Frequency Therapeutics — Hearing Loss Regeneration

[FGG]

This is what I have gathered:

IHCs are what transmits the signal to the auditory nerve (after synapsing with the SGNs).

OHCs increase loudness. They amplify the sound and they also, through their movements, also help to stimulate glutamate release across to the Spiral Ganglion.

You need both to hear obviously. But "clarity" seems to have more to do with IHC and their synapses. Though if you can't hear some sounds amplified enough, obviously complex sounds (like speech) would be less clear, too.

Anyone have more? This would be a great thing to try to parse out.

 

[d'Wooluf]

Oh goodie. I thought everyone else had a complete understanding.

A quick Google found https://www.intechopen.com/books/update-on-hearing-loss/cochlear-model-for-hearing-loss. I've just skimmed through but it's almost intelligible until they get to the math. It's about 5 years old.

This little snippet might set the cat amongst the pigeons:

In general, OHC loss mostly effects the high frequencies, while the effect of IHC loss is mostly expressed in the low frequencies.

If true, this might cast doubt on the lack of penetration into the cochlea theory. Or at least that might not be the only factor at work.

 

[FGG]

Oh goodie. I thought everyone else had a complete understanding.

A quick Google found https://www.intechopen.com/books/update-on-hearing-loss/cochlear-model-for-hearing-loss. I've just skimmed through but it's almost intelligible until they get to the math. It's about 5 years old.

This little snippet might set the cat amongst the pigeons:

In general, OHC loss mostly effects the high frequencies, while the effect of IHC loss is mostly expressed in the low frequencies.

If true, this might cast doubt on the lack of penetration into the cochlea theory. Or at least that might not be the only factor at work.

Can you clarify that a bit? Do you mean it says that the effects of IHC loss is more apparent in lower frequencies or that it occurs more often?

 

[FGG]

@d'Wooluf , you were not kidding about dense! It seems to be saying most people have mixed IHC and OHC pathology and this has an additive effect. Interesting that, on its own, inner hair cell death can result in audiogram changes below 1000 Hz, where that doesn't seem to happen at higher frequencies.

I would love to know Dr. Miriam Furst's (the paper's author) thoughts on how we could clinically distinguish the two and her thoughts on FX-322 increasing clarity. Should I try to write her?

 

[d'Wooluf]

Should I try to write her?

Why not? You've got results before! It would be nice to get input from someone who hasn't got money riding on it.

 

[MRItechssuck]

What questions did the person from Frequency Therapeutics ask people on the initial phone call?

What tests, if any, did they expect you to have to present to them... normal audiogram, extended audiogram, etc... and did you email the results or how did they get the information?

I see no mention of bilateral or unilateral tinnitus... did they care?

Was travel an issue, since it is not mentioned as an exclusion?

"Documented medical history consistent with hearing loss being caused by noise exposure"

What type of medical history did they require?

"Any conductive hearing loss of greater than 15 dB at a single frequency or greater than 10 dB at two or more contiguous octave frequencies in the study ear at the Screening visit or on the prior audiogram (if the Investigator feels there is not a true conductive hearing loss, the Medical Montior should be consulted)."

Would this be covered on my standard audiogram up to 8 kHz? Please explain what I should be looking at?

Thanks.

 

[FGG]

What questions did the person from Frequency Therapeutics ask people on the initial phone call?

What tests, if any, did they expect you to have to present to them... normal audiogram, extended audiogram, etc... and did you email the results or how did they get the information?

I see no mention of bilateral or unilateral tinnitus... did they care?

Was travel an issue, since it is not mentioned as an exclusion?

What type of medical history did they require?

Would this be covered on my standard audiogram up to 8 kHz? Please explain what I should be looking at?

Thanks.

I didn't do a phone interview. My interview was in person. I'm not sure if they do phone interviews.

For my interview, they asked for copies of audiograms (you need at least one six months previously to show whether it changed or not. They don't want change or at least minor change only within 6 months) and then had me sign a medical release to get my full otology record from my Otologist. They were going to fax them themselves I think.

