Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

I would think if recruiting was so difficult (and we can now assume it was), they would prioritize clarity over PTA.

I think the reason they didn't was because for some reason they wanted to do a separate safety trial on the severe group. I don't know what that reason is but in hindsight, they should have focused on clarity and let in the severe patients at onset.

 

[Diesel]

I get what you're saying about genuine challenges in obtaining this specific patient class.

But here's why I still don't feel sympathetic. I would think if recruiting was so difficult (and we can now assume it was), they would prioritize clarity over PTA. In other words, just give up on this perfect patient. Just grab someone with IHC loss who probably has OHC loss (like the severe trial).

Now, of course, if the severe trial is a flop, I'll play Monday morning quarterback and change positions, saying something like "You thought the first hearing regeneration drug would work on people with the worst hearing loss?!?"

I'm just so confused. The only out I can give them is that they are working against investors that aren't sympathetic to these recruiting nuances and just want to see audiogram gains.

They may in a future trial. When the Phase 2A was designed 2+ years ago, it's clear they didn't know what they know today. Even the design of the Severe and Age-Related Hearing Loss Phase 1Bs where done probably the summer prior to their announcement in September 2020.

I'd also like to point out the contrast between the average "retail" investor expectations (that includes many here) and what has been observed from professionals in the hearing practice + hearing research fields. It seems to me that the average observer puts way too much weight on the audiogram, and has generally set expectations for FX-322 to be a "cure" or "near cure" for hearing loss. And somehow the "cure" is only justified by a perfect audiogram. That bar may be too high right now. We've seen it here with the "told ya so" group coming out of the woodwork after the Phase 2A collapse.

However, the more I have been looking into professional commentary on FX-322 and hearing regeneration, like that of Dr. Cliff's video, where he points to IHC being potentially restored; the more I think the professionals in the field "get" that the audiogram is a measurement but it isn't perfect; and the other clinical measures used (WR/WIN) are equally as important for diagnosis / future treatment paths. It also seems to be reiterate from the professionals that the bar is so low for treatment, that even a drug that "works but we don't fully understand why" stands a chance for succeeding

 

[Zugzug]

However, the more I have been looking into professional commentary on FX-322 and hearing regeneration, like that of Dr. Cliff's video, where he points to IHC being potentially restored; the more I think the professionals in the field "get" that the audiogram is a measurement but it isn't perfect; and the other clinical measures used (WR/WIN) are equally as important for diagnosis / future treatment paths. It also seems to be reiterate from the professionals that the bar is so low for treatment, that even a drug that "works but we don't fully understand why" stands a chance for succeeding

I say this out of pure ignorance. There's no question that the hearing professionals understand this stuff, and a lot better than people like me, at that (although they should lose the arrogance with hyperacusis).

But how much do the people who actually fork over the money understand this stuff? Obviously they hear this stuff about word scores versus audiograms. Do they view it as an excuse or with genuine patience and understanding?

 

[FGG]

drug that "works but we don't fully understand why" stands a chance for succeeding

This is way more common than you think. Off the top of my head:

--Tylenol (as long as this drug has been out, we still aren't sure about its mechanism of action).

--Inhaled anesthetic gasses (we know some of the effects but not enough to explain how it works).

--Keppra (not only is there many unknowns about the mechanism of action almost all seizure drugs work in some people and not others for very unclear reasons, same with pets).

 

[Tezcatlipoca]

They may in a future trial. When the Phase 2A was designed 2+ years ago, it's clear they didn't know what they know today. Even the design of the Severe and Age-Related Hearing Loss Phase 1Bs where done probably the summer prior to their announcement in September 2020.

I'd also like to point out the contrast between the average "retail" investor expectations (that includes many here) and what has been observed from professionals in the hearing practice + hearing research fields. It seems to me that the average observer puts way too much weight on the audiogram, and has generally set expectations for FX-322 to be a "cure" or "near cure" for hearing loss. And somehow the "cure" is only justified by a perfect audiogram. That bar may be too high right now. We've seen it here with the "told ya so" group coming out of the woodwork after the Phase 2A collapse.

