation from the FDA for Fast Track approval and off-label use because tinnitus has ruined our lives and taken our souls.
We want our insurance companies to pay for it.
We want it all yesterday because every day we wait is torturous.

Yet at a crucial point in the testing we are going to blatantly work against them all by relentlessly re-posting to this forum word for word broken NDAs like there's absolutely no possibility that this could be an obstacle in some way to the progress of this drug right now and to the possibility of us getting it as fast as possible.

Someone explain how re-posting speculation from people who have broken their NDAs and have not finished the treatment or even known exactly what treatment they received is helping anyone with tinnitus in any way that is worth double crossing Frequency Therapeutics.

You know what they say about karma.
Just don't act surprised when this broken NDA stuff gets ugly and has consequences that most of us don't like and cannot afford.

If FX-322 helps tinnitus in any way, then I am willing to give Frequency Therapeutics the benefit of the doubt that they will let it be known as soon as they possibly can.

My tinnitus is becoming so loud that I am now actually fearful of going deaf to everything else eventually.
I am out of my mind with it.
Yet I still would not want anyone to break their NDA with Frequency Therapeutics this late in the game just to give me some hope.
I feel much better off to keep looking forward to hearing soon in some way from Frequency Therapeutics exactly what this drug can possibly do for us.

 

[Diesel]

Presumably, there is a threshold for damage below which we don't perceive any tinnitus, therefore it's probable we don't need to get our ears back to virgin condition, just good enough to cross back over that threshold. I know from prior hearing tests I had hearing damage years before my tinnitus became evident; it was only a problem once I crossed over a certain boundary line.

I very much suspect that a 'tinnitus experience gradient' will be more clearly defined as a symptom for NIHL/SNHL as regeneration is applied to the masses. Perhaps TFI will start to include a tone-matching reference to better capture the location of the tinnitus?

In terms of the gradient, it may be discovered that a regeneration to a 10-20 dB threshold at a set of frequency bands on the audiogram results in no tinnitus, restoration to 20-40 dB results in tinnitus noticeable in "quite room" settings, and 40 dB on begins to the downward slope to "hearing it everywhere."

I can't help but think that ENTs will need some type of reference from the patient in order to establish a drug dosage.

 

[paul mclean]

I wonder what happens to the dead hair cells in the cochlea once FX-322 is administered?

Do the new hair cells replace them or are the dead hair cells still there and the new hair cells are just grown around them?

If the new hair cells replace the old ones, then that would be good I think.

 

[Orions Pain]

Notice how with (1) positive story people were elated but as soon as a "negative" anecdotal report came out some went right back to the despair. It's nice having crumbs of hope with a couple of positive stories but I agree that this is why NDAs shouldn't be broken and this applies to both positive and negative outcomes.

Particularly negative/neutral outcomes. It may not affect the actual results of current participants but should they open enrollment again people may be more hesitant to sign up with negative stories circulating on the internet.

 

[FGG]

I doubt FX-322 would 'burn' whereas placebo wouldn't. The entire idea behind a double blind study is that both the doctor and the patient don't know what they administer/get.

Lack of results could also be explained by the fact this patient only has some hearing loss in the mid-frequencies.

I think this very easily could be an artifact of how the injections were given, too.

For a personal anecdote, I used to get Intramuscular Magnesium injections at home and since they were best given in the glutes, i usually just had my ex husband do it (since it's much harder to do on yourself) but twice he was out of town and I asked my friend to do it and she just wasn't as good at it and it hurt a lot both times, when it didn't usually. Same drug, given same way but with different technique.

Even with the same doctor there could be differences in injections depending on whether they took their time more, how relaxed the patient was (which makes manipulating their pinna easier, etc)

But again, this is why anecdotes are sketchy to interpret, so many unknowns and at worse, they can dissuade people from trials (while the people with better results are more excited and want to help the company more by honoring their NDA) by reading results of someone who could very well have gotten placebo.

Luckily, we will get some aggregate data in March.

 

[Gb3]

SSHL due to very loud noise tends to be bilateral. Idiopathic or viral SSHL is unilateral.

Though, it is much more common for people with localization issues to be unilateral so it would make sense in this case.