I told them I had bilateral tinnitus. They were fine with that. I suspect unilateral would be ok too since they are only doing one ear anyway. I'm not sure though.

Not sure if you would be excluded due to distance but you do have to come in very frequently (every 1-2 weeks I think she said unless that was just initially) so that would be difficult for most people.

 

[serendipity1996]

Frequency Therapeutics expanding their leadership team - https://investors.frequencytx.com/n...utics-expands-leadership-team-newly-appointed

Also, not really related to Frequency Therapeutics but nonetheless an interesting article on Silencity that was shared by Hyperacusis Research on Twitter. Interesting about the sub-typing within noise trauma - does this suggest that different cochlear structures could be damaged in the case of say, a sudden acoustic trauma vs chronic noise exposure over time?
https://www.silencity.com/2020/02/07/draft-323/

"In a 2019 article titled "Why is there no cure for tinnitus?" the authors looked at whether studies had dentified if participants have a history of significant noise exposure that could cause decreased sound tolerance, like hyperacusis or tinnitus. A cure for noise-induced tinnitus and hyperacusis, the authors noted, could be very different from a cure for tinnitus or hyperacusis from other causes, like aging or head injury.

The article shows that it's important for research to identify noise sub-types when evaluating potential cures. The underlying hearing health damage for sudden high level noise like acoustic trauma is different than damage from chronic moderate level noise over time. That is, the cure for noise-induced tinnitus and hyperacusis from bomb blasts or firearms is likely different than the cure for noise-induced tinnitus and hyperacusis from being exposed to unhealthy noise at school, on public transit systems, or at noisy workplaces."

 

[Piney]

They should have new spots open in NY and VA, everything can be done by email or have large hard copies brought. It's a lot of visits initially then tapers down. I was denied in NC but I can still try other locations if my word score goes up.

 

[MRItechssuck]

I didn't do a phone interview. My interview was in person. I'm not sure if they do phone interviews.

For my interview, they asked for copies of audiograms (you need at least one six months previously to show whether it changed or not. They don't want change or at least minor change only within 6 months) and then had me sign a medical release to get my full otology record from my Otologist. They were going to fax them themselves I think.

I told them I had bilateral tinnitus. They were fine with that. I suspect unilateral would be ok too since they are only doing one ear anyway. I'm not sure though.

Not sure if you would be excluded due to distance but you do have to come in very frequently (every 1-2 weeks I think she said unless that was just initially) so that would be difficult for most people.

They want two audiograms then 6 months apart? Do standard 8 kHz ones work?

I can't find my audiogram from a decade ago. It sounds like I will have to wait 6 months from the one I had from this trauma and get another one?

For the audiogram-reading challenged folks like myself... if I have normal age related hearing loss up to 8 kHz, basically normal until sloping down at a 45 degree angle...

What is meant by this exclusion?

"Any conductive hearing loss of greater than 15 dB at a single frequency or greater than 10 dB at two or more contiguous octave frequencies in the study ear at the Screening visit or on the prior audiogram (if the Investigator feels there is not a true conductive hearing loss, the Medical Montior should be consulted)."

This is only for conductive versus sensorineural hearing loss? My ENT didn't make a differentiation at my visit.

One quick question... is there any benefit to seeing a neurologist?

(The Ortho that gave me the MRI mentioned he could give a referral to see one... but he didn't offer to pay for it, and I think he was trying to cover his @ss...)

Sorry if I'm taking away from the discussion, I don't want to answer incorrectly out of ignorance.

 

[FGG]

They want two audiograms then 6 months apart? Do standard 8 kHz ones work?

I can't find my audiogram from a decade ago. It sounds like I will have to wait 6 months from the one I had from this trauma and get another one?

For the audiogram-reading challenged folks like myself... if I have normal age related hearing loss up to 8 kHz, basically normal until sloping down at a 45 degree angle...