However, the more I have been looking into professional commentary on FX-322 and hearing regeneration, like that of Dr. Cliff's video, where he points to IHC being potentially restored; the more I think the professionals in the field "get" that the audiogram is a measurement but it isn't perfect; and the other clinical measures used (WR/WIN) are equally as important for diagnosis / future treatment paths. It also seems to be reiterate from the professionals that the bar is so low for treatment, that even a drug that "works but we don't fully understand why" stands a chance for succeeding

That was my impression too when Phase 2 data was out, it was a blow because the phase itself failed, but only in tinnitus circles was this taken as "game over", most publications and journals were still optimistic, even after that.

The status quo of the hearing industry also means the FDA probably wants this to happen too.

 

[Lucifer]

Did anyone in the Phase 1b trials do an extended high frequency hearing test before and after the trials were completed?

It would have been good to know if there were any improvements in the audiogram between 8-20 kHz.

 

[Diesel]

But how much do the people who actually fork over the money understand this stuff? Obviously they hear this stuff about word scores versus audiograms. Do they view it as an excuse or with genuine patience and understanding?

Anecdote - In my career I had a few opportunities to work for firms seeing angel and series-A investment, and directly where I was one of the founders pitching our business. All of these investor interactions was pretty much one of two camps; there was the "enthusiast/advocate investor" that already had some type of exposure to the product/consumer and was just really excited to be part of "the next step." They weren't always necessarily super deep into the product/business, but had typically had a relevant background/enough knowledge to believe the firm seeking investment was going in a direction they understood.

The second camp was the pure capitalist. They were more interested in analyzing the outlook/structure of the business/leadership, the condition of the industry, and the appetite for the product by market. They succeeded by measuring risk from a macro- and micro- standpoint. The product didn't matter, as long as you could show them evidence the return was possible, entrance from competitors was low, and that consumers would PAY PAY PAY for the product. They wanted to make sure they people they gave money where capable of turning $1 of their investment into $10 without major risk.

I can't tell you how many times investor meetings went in the direction of either camp. Either one is good to have, to be honest.

For the pre-IPO rounds and the private placement in 2020, this is very much what it looks like for Frequency Therapeutics based on what we know about the major share holders. Some are into the furthering of science and medicine, and probably believe strongly in PCA. Others see a competent exec team and a product that can make some serious cash, even if its to a small market at first.

 

[kiki]

Developing plans to mitigate bias in future studies

If everyone expects a therapeutic effect, is there a way to mitigate bias in patient enrollment?

This is a joke, but could they make the patient enrollment rule as follows?

"Everyone, we will check PTA and WR, but we will make the final selection by lottery."

Can you think of any good way?

 

[RichieTheKid]

Hey guys, I may just be coming to the US at the end of the year, November - December.

Would Frequency Therapeutics have any trials running around that time that I can join hopefully?

If anyone has any sort of idea about their schedule, please let me know. This is really important to me, I have been fighting a long hard battle and I got to try and do something when I get there. Other companies' timelines would be appreciated too.

 

[Ed209]

Firstly, buying biotech stock is support only if you take part in IPO or during capital raise. If you buy FREQ after that, it is not support at all.

Secondly, I appreciate the time and effort of many people here. But unfortunately, it doesn't bring diagnostics or treatments much closer. More action is needed.

Can you show me where I talked about a charity? I also don't send money to them because if they sponsor things like CBT, then I can throw money out of the window and the effect will be the same.

There was a very interesting Tinnitus Talk Podcast episode in February with Dr. Shoushtarian from the Bionics Institute. She mentioned several times that progress is subject to financing. Meanwhile, their donation page looks like this:

View attachment 44497

No need to mention that some people here lost more than $100,000 USD by their investment in FREQ. Money that could help tinnitus research was successfully wasted. Congratulations :-(

All tinnitus fundraisers are the same, unfortunately. It's something that I've never really understood, as many people want treatments, but only a micro-fraction are prepared to contribute in some way. Dr Rauschecker, Dr Susan Shore, the Hough Hearing Institute, and every other tinnitus-related fundraiser I've ever seen - on various donation platforms - have all performed badly. This also includes the JustGiving campaign for the famous drummer, Craig Gill, who tragically hung himself.