People with unilateral loss and localization issues usually have at least moderately severe loss.

From this, my guess is he/she still has some loss in the bands tested but they are greatly improved. I bet they would benefit (in terms of tinnitus) from more injections.

If it's caused by noise especially, there is likely to be some synaptopathy too.

That is correct. I suffered ISSHL and was only affected in one ear. My hearing loss is in the high frequencies dropping off at 2500 Hz. My Tinnitus did not start until the hearing loss.

 

[GBB]

I very much suspect that a 'tinnitus experience gradient' will be more clearly defined as a symptom for NIHL/SNHL as regeneration is applied to the masses. Perhaps TFI will start to include a tone-matching reference to better capture the location of the tinnitus?

In terms of the gradient, it may be discovered that a regeneration to a 10-20 dB threshold at a set of frequency bands on the audiogram results in no tinnitus, restoration to 20-40 dB results in tinnitus noticeable in "quite room" settings, and 40 dB on begins to the downward slope to "hearing it everywhere."

I can't help but think that ENTs will need some type of reference from the patient in order to establish a drug dosage.

That makes sense - let me just point out I have fairly loud tinnitus with generally 10-15 dB readings across the board - my tinnitus was 100% noise-induced from a train horn - so I suspect the loss is all relative and you won't be able to benchmark tinnitus severity to a dB loss amount for the general population (or maybe I am an outlier). Mine is disturbingly loud in silence in my 5th month, and can be heard over my TV and ambient household noise.

 

[GBB]

Notice how with (1) positive story people were elated but as soon as a "negative" anecdotal report came out some went right back to the despair. It's nice having crumbs of hope with a couple of positive stories but I agree that this is why NDAs shouldn't be broken and this applies to both positive and negative outcomes.

Particularly negative/neutral outcomes. It may not affect the actual results of current participants but should they open enrollment again people may be more hesitant to sign up with negative stories circulating on the internet.

We desperately want this company to somehow go well out of their way to allow and implement compassionate use of their product to this community.
We want special designation from the FDA for Fast Track approval and off-label use because tinnitus has ruined our lives and taken our souls.
We want our insurance companies to pay for it.
We want it all yesterday because every day we wait is torturous.

Yet at a crucial point in the testing we are going to blatantly work against them all by relentlessly re-posting to this forum word for word broken NDAs like there's absolutely no possibility that this could be an obstacle in some way to the progress of this drug right now and to the possibility of us getting it as fast as possible.

Someone explain how re-posting speculation from people who have broken their NDAs and have not finished the treatment or even known exactly what treatment they received is helping anyone with tinnitus in any way that is worth double crossing Frequency Therapeutics.

You know what they say about karma.
Just don't act surprised when this broken NDA stuff gets ugly and has consequences that most of us don't like and cannot afford.

If FX-322 helps tinnitus in any way, then I am willing to give Frequency Therapeutics the benefit of the doubt that they will let it be known as soon as they possibly can.

My tinnitus is becoming so loud that I am now actually fearful of going deaf to everything else eventually.
I am out of my mind with it.
Yet I still would not want anyone to break their NDA with Frequency Therapeutics this late in the game just to give me some hope.
I feel much better off to keep looking forward to hearing soon in some way from Frequency Therapeutics exactly what this drug can possibly do for us.

People are severely overestimating the consequences of a broken NDA - I will be SHOCKED if it has any material impact whatsoever. People hyping fear about this need to point to a precedent of a broken NDA derailing a clinical trial (hint: there is no precedent, because nobody cares very much - some leakage is always anticipated), otherwise they are just fearmongering with no basis. Likewise, it is not going to make recruitment harder or easier, there are a limitless mass of bodies who will join without regard for someone else's anecdotal experience if they have a chance at hearing restoration.

Agree we need hard data en masse to understand the therapy's effectiveness, but can everyone just chill the F out about broken NDAs?

 

[Gb3]

I am so confused on what to do. I do want to help out but I need help too and I'm afraid I won't get it. I do not know man. I'm just really down after reading through here this am.

Just because you get the placebo doesn't mean you can't get the real thing when it's available.