What is meant by this exclusion?

This is only for conductive versus sensorineural hearing loss? My ENT didn't make a differentiation at my visit.

One quick question... is there any benefit to seeing a neurologist?

(The Ortho that gave me the MRI mentioned he could give a referral to see one... but he didn't offer to pay for it, and I think he was trying to cover his @ss...)

Sorry if I'm taking away from the discussion, I don't want to answer incorrectly out of ignorance.

They should have mentioned to you if you had a conductive loss. This would show up as a difference between air and bone conduction on your audiogram.

Up to 8 kHz would work if you have loss there. They will do another audiogram there. You might be able to apply if your noise exposure was 6 months ago and they could repeat the audiogram there. If you could get a hold of you records a decade ago, that would work too provided there was no change between that and your last audiogram.

How many months has it been since you got an audiogram last?

I don't see what a neurologist would do unless they suspect something specific like an acoustic neuroma or other primary neuro cause. Was your MRI abnormal?

 

[MRItechssuck]

They should have mentioned to you if you had a conductive loss. This would show up as a difference between air and bone conduction on your audiogram.

Up to 8 kHz would work if you have loss there. They will do another audiogram there. You might be able to apply if your noise exposure was 6 months ago and they could repeat the audiogram there. If you could get a hold of you records a decade ago, that would work too provided there was no change between that and your last audiogram.

How many months has it been since you got an audiogram last?

I don't see what a neurologist would do unless they suspect something specific like an acoustic neuroma or other primary neuro cause. Was your MRI abnormal?

Audiogram from mid-October.

No the MRI for my back was normal... it just shows the ortho has no idea what tinnitus is, or protecting himself from a potential lawsuit... which if I could get my old audiogram would help my case too... but that audiologist has disappeared. IF the MRI tech had only followed standard protocols and the actual manual of Siemens, stating hearing protection is required... but that is the past.

I'll just have to call the Frequency Therapeutics folks. Maybe I can email the audiogram I have and see what they say. I'm very apprehensive I'll get turned away... it'll be a 5 hour travel time for the appointment so I'm hopeful I can find out and not waste the day if I don't have a chance before making the trip.

I personally hear a lot worse after the the MRI in my opinion, but the ENT saw the same downwards curve in both ears and concluded it was age related hearing loss, in other words... no hearing loss from the MRI just tinnitus... (which he was betting would resolve after a month... hahaha...)

 

[FGG]

Audiogram from mid-October.

No the MRI for my back was normal... it just shows the ortho has no idea what tinnitus is, or protecting himself from a potential lawsuit... which if I could get my old audiogram would help my case too... but that audiologist has disappeared. IF the MRI tech had only followed standard protocols and the actual manual of Siemens, stating hearing protection is required... but that is the past.

I'll just have to call the Frequency Therapeutics folks. Maybe I can email the audiogram I have and see what they say. I'm very apprehensive I'll get turned away... it'll be a 5 hour travel time for the appointment so I'm hopeful I can find out and not waste the day if I don't have a chance before making the trip.

I personally hear a lot worse after the the MRI in my opinion, but the ENT saw the same downwards curve in both ears and concluded it was age related hearing loss, in other words... no hearing loss from the MRI just tinnitus... (which he was betting would resolve after a month... hahaha...)

When you call, ask if they are likely to still be recruiting mid-April. Maybe you could still get in if so.

 

[Mitch]

Well friends, I applied for the FX-322 clinical trial, but I was rejected. I had an extended audiogram done up to 16kHz, but no dice. They wouldn't give me any specific details on why I don't meet the inclusion criteria either.

I can't say I'm surprised, but I am disappointed.

 

[FGG]

Well friends, I applied for the FX-322 clinical trial, but I was rejected. I had an extended audiogram done up to 16kHz, but no dice. They wouldn't give me any specific details on why I don't meet the inclusion criteria either.

I can't say I'm surprised, but I am disappointed.

