Episode 12: Hearing Lost and Found — Frequency Therapeutics

[Tinnitus Talk]

Hi everybody!

Our thread on Frequency Therapeutics has garnered nearly 900,000 views over the years. We've seen hypes come and go on this forum, but so far this one's here to stay. So, you can imagine how excited we are to be able to bring you this content as part of the Tinnitus Talk Podcast: an interview with Carl LeBel, Chief Development Officer of Frequency Therapeutics.

A LOT of work went into this episode. We won't bore you with the details, but this was our most laborious production yet; hopefully the quality speaks for itself!

In this episode, you will learn about the promising Phase 1 trial results for the company's hearing regeneration drug FX-322, the potential benefits for tinnitus, why speech intelligibility should be the primary measure of hearing, and when we might expect to see this treatment hit the market.

​

Listen on:

• Tinnitus Talk Podcast (incl. timestamps and transcript)
  
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We welcome any discussion, but please keep the following in mind when commenting:

• Off-topic comments, i.e. not directly responding to the content of the podcast, will be removed. So please do listen before commenting!
• While we welcome constructive criticism on ideas or policies, we do not tolerate direct attacks on individuals.

This episode was produced, as usual, by @Markku and @Hazel and @Autumnly. Amazing content was contributed by @mrbrightside614 and @FGG. And the transcription was made by the wonderful Axel Schiller, from Regensburg University (from where the EU research actions ESIT and UNITI are managed, of which Tinnitus Hub is a part. Do you want to volunteer as well? Let us know!

We also thank our Patreon supporters for making this podcast possible.

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[patorjk]

When I listened to this last week, there was one part that really stood out to me, it's at 39:26:

Jackson: But were there any anecdotes or patient testimonials that kind of corroborate our theory? (that FX-322 could be beneficial for tinnitus)

Carl: Again, we don't have data. Certainly there is anecdotal reports as patients have come back and visited with ENTs when they have had conversations with them about how they are doing. Some of them have offered that they have had improvements in tinnitus, there's nothing that we can quantitate there.

A wave of relief came over me when I heard that. The fact that patients told their ENTs - seemingly unprompted - that the drug improved their tinnitus is huge. I understand Carl pivoting away from this since it's unquantifiable at the moment, but this is a revelation. It's made me really excited about the coming Phase 2a results.

Imagine if someone from the Phase 2a studies came on this forum and said that FX-322 had improved their tinnitus, we'd all be going nuts. What Carl just said is that multiple people have experienced this. Now the big questions are how big an improvement they had and will we see the same thing in Phase 2a.

 

[Manny]

What a great interview! I listened once, read the helpful transcript and I'm sure I will listen again. A huge thank you to @Hazel, @mrbrightside614, @FGG and of course the good Dr. LeBel for giving us this excellent and informative podcast.

I think I can safely say that all of us at Tinnitus Talk truly appreciate what you do.

Oh and I really liked the musical intro - great subtle remix

 

[sssing]

Thanks a million to @Hazel, @Markku, @Autumnly, @mrbrightside614, @FGG and all who put in much of their time, effort, money and labour to produce this podcast. I'm grateful that we have you representing the needs of our community!

 

[sssing]

When I listened to this last week, there was one part that really stood out to me, it's at 39:26:

A wave of relief came over me when I heard that. The fact that patients told their ENTs - seemingly unprompted - that the drug improved their tinnitus is huge. I understand Carl pivoting away from this since it's unquantifiable at the moment, but this is a revelation. It's made me really excited about the coming Phase 2a results.

Imagine if someone from the Phase 2a studies came on this forum and said that FX-322 had improved their tinnitus, we'd all be going nuts. What Carl just said is that multiple people have experienced this. Now the big questions are how big an improvement they had and will we see the same thing in Phase 2a.

Me too, I really pray that it is so

 

[Adaś]

@Hazel, @Markku, @Autumnly, @mrbrightside614, @FGG, many thanks for your dedication and making this interview. It was very informative and brings some hope which is sooo important for us all here.

Finally it was really great and soothing to hear your voices. I am not a very spiritual person, but if angels exist then you are them.

Let's stay strong and look forward to Phase 2A results.

 

[BigNick]

Thanks so much guys.

 

[TuxedoCat]

Thanks for another awesome podcast!