 

[FGG]

People are severely overestimating the consequences of a broken NDA - I will be SHOCKED if it has any material impact whatsoever. People hyping fear about this need to point to a precedent of a broken NDA derailing a clinical trial (hint: there is no precedent, because nobody cares very much - some leakage is always anticipated), otherwise they are just fearmongering with no basis. Likewise, it is not going to make recruitment harder or easier, there are a limitless mass of bodies who will join without regard for someone else's anecdotal experience if they have a chance at hearing restoration.

Agree we need hard data en masse to understand the therapy's effectiveness, but can everyone just chill the F out about broken NDAs?

Actually, the reason Otonomy failed the first Phase 3 Otividex trial is that the results were so great in Phase 2 that ENTs were literally pushing people into the trial who had poorly controlled attacks telling them the drug is great and it was so hyped that the placebo patients also had less vertigo attacks (so the difference wasn't statistically significant enough). Otonomy then had to meet with the FDA and restart the entire Phase 3 trial.

Granted, Meniere's attacks are very linked to mental state as one cofactor and hearing is not (but tinnitus can be!). That is one example where word of mouth significantly delayed the trial though obviously this was ENTs using Phase 2 data and not individuals breaking their NDA.

I personally could also see it delaying recruitment because stuff on this forum gets disseminated to Facebook groups and Reddit etc and vice versa. Word gets around. You already have people here trying to work out how many injections they think will help them and the odds of getting into that cohort.

You don't have to be "the sky is falling down" about it but I personally think it's a bad choice when aggregate data is 3 months away. You are obviously free to disagree.

 

[Diesel]

People are severely overestimating the consequences of a broken NDA - I will be SHOCKED if it has any material impact whatsoever. People hyping fear about this need to point to a precedent of a broken NDA derailing a clinical trial (hint: there is no precedent, because nobody cares very much - some leakage is always anticipated), otherwise they are just fearmongering with no basis. Likewise, it is not going to make recruitment harder or easier, there are a limitless mass of bodies who will join without regard for someone else's anecdotal experience if they have a chance at hearing restoration.

Agree we need hard data en masse to understand the therapy's effectiveness, but can everyone just chill the F out about broken NDAs?

This exactly. As someone who has signed many NDAs throughout my career; I can tell you that most aren't worth the paper they are written on. In fact, depending on the state in the US that they are signed between both parties, they're hardly enforceable.

From what I have read about Clinical Trial NDAs, is they're specific about revealing details of the trial itself, or potential trade-secret information known by the participant.

It would also be bad business / bad press for Frequency Therapeutics to bring the legal hammer down on a trial participant.

What might be more likely is they decline to interview on additional Tinnitus Talk Podcasts, request that the comments be pulled down (which basically verifies them).

 

[Philip83]

That makes sense - let me just point out I have fairly loud tinnitus with generally 10-15 dB readings across the board - my tinnitus was 100% noise-induced from a train horn - so I suspect the loss is all relative and you won't be able to benchmark tinnitus severity to a dB loss amount for the general population (or maybe I am an outlier). Mine is disturbingly loud in silence in my 5th month, and can be heard over my TV and ambient household noise.

Like I've mentioned before and like you are stating, I don't think the loss of dBs in an audiogram is what mainly matters to the volume of one's tinnitus. I think it depends on how quickly that loss is acquired. A sudden trauma has a higher likelihood of causing tinnitus than a slightly loud enough to be damaging noise over a longer period of time. Only my uneducated guess though.

 

[GBB]

Actually, the reason Otonomy failed the first Phase 3 Otividex trial is that the results were so great in Phase 2 that ENTs were literally pushing people into the trial who had poorly controlled attacks telling them the drug is great and it was so hyped that the placebo patients also had less vertigo attacks (so the difference wasn't statistically significant enough). Otonomy then had to meet with the FDA and restart the entire Phase 3 trial.

Granted, Meniere's attacks are very linked to mental state as one cofactor and hearing is not (but tinnitus can be!). That is one example where word of mouth significantly delayed the trial though obviously this was ENTs using Phase 2 data and not individuals breaking their NDA.

I personally could also see it delaying recruitment because stuff on this forum gets disseminated to Facebook groups and Reddit etc and vice versa. Word gets around. You already have people here trying to work out how many injections they think will help them and the odds of getting into that cohort.