Do you know if you were rejected due to your audiogram or something else in your medical history?

 

[Lucifer]

@HootOwl

Hopefully Frequency Therapeutics give you the good news about accepting you for the clinical trials.

 

[Mitch]

Do you know if you were rejected due to your audiogram or something else in your medical history?

Here is exactly the response I got:

"Thank you for providing your audiogram from last week. Unfortunately, your audiometric data does not meet the requirements for the FX-322 drug trial study."

I then asked if they could give me a more specific reason and got this response:

"I am sorry but cannot release detailed information for why you do not meet the criteria for this study. I have added you to our research database and we will be in contact if you meet the criteria for future studies."

 

[FGG]

Here is exactly the response I got:

I then asked if they could give me a more specific reason and got this response:

Same. The only thing I gathered from mine is it seemed that I didn't have enough data points of loss to reach an overall average (I think) that they were looking for.

 

[FGG]

Anyone else think it's weird that they have added new testing sites when they haven't fully maxed out on participation yet?

Knowing that the FDA has given them fast track status, could this have something to do with it you think? Could the FDA be helping them get enough robust data to be approved faster? What other reasons could there be?

 

[Lucifer]

Anyone else think it's weird that they have added new testing sites when they haven't fully maxed out on participation yet?

Knowing that the FDA has given them fast track status, could this have something to do with it you think? Could the FDA be helping them get enough robust data to be approved faster? What other reasons could there be?

Now that you mention it I really hope that's the case that the more trial locations they have the faster they can release the drug into the market since they have more people.

Before they added more clinical trial locations, the majority of the locations were in the west of USA. Maybe they needed some states in the east so they could better compare.

 

[Mitch]

Same. The only thing I gathered from mine is it seemed that I didn't have enough data points of loss to reach an overall average (I think) that they were looking for.

I think so too, all of my hearing loss is in the high frequency range above 8kHz. My tinnitus is extremely high pitched, somewhere in the realm of 14-16kHz and about 40 decibels in volume. The inclusion criteria listed on clinicaltrials.gov is so vague and subjective... all it says is "established diagnosis of stable sensorineural hearing loss". I am guessing that they are looking for people with hearing loss below 8kHz.

 

[Serouj]

I think so too, all of my hearing loss is in the high frequency range above 8kHz. My tinnitus is extremely high pitched, somewhere in the realm of 14-16kHz and about 40 decibels in volume. The inclusion criteria listed on clinicaltrials.gov is so vague and subjective... all it says is "established diagnosis of stable sensorineural hearing loss". I am guessing that they are looking for people with hearing loss below 8kHz.

They are interested with hearing l in the lower range below 8 kHz since FX-322 is easily penetrating the higher region.

 

[MRItechssuck]

They are interested with hearing l in the lower range below 8 kHz since FX-322 is easily penetrating the higher region.

Are you surmising this, or do you know from some publication? Also, are you saying that it seems like they have seen the higher range improved and are now trying to see the effects on the lower... cuz lucky me... I've got hearing loss everywhere.

 

[Tweedleman]

So it sounds like worst case scenario we'll definitly get our UHF back?

 

[Lucifer]

They are interested with hearing l in the lower range below 8 kHz since FX-322 is easily penetrating the higher region.

That does make sense. They already know it works with high frequency hearing loss. Maybe they are trying to see if they can improve low frequency hearing loss without changing their delivery method.

 

[mrbrightside614]

So it sounds like worst case scenario we'll definitly get our UHF back?

Probably, yes. 8kHz+. However...

I can't remember the article or where it was posted, but there was a theory that low frequency hearing loss (and tinnitus) could theoretically crank up the gain at higher frequencies. This is fucked, IMO, because the lower tinnitus that was present the day after my car accident was not yet bothersome and I actually mistook for distant summer construction noises. It was a month later that I woke up in the middle of the night with the nightmarish piercing "eeee". This theory basically would imply that my high frequency tinnitus perception is merely a product of the gain cranked up due to my extremely modest, lower frequency hearing damage (6kHz). I definitely had some form of hearing loss for at least a month because I couldn't hear the lyric to this song that was (ironically) "can you hear me hear me hear me hear me now?" What I heard was "can you heeeeeeeee-eeee-eeaahy now?" Now I can understand what Cudi was saying, but still have the high tinnitus.