Great job @mrbrightside614 and @FGG, thanks for those important and well thought out questions and explanations. I'm excited to think there may be something on the horizon for you and others like you.

As for Frequency Therapeutics and Carl LeBel - who could not be impressed? They know and understand the target tissue, have a clear clinical development plan and concise interpretation of the results. It's any researcher's dream come true!

One significant piece of information for me was that Frequency Therapeutics is interacting with FDA and in the process is likely breaking ground for later development of FDA guidelines for testing drugs for hearing loss and for tinnitus. I caught the comment that, at least for right now, the Tinnitus Functional Index (TFI) is FDA's preferred outcome for tinnitus, something to keep in mind when considering or evaluating protocols or projects from other researchers.

As always, a big thank you to @Hazel and @Markku for making all of this possible.

TC

 

[UKBloke]

This was just such a wonderful podcast. To hear Carl LeBel state that he was essentially retiring and looking forward to kayaking with his grandson but that developments in the field that ultimately led to FX-322 pulled him back in to work was as encouraging as it was heartwarming. The rest of the discussion was incredibly informative and educational. Well done guys and thank you for all your time and effort.

 

[Lucifer]

When I listened to this last week, there was one part that really stood out to me, it's at 39:26:

A wave of relief came over me when I heard that. The fact that patients told their ENTs - seemingly unprompted - that the drug improved their tinnitus is huge. I understand Carl pivoting away from this since it's unquantifiable at the moment, but this is a revelation. It's made me really excited about the coming Phase 2a results.

Imagine if someone from the Phase 2a studies came on this forum and said that FX-322 had improved their tinnitus, we'd all be going nuts. What Carl just said is that multiple people have experienced this. Now the big questions are how big an improvement they had and will we see the same thing in Phase 2a.

I read the transcript and I must have skipped this part by accident. I can't believe Carl just admitted that some of the patients had a reduction in their tinnitus.

 

[GlennS]

I was highly skeptical at first but after this interview I'm pretty far along on getting back on a hype train after the letdown of neuromodulation. I feel like I have reason to hope now.

 

[FGG]

One significant piece of information for me was that Frequency Therapeutics is interacting with FDA and in the process is likely breaking ground for later development of FDA guidelines for testing drugs for hearing loss and for tinnitus. I caught the comment that, at least for right now, the Tinnitus Functional Index (TFI) is FDA's preferred outcome for tinnitus, something to keep in mind when considering or evaluating protocols or projects from other researchers.

You are so right about TFI. I missed the full significance of that. Researchers should be universally aware of this.

 

[patorjk]

You are so right about TFI. I missed the full significance of that. Researchers should be universally aware of this.

Is this it? https://www.ata.org/sites/default/files/TFI.pdf

My big concern with it would be how susceptible it is to the placebo effect. Just think about many people think they get benefit from taking certain supplements. Although hopefully with just one ear being treated, patients will be less likely experience the effect.

Another concern I have is that it seems geared towards tinnitus in general, rather than what one experiences in a particular ear (ex: "What percentage of your time awake were you consciously AWARE OF your tinnitus?" - one will still be aware of their tinnitus if just one ear is treated). Hopefully they'll use an altered version of the TFI that is particular to the treated ear.

 

[FGG]

Is this it? https://www.ata.org/sites/default/files/TFI.pdf

My big concern with it would be how susceptible it is to the placebo effect. Just think about many people think they get benefit from taking certain supplements. Although hopefully with just one ear being treated, patients will be less likely experience the effect.

Another concern I have is that it seems geared towards tinnitus in general, rather than what one experiences in a particular ear (ex: "What percentage of your time awake were you consciously AWARE OF your tinnitus?" - one will still be aware of their tinnitus if just one ear is treated). Hopefully they'll use an altered version of the TFI that is particular to the treated ear.

Hopefully there would be a way to answer that per ear otherwise it would be like "my 14000 Hz tone in my right ear is better but I still hear the 1000 Hz tone in the left so 100% of the time, I still hear tinnitus" and yes that would be worthless.

I think all tinnitus tests are potentially subject to placebo but you should see a much greater result in drug cohort vs placebo cohort.

Would be easier if technology existed to objectively measure it.

 

[Jcb]

Thanks @FGG and @mrbrightside614 for all your hard work on this podcast, I really enjoy listening to these podcasts and even though I don't contribute much at all on the research threads I do read them and appreciate everybody's input.