It is not entirely a money-centric issue, either. The vast majority are also reluctant to share material that can increase the chances of better funding and/or awareness. It's so bad, that even signing a petition is too much for many.

This is the paradoxical reality of the tinnitus community: desperate for help, but unwilling to help.

 

[FGG]

Hey guys, I may just be coming to the US at the end of the year, November - December.

Would Frequency Therapeutics have any trials running around that time that I can join hopefully?

If anyone has any sort of idea about their schedule, please let me know. This is really important to me, I have been fighting a long hard battle and I got to try and do something when I get there. Other companies' timelines would be appreciated too.

No one will have non public information on this (dates or locations) before any company starts recruiting. The best thing to do would be to keep up with ClinicalTrials.gov.

Some guesses:

I think you will miss the window on OTO-313 (assuming you even have unilateral tinnitus).
You won't be eligible for SPI-1005 without Meniere's (and might miss the window there, too).

FX-322 isn't likely to be starting a new Phase 2 quite then because they are reporting their severe arm this fall.

PIPE-505 maybe.
OTO-413 maybe.

 

[FGG]

If everyone expects a therapeutic effect, is there a way to mitigate bias in patient enrollment?

This is a joke, but could they make the patient enrollment rule as follows?

"Everyone, we will check PTA and WR, but we will make the final selection by lottery."

Can you think of any good way?

Consistent longer term medical records as part of the requirement and include a population (severe) much more likely to have genuinely low word scores.

 

[Zugzug]

Hey guys, I may just be coming to the US at the end of the year, November - December.

Would Frequency Therapeutics have any trials running around that time that I can join hopefully?

If anyone has any sort of idea about their schedule, please let me know. This is really important to me, I have been fighting a long hard battle and I got to try and do something when I get there. Other companies' timelines would be appreciated too.

Hey, @RichieTheKid, here's some information. Your guess is as good as mine as to the exact timeline for a Phase 2 repeat, if that's what you have in mind.

The Phase 1/2 readout was on April 9, 2019 with recruiting for Phase 2a starting shortly after. Following successful recruitment, Phase 2a dosing commencement was on October 10, 2019 -- so approximately 6 months.

Day 210 readout from this past failed Phase 2a will be late Q2, 2021. Let's say it's the end, so late June. Under the assumption of a repeat timeline (6 months recruiting, but could be more since they want to get it right), that puts the start of another Phase 2 at around December, 2021 to early-mid, 2022.

Sadly, I think it's unlikely that, assuming you were accepted, you would be able to receive dosing in November-December, 2021.

I hope this helps.

 

[Jazzer]

All tinnitus fundraisers are the same, unfortunately. It's something that I've never really understood, as many people want treatments, but only a micro-fraction are prepared to contribute in some way. Dr Rauschecker, Dr Susan Shore, the Hough Hearing Institute, and every other tinnitus-related fundraiser I've ever seen - on various donation platforms - have all performed badly. This also includes the JustGiving campaign for the famous drummer, Craig Gill, who tragically hung himself.

It is not entirely a money-centric issue, either. The vast majority are also reluctant to share material that can increase the chances of better funding and/or awareness. It's so bad, that even signing a petition is too much for many.

This is the paradoxical reality of the tinnitus community: desperate for help, but unwilling to help.

It is perfectly understandable to me that folks looking for a good investment possibility would not consider investing in tinnitus research.

All of the interest, research, and money thrown at it so far has yielded precisely 'Zilch.'

There has not, to my knowledge, been a decrease in tinnitus volume of even one single decibel, for even one sufferer.

Please tell me if I'm wrong.

 

[Tezcatlipoca]

It is perfectly understandable to me that folks looking for a good investment possibility would not consider investing in tinnitus research.

All of the interest, research, and money thrown at it so far has yielded precisely 'Zilch.'

There has not, to my knowledge, been a decrease in tinnitus volume of even one single decibel, for even one sufferer.

Please tell me if I'm wrong.

You're wrong.

 

[Ed209]

All of the interest, research, and money thrown at it so far has yielded precisely 'Zilch.'