This is textbook hearing-loss related tinnitus, no? I can't think of a scenario where FX-322 is released and my tinnitus isn't cured in time, or by the drug. If this was concussion-based tinnitus, I would think it would be bilateral, and probably more volatile. The only thing that affects my tinnitus & hyperacusis is noise exposure, and it's all left-sided. I don't think I'll be able to handle a future where I don't succeed in eliminating this thing.

 

[dmorg]

Anyone else think it's weird that they have added new testing sites when they haven't fully maxed out on participation yet?

Knowing that the FDA has given them fast track status, could this have something to do with it you think? Could the FDA be helping them get enough robust data to be approved faster? What other reasons could there be?

I thought the opposite. I was thinking the recruiting is taking longer than they anticipated (the previous phase albeit smaller numbers went pretty quick). Maybe they are adding sites to help fill out the trial more quickly? Pure speculation here, but is there an advantage to expanding the number of sites this phase so they're familiar with the procedure in preparation for the next phase?

 

[FGG]

Probably, yes. 8kHz+. However...

I can't remember the article or where it was posted, but there was a theory that low frequency hearing loss (and tinnitus) could theoretically crank up the gain at higher frequencies. This is fucked, IMO, because the lower tinnitus that was present the day after my car accident was not yet bothersome and I actually mistook for distant summer construction noises. It was a month later that I woke up in the middle of the night with the nightmarish piercing "eeee". This theory basically would imply that my high frequency tinnitus perception is merely a product of the gain cranked up due to my extremely modest, lower frequency hearing damage (6kHz). I definitely had some form of hearing loss for at least a month because I couldn't hear the lyric to this song that was (ironically) "can you hear me hear me hear me hear me now?" What I heard was "can you heeeeeeeee-eeee-eeaahy now?" Now I can understand what Cudi was saying, but still have the high tinnitus.

This is textbook hearing-loss related tinnitus, no? I can't think of a scenario where FX-322 is released and my tinnitus isn't cured in time, or by the drug. If this was concussion-based tinnitus, I would think it would be bilateral, and probably more volatile. The only thing that affects my tinnitus & hyperacusis is noise exposure, and it's all left-sided. I don't think I'll be able to handle a future where I don't succeed in eliminating this thing.

I haven't heard that tinnitus, unlike hyperacusis (which definitely is) is due to "turning up the central gain" across many frequencies. A lot of times cell damage isn't permanent or as severe until weeks later, otherwise steroids wouldn't work for so many people (in the case of IT steroids, they can even be given weeks later).

My guess is your lower frequency damage didn't cause tinnitus in higher frequencies a month later but rather that you may have synapse or IHC damage at higher frequencies that didn't become as apparent until after the Neuro inflammation and oxidative stress reached it's peak.

 

[Mitch]

That does make sense. They already know it works with high frequency hearing loss. Maybe they are trying to see if they can improve low frequency hearing loss without changing their delivery method.

Great, so the cure for those of us with high frequency tinnitus exists, but we can't have it yet.

 

[Serouj]

Are you surmising this, or do you know from some publication? Also, are you saying that it seems like they have seen the higher range improved and are now trying to see the effects on the lower... cuz lucky me... I've got hearing loss everywhere.

During their recent presentation and Q&A they confirmed that FX-322 was most efficient in the +8kHz region since it penetrated that region first. They also added that they will determine whether FX-322 will penetrate down to 4 kHz and find some improvment during phase 2 since they are using multiple doses. The only missing thing is that they did not report any data at the higher region. By data I mean improvement in decibels.