Of course thanks to the two big people as usual @Markku and @Hazel who put so much hard work and effort into this site and all its content, I'm always appreciative.

edit: and of course @Autumnly

 

[mrbrightside614]

Repost but I just want to say again thanks so much for @Markku and @Hazel's persistence and commitment to excellence throughout this process. I was super happy to be involved but as I said on the podcast, I've been doing less than well due to circumstances beyond my control and I'm sorry that I'm not very active on these boards much.

The only thing I want to add is that Dr. LeBel touched on the lack of scientific data to defend steroidal interventions in treating tinnitus. While this is true, it's mostly because the studies are very poorly designed. Oftentimes the steroids are administered well outside of the window of therapeutic efficacy, so one can not appropriately deduce that they are ineffective from these studies. Any steroid treatment is still worth a shot if you're in the extremely acute window.

Beyond that, again I am sorry that we could not address the hyperacusis question. My thinking was that they're not measuring it in phase two, and have neither done so much as mention it once during all of their press releases/Fireside chats. I don't think Frequency Therapeutics would be able to speak on whether or not it would be effective through this next phase. If we get to speak with them again after phase 2 I will definitely ask.

Thanks everybody for helping and listening. Special thank you to @FGG for her brilliant mind and big heart.

Oh and I was super nervous for the interview so I'm sorry if I said "uhm" too much! That's a huge pet peeve of mine.

 

[Tanni]

Oh and I was super nervous for the interview so I'm sorry if I said "uhm" too much! That's a huge pet peeve of mine.

No, you were a natural -- you did a great job! All three of you have really lovely accents.

It was all a bit over my head, but if others think it will work then I'm excited

 

[mrbrightside614]

Oh my god, how could I leave out @Autumnly.

Thank you so much for everything you do!

 

[Halsy]

Hype train? No. Cautiously optimistic, yes. As I've stated on several occasions, tinnitus is a neurological condition that's generally predicated on a combination of hearing loss/damage, and/or neuromuscular inflammation due to CTL issues, and/or TMJ/trigeminal nerve issues. I don't know if restoring those missing ranges in the brain will quell the confusion in the brain that causes said condition. Ultimately, you need to retrain the brain to allow the decay of those synaptic pathways that make tinnitus a persistent and ongoing problem. Maybe this qualifies as tricking the brain into that. Only time will tell on that front.

I've also always said that I seriously doubt - at least not anytime soon - there will be a silver bullet cure that works for everyone. Neuromodulation works for some, not others. I don't foresee FX-322 being any different.

Yet, even if it helps to any real degree in lowering it permanently, well, C is for cookie and that's good enough for me.

 

[Zam]

I can't wait for the results of phase 1/2.

In my case I've got several different kinds/frequencies of tinnitus (5 to 10 different sounds) on top of hyperacusis, and I'm looking forward to potentially getting rid of most of the worse ones (I "only" had 3 or 4 before SNHL), and I'd also love to catalog the changes.

Any idea when clinical trials will be coming to Canada?

Also, any discussions on diplacusis/distortions? I'm guessing if intelligibility is improved, it could imply diplacusis could be reversed as well. In my case, I've identified three separate instances of distortions depending on the frequencies (two of which blast me with tinnitus). I know this isn't likely to be an ear panacea, but it's certainly exciting.

 

[APJ]

Thank you for making the effort to put this podcast together and for assisting in clarifying all the tech jargon.

When can we expect the next exciting installment (results of phase 2)?

 

[Alan Laguna]

Hi Jackson -

You were terrific interviewing Dr. LeBel.

I have a question regarding FX-322 that I'm hoping to get an answer to.

I was in a clinical trial for AM-101 - It certainly didn't cure the tinnitus (although I won't rule-out that it didn't help). Without going into the science behind AM-101, I am concerned about it being contraindicated with FX-322, in light of Dr. LeBel's comments that other protocols may adversely affect progenitor cells that would interfere with FX-322. Essentially, does AM-101 fall in the category of the "other" protocols Dr. LeBel was referring to? That would be quite disappointing in my case, as I am greatly looking forward to FX-322 as hope for my tinnitus.

Thank you.

P.S. I have had moderate success with Melatonin - and have been diagnosed with sleep apnea — I believe there is a causal relationship with tinnitus - Are you aware of any research in this regard?