All conditions require research funding for there to be any hope of treatments. The problem is that hardly any money goes towards tinnitus or hyperacusis research, and it shows. They have been painfully underfunded for decades. The lack of progress is an indictment of how bad the situation is, although, it has been getting marginally better in recent times.

 

[Diesel]

All conditions require research funding for there to be any hope of treatments. The problem is that hardly any money goes towards tinnitus or hyperacusis research, and it shows. They have been painfully underfunded for decades. The lack of progress is an indictment of how bad the situation is, although, it has been getting marginally better in recent times.

Why invest in treating a symptom (tinnitus/hyperacusis) when it makes macro-economic + business sense to treat a really common underlying condition (hearing loss)?

 

[Jazzer]

You're wrong.

I'd love to learn of a genuine success story where the decibel level of tinnitus has actually reduced.

 

[Ed209]

Why invest in treating a symptom (tinnitus/hyperacusis) when it makes macro-economic + business sense to treat a really common underlying condition (hearing loss)?

It's all under the same umbrella. It's semantics; I was going to say auditory research but said tinnitus and hyperacusis as they are the main concerns of this site.

We also don't know if fixing hearing loss will make any difference to tinnitus. Will the maladaptive plasticity correct itself?

 

[Ed209]

I'd love to learn of a genuine success story where the decibel level of tinnitus has actually reduced.

More research could potentially lead to this on a much larger scale, and I think that's the point. Nobody cares about hearing conditions, and the funding to help change the situation has always been abysmal.

 

[FGG]

Why invest in treating a symptom (tinnitus/hyperacusis) when it makes macro-economic + business sense to treat a really common underlying condition (hearing loss)?

Right. Especially with such a multi-factorial disease with individual factors and severity co-factors, it makes zero sense not to prioritize research into treating the underlying causes.

Hydrops, hearing loss, TMJ, anti-depressants, and perilymph fistula can all cause tinnitus and are all vastly different in how you would treat them.

Not that there is no value in more general research that may lead to symptomatic treatment, but would you rather treat the pain from a broken bone with opioids or set the bone and fix the problem?

It is extremely unlikely that there will be one cure for everyone. Even with CNS modulating or ion channel drugs. Look at NMDA receptor drugs like Ketamine. Dramatically helps some people, makes others spike horribly.

Researching tinnitus in an unfocused, general way is not what should be prioritized imo with such an multi-factorial disease.

It's like saying "let's donate to cancer research." Okay? What cancer and what research? Yes, you can learn commonalities like what triggers excessive and unrestricted growth but the expedited progress is being made when you look at each cancer separately. Even "breast cancer" is too broad for treatment. They subdivide people based on whether they are positive for the HER2 receptor or not to treat them effectively.

 

[Ed209]

Right. Especially with such a multi-factorial disease with individual factors and severity co-factors, it makes zero sense not to prioritize research into treating the underlying causes.

Hydrops, hearing loss, TMJ, anti-depressants, and perilymph fistula can all cause tinnitus and are all vastly different in how you would treat them.

Not that there is no value in more general research that may lead to symptomatic treatment, but would you rather treat the pain from a broken bone with opioids or set the bone and fix the problem?

It is extremely unlikely that there will be one cure for everyone. Even with CNS modulating or ion channel drugs. Look at NMDA receptor drugs like Ketamine. Dramatically helps some people, makes others spike horribly.

Researching tinnitus in an unfocused, general way is not what should be prioritized imo with such an multi-factorial disease.

It's like saying "let's donate to cancer research." Okay? What cancer and what research? Yes, you can learn commonalities like what triggers excessive and unrestricted growth but the expedited progress is being made when you look at each cancer separately. Even "breast cancer" is too broad for treatment. They subdivide people based on whether they are positive for the HER2 receptor or not to treat them effectively.

I wasn't expecting a deep analysis of such a simple statement. I think nearly everyone here is aware of how heterogeneous tinnitus is, and how unlikely it is that a single treatment will solve the problem for everyone.

The only point I was making is that there isn't enough money going into this kind of research.

 

[Street Novelist]

I understand this message board is for all tinnitus sufferers, but the main cause of tinnitus is hearing loss. So the main focus should be on restoring hearing. As the previous poster mentioned, there are just too many potential causes of tinnitus. It's best to focus on restoring hearing.