You don't have to be "the sky is falling down" about it but I personally think it's a bad choice when aggregate data is 3 months away. You are obviously free to disagree.

I think a doctor explicitly biasing the patient at point of matriculation is much more severe than a few people putting their opinion out into the ether, but that's just my take. I respect your opinion.

 

[tommyd87]

Like I've mentioned before and like you are stating, I don't think the loss of dBs in an audiogram is what mainly matters to the volume of one's tinnitus. I think it depends on how quickly that loss is acquired. A sudden trauma has a higher likelihood of causing tinnitus than a slightly loud enough to be damaging noise over a longer period of time. Only my uneducated guess though.

I think that there was research from university groups (I think it was either Harvard or Stanford) suggesting that there tends to be a lot of the older population with hearing loss who do not have tinnitus anyway. Also a lot of this older population is not thought to have synapse damage either coincidentally from things like an acoustic trauma.

Thus this raises two very key queries with what causes tinnitus:

A. Whether the tinnitus is caused by what you have stated being shocks to the auditory area

B. Whether busted synapses play a significant role in the causation of tinnitus. This has been a key thing which was identified in the research by groups like Hough Ear Institute and is quite well supported by the fact that many people have regular hearing on an audiogram and also have tinnitus too.

 

[Orions Pain]

To clarify, I'm not of the belief that a couple of anecdotal leaks here and there will unravel a multi-million dollar trial. I'm sure every company probably accounts for some leaks here and there. I just think that if NDAs were totally useless and didn't have their place in clinical trials, they wouldn't be used right?

Anyways, I'm looking forward to seeing official FX-322 data wrapped up in a neat little bow once trials are completed

 

[FGG]

I think a doctor explicitly biasing the patient at point of matriculation is much more severe than a few people putting their opinion out into the ether, but that's just my take. I respect your opinion.

Absolutely it's a huge difference but I am being a bit conservative in my thinking about this especially considering that March isn't really that far away.

 

[Princebeyel]

Just because you get the placebo doesn't mean you can't get the real thing when it's available.

Not necessarily worried about getting placebo or not. That's a risk I'm willing to take.

I just don't want to risk the fact that I know I'll need more then one injection and won't know if I can get into a future study because I've participated in the single injection one.

 

[Lucifer]

To clarify, I'm not of the belief that a couple of anecdotal leaks here and there will unravel a multi-million dollar trial. I'm sure every company probably accounts for some leaks here and there. I just think that if NDAs were totally useless and didn't have their place in clinical trials, they wouldn't be used right?

Anyways, I'm looking forward to seeing official FX-322 data wrapped up in a neat little bow once trials are completed

I don't think Frequency Therapeutics care if someone breaks the NDA. If the patient results were positive and they told us that it works then people will trust FX-322 and the company. It's only when a patient has a negative result, then it may be bad for Frequency Therapeutics.

So far results have been looking good but we need to find out more in March and May to see whether patients who have received additional doses of FX-322 improved a lot compared to those who got 3 doses of FX-322 or less. I do hope when the results are positive in March and May that they open up compassionate use or being able to release the drug into the market after Phase 2a.

 

[Diesel]

To clarify, I'm not of the belief that a couple of anecdotal leaks here and there will unravel a multi-million dollar trial. I'm sure every company probably accounts for some leaks here and there. I just think that if NDAs were totally useless and didn't have their place in clinical trials, they wouldn't be used right?

Anyways, I'm looking forward to seeing official FX-322 data wrapped up in a neat little bow once trials are completed

NDAs have a place in court when the signee does something like try to profit, gain notoriety, or discredit the institution on the other end of the agreement. For example, if a participant of an FX-322 trial tried to get some personal publicity on the trial by being interviewed by the media, or received payment in exchange for their experience in the trial; by telling people that it worked miracles for them, or was a scam. These situations would be where an NDA could be enforced in a court and the institution may be able to receive damages or a judge-ordered gag. There would need to be evidence that the signee intentionally broke the NDA to make a gain (usually financial) at the expense of the institution.

I doubt Frequency Therapeutics would go through all this expensive and time-consuming trouble for a few lay-people talking about the drug on social media; even if social media discussion about the trial was banned in the NDA.