 

[FGG]

Hi Jackson -

You were terrific interviewing Dr. LeBel.

I have a question regarding FX-322 that I'm hoping to get an answer to.

I was in a clinical trial for AM-101 - It certainly didn't cure the tinnitus (although I won't rule-out that it didn't help). Without going into the science behind AM-101, I am concerned about it being contraindicated with FX-322, in light of Dr. LeBel's comments that other protocols may adversely affect progenitor cells that would interfere with FX-322. Essentially, does AM-101 fall in the category of the "other" protocols Dr. LeBel was referring to? That would be quite disappointing in my case, as I am greatly looking forward to FX-322 as hope for my tinnitus.

Thank you.

P.S. I have had moderate success with Melatonin - and have been diagnosed with sleep apnea — I believe there is a causal relationship with tinnitus - Are you aware of any research in this regard?

Hey... I can answer this. AM-101 is not a hearing regenerative drug. It doesn't act on any of the support or hair cells. It acts on the NMDA receptors. It should not affect any of the regenerative drugs.

 

[mrbrightside614]

Hi Jackson -

You were terrific interviewing Dr. LeBel.

I have a question regarding FX-322 that I'm hoping to get an answer to.

I was in a clinical trial for AM-101 - It certainly didn't cure the tinnitus (although I won't rule-out that it didn't help). Without going into the science behind AM-101, I am concerned about it being contraindicated with FX-322, in light of Dr. LeBel's comments that other protocols may adversely affect progenitor cells that would interfere with FX-322. Essentially, does AM-101 fall in the category of the "other" protocols Dr. LeBel was referring to? That would be quite disappointing in my case, as I am greatly looking forward to FX-322 as hope for my tinnitus.

Thank you.

P.S. I have had moderate success with Melatonin - and have been diagnosed with sleep apnea — I believe there is a causal relationship with tinnitus - Are you aware of any research in this regard?

Yeah, @FGG is right. I appreciate your kind words! Without knowing your exact situation, you stand to benefit from FX-322 as much as anyone who wasn't treated with AM-101.

 

[mrbrightside614]

Hype train? No. Cautiously optimistic, yes. As I've stated on several occasions, tinnitus is a neurological condition that's generally predicated on a combination of hearing loss/damage, and/or neuromuscular inflammation due to CTL issues, and/or TMJ/trigeminal nerve issues. I don't know if restoring those missing ranges in the brain will quell the confusion in the brain that causes said condition. Ultimately, you need to retrain the brain to allow the decay of those synaptic pathways that make tinnitus a persistent and ongoing problem. Maybe this qualifies as tricking the brain into that. Only time will tell on that front.

I've also always said that I seriously doubt - at least not anytime soon - there will be a silver bullet cure that works for everyone. Neuromodulation works for some, not others. I don't foresee FX-322 being any different.

Yet, even if it helps to any real degree in lowering it permanently, well, C is for cookie and that's good enough for me.

Stating that it's a neurological condition as a blanket statement is incorrect. Tinnitus has many different origins.

 

[just1morething]

Stating that it's a neurological condition as a blanket statement is incorrect. Tinnitus has many different origins.

I believe @Bam had a similar car accident like you. Not sure he got any better? I certainly hope you do. I was in an accident in 2017 that was my fault and the air bag went off in her car. I never heard that she got tinnitus, just a broken foot. She actually never settled the claim yet. You have 5 years in Minnesota.

I was on a muscle relaxer and taking Sudafed so I may have been a little groggy. On Easter the previous day I had horrible noises. My noises may be from left TMJ and Eustachian tube dysfunction or airplane barotrauma. I do have an abnormal left ear Eustachian tube. I wanted an ENT to use the balloon dilation system up my left Eustachian tube. The ENTs all want to say HF hearing loss, but that may not necessarily be the cause as you say the condition can have different origins. This condition is so torturous.

I do hope you can find some relief @mrbrightside614 as I know you are suffering greatly.

 

[mrbrightside614]

I believe @Bam had a similar car accident like you. Not sure he got any better? I certainly hope you do. I was in an accident in 2017 that was my fault and the air bag went off in her car. I never heard that she got tinnitus, just a broken foot. She actually never settled the claim yet. You have 5 years in Minnesota.