 

[FGG]

I wasn't expecting a deep analysis of such a simple statement. I think nearly everyone here is aware of how heterogeneous tinnitus is, and how unlikely it is that a single treatment will solve the problem for everyone.

The only point I was making is that there isn't enough money going into this kind of research.

My point was that there is much more funding than it appears because people dismiss the funding that goes towards the individual causes. Take Meniere's for instance. Meniere's causes tinnitus in some people and research is increasingly funded.

And to @Diesel's point, hearing loss research is tinnitus research.

 

[Tezcatlipoca]

I'd love to learn of a genuine success story where the decibel level of tinnitus has actually reduced.

Off the top of my head? Ebselen, NMDA antagonists, Kv7 channel openers, whatever OTO-313 is.

 

[Tezcatlipoca]

Will the maladaptive plasticity correct itself?

Yes, by definition plasticity goes both ways, restore hearing and in some amount of time the side effects of hearing loss will subside.

 

[Ed209]

Yes, by definition plasticity goes both ways, restore hearing and in some amount of time the side effects of hearing loss will subside.

Nobody knows this yet, but it is one of the most intriguing questions. One hypothesis is that there is a faulty gating mechanism within the brain in those that are aware of their tinnitus (meaning that all those with hearing loss have some sort of tinnitus, but in most cases, their brain filters it out).

The question we need to answer is why do some become aware of tinnitus (who have hearing loss) whilst others do not? What stops the increased synchronicity of fusiform cells from reaching the higher consciousness? And does it matter what the underlying mechanism is when it comes to the brain's ability to filter it?

The brain is certainly plastic in both directions, but there has to be something that drives the change. It is unknown what effect restoring one's hearing loss will have, but it will likely be a positive one. There are no studies that verify this, though.

 

[Tezcatlipoca]

Nobody knows this yet, but it is one of the most intriguing questions. One hypothesis is that there is a faulty gating mechanism within the brain in those that are aware of their tinnitus (meaning that all those with hearing loss have some sort of tinnitus, but in most cases, their brain filters it out).

The question we need to answer is why do some become aware of tinnitus (who have hearing loss) whilst others do not? What stops the increased synchronicity of fusiform cells from reaching the higher consciousness? And does it matter what the underlying mechanism is when it comes to the brain's ability to filter it?

The brain is certainly plastic in both directions, but there has to be something that drives the change. It is unknown what effect restoring one's hearing loss will have, but it will likely be a positive one. There are no studies that verify this, though.

What are you talking about? These are all 2012 theories! And they are all wrong.

And we do know what restoring hearing does, it reduces phantom cochlea symptoms. We have several examples of people in this very forum. Please update on the status quo of the hearing science.

 

[Ed209]

What are you talking about? These are all 2012 theories! And they are all wrong.

And we do know what restoring hearing does, it reduces phantom cochlea symptoms. We have several examples of people in this very forum. Please update on the status quo of the hearing science.

This is not true. If there are any examples out there they will be anecdotal.

I'm not sure what you mean by 2012 ideas? This is still ongoing. It works on the same principles as phantom limb syndrome and chronic pain. How do you explain why some get tinnitus with hearing loss and some don't? Why do some get tinnitus from neck injuries or other traumas? The list is endless.

I think you are looking at this far too simplistically. The complexity of this condition goes far beyond hearing loss. If that was the primary issue, then everyone on the planet would have tinnitus, as we all have some form of hearing loss.

 

[Cernuto]

This is not true. If there are any examples out there they will be anecdotal.

I'm not sure what you mean by 2012 ideas? This is still ongoing. It works on the same principles as phantom limb syndrome and chronic pain. How do you explain why some get tinnitus with hearing loss and some don't? Why do some get tinnitus from neck injuries or other traumas? The list is endless.

I think you are looking at this far too simplistically. The complexity of this condition goes far beyond hearing loss.

If I have a faulty gating mechanism, why is my tinnitus extremely loud one day, then hardly noticeable the very next? It's intermittently faulty? Also, people with Meniere's disease who get random attacks of tinnitus. That's due to faulty gating mechanism as well?