I was on a muscle relaxer and taking Sudafed so I may have been a little groggy. On Easter the previous day I had horrible noises. My noises may be from left TMJ and Eustachian tube dysfunction or airplane barotrauma. I do have an abnormal left ear Eustachian tube. I wanted an ENT to use the balloon dilation system up my left Eustachian tube. The ENTs all want to say HF hearing loss, but that may not necessarily be the cause as you say the condition can have different origins. This condition is so torturous.

I do hope you can find some relief @mrbrightside614 as I know you are suffering greatly.

Thanks man, same to you. I'm really banking on this tech working out.

 

[Halsy]

Stating that it's a neurological condition as a blanket statement is incorrect. Tinnitus has many different origins.

It doesn't matter what the origin is. The condition itself is a neurological one, period. It's confusion in the brain that results in creating synaptic pathways that promote a self-reinforced negative feedback loop. The end result is the constant misfiring of the fusiform cells in the DCN. Most people that develop tinnitus already have a few other conditions that make them prime targets for. The final thing that actually sets it off is the straw that breaks the camel's back so to speak. And once it starts it's much more difficult to stop even if you resolve the physical issues that created it. That's because the condition represents a maladaptive plasticity in the brain. Most normal brains let those lost ranges go without a hitch - as they're supposed to. Ours don't. Lucky us.

This is why I have far more faith in neuromodulation devices to overcome this in the long run than chemical treatments. This is precisely what Susan Shore's work is about. Microshocks that interrupt the fusiform cells thereby resetting the DCN. That in turn should allow the brain the let those maladaptive pathways decay and there you have resolution of tinnitus regardless of its origin. Just like rebooting a PC.

Beyond the new neuroplasticity created by neuromodulation devices, they have a whole host of benefits, the most important being warding off memory loss and cognitive decline - actually reversing them in many cases.

 

[serendipity1996]

It doesn't matter what the origin is. The condition itself is a neurological one, period. It's confusion in the brain that results in creating synaptic pathways that promote a self-reinforced negative feedback loop. The end result is the constant misfiring of the fusiform cells in the DCN. Most people that develop tinnitus already have a few other conditions that make them prime targets for. The final thing that actually sets it off is the straw that breaks the camel's back so to speak. And once it starts it's much more difficult to stop even if you resolve the physical issues that created it. That's because the condition represents a maladaptive plasticity in the brain. Most normal brains let those lost ranges go without a hitch - as they're supposed to. Ours don't. Lucky us.

This is why I have far more faith in neuromodulation devices to overcome this in the long run than chemical treatments. This is precisely what Susan Shore's work is about. Microshocks that interrupt the fusiform cells thereby resetting the DCN. That in turn should allow the brain the let those maladaptive pathways decay and there you have resolution of tinnitus regardless of its origin. Just like rebooting a PC.

Beyond the new neuroplasticity created by neuromodulation devices, they have a whole host of benefits, the most important being warding off memory loss and cognitive decline - actually reversing them in many cases.

Do you have a paper/evidence to suggest that tinnitus of cochlear origin would fail to resolve even if you tackle the underlying issue? What about people whose tinnitus improves with hearing aids/cochlear implantation?

Also do you have a source for "Most people that develop tinnitus already have a few other conditions that make them prime targets for it"?

I certainly didn't...

Don't mean to sound rude or anything, just think you've made some pretty bold statements and would be interested to see more of where you're coming from.

 

[Halsy]

Do you have a paper/evidence to suggest that tinnitus of cochlear origin would fail to resolve even if you tackle the underlying issue? What about people whose tinnitus improves with hearing aids/cochlear implantation?

Also do you have a source for "Most people that develop tinnitus already have a few other conditions that make them prime targets for it"?

I certainly didn't...

Don't mean to sound rude or anything, just think you've made some pretty bold statements and would be interested to see more of where you're coming from.

The research is out there through PubMed and other medical research sources. I have neither the time, nor inclination, to chase it all down to present it. Feel free to accept it or not, but it's factual. It's only in the last several years as more data has been collated on the subject that the picture has become clearer that most people who suffer from tinnitus suffer from somatosensory tinnitus as related to the aforementioned issues - estimated now upward of 70% of all tinnitus sufferers.

And it doesn't matter if it's somatic tinnitus or not. Tinnitus is a neurological condition, period. It starts and stops because of confusion and resolution in the brain. It's not an ear condition.