Otonomy OTO-413 — Treatment of Hidden Hearing Loss

[FGG]

I'm going off of what @patorjk posted in the post of theirs I quoted when he makes references to a pig and states BDNF synapses aren't that durable.

Pretty much my comment was a direct reply to what he had posted.

Ah ok. Interestingly, Otividex has to be dosed every 3-6 months so it would be interesting if this was a similar kind of maintenance therapy.

 

[GBB]

in one of the studies I read it stated that the synapses created by BDNF in pigs weren't that durable. After a certain period of time (I can't remember - maybe 6 months?), many of the new ones died off. If the same is true in humans, I bet the plan will be to just have people continuously be re-treated.

I would be interested to see that pig study if you ever find it again.

 

[Croaker]

Ah ok. Interestingly, Otividex has to be dosed every 3-6 months so it would be interesting if this was a similar kind of maintenance therapy.

"First hit is free!"

 

[Joly]

So OTO-313 doesn't work for chronic tinnitus? It's only for acute tinnitus?

 

[patorjk]

I would be interested to see that pig study if you ever find it again.

I can't seem to find it. I did this research back in September, there's a chance I might be mixing things up. Though I distinctly remember being bummed when I read it. Maybe when Tinnitus Talk interviews Otonomy later this month (or next) they can ask them about what their internal studies say on the durability of newly created synapses.

In the meantime, if I come across the article/study again, I'll post it here.

 

[tommyd87]

I can't seem to find it. I did this research back in September, there's a chance I might be mixing things up. Though I distinctly remember being bummed when I read it. Maybe when Tinnitus Talk interviews Otonomy later this month (or next) they can ask them about what their internal studies say on the durability of newly created synapses.

In the meantime, if I come across the article/study again, I'll post it here.

Brain-derived neurotrophic factor in serum as an animal welfare indicator of environmental enrichment in pigs

This wasn't it, was it?

 

[patorjk]

Brain-derived neurotrophic factor in serum as an animal welfare indicator of environmental enrichment in pigs

This wasn't it, was it?

No, that's not it. I'm starting to doubt myself on this one, as I spent a few hours last night searching around and found nothing stating that the durability wasn't good. I remember reading these studies:

• Brain-Derived Nerve Growth Factor in the Treatment of Sensorineural Hearing Loss
• Brain-derived nerve growth factor in the cochlea – a reproducibility study

Neither says anything about durability. I could have sworn I read something that said that many of the new synapses didn't last - maybe I'm wrong though.

Those pig studies are encouraging though. One states that there was an 11dB gain across all frequency bands, but that it wasn't enough to be clinically significant. However, I'm not so sure, especially if the synapses aid in words-in-noise type hearing (and the fact that OTO-413 is extended release should increase the benefit too).

 

[frpp]

No, that's not it. I'm starting to doubt myself on this one, as I spent a few hours last night searching around and found nothing stating that the durability wasn't good. I remember reading these studies:

• Brain-Derived Nerve Growth Factor in the Treatment of Sensorineural Hearing Loss
• Brain-derived nerve growth factor in the cochlea – a reproducibility study

Neither says anything about durability. I could have sworn I read something that said that many of the new synapses didn't last - maybe I'm wrong though.

Those pig studies are encouraging though. One states that there was an 11dB gain across all frequency bands, but that it wasn't enough to be clinically significant. However, I'm not so sure, especially if the synapses aid in words-in-noise type hearing (and the fact that OTO-413 is extended release should increase the benefit too).

I genuinely wonder why an 11 dB gain across all frequencies is deemed clinically insignificant. Personally I'm 10005% sure I'd notice that much of a gain with everything sounding 2x louder, same thing with FX-322 and people gaining 10-15 dB at 8 kHz and who knows what it did at the frequencies above that.

It feels to me like if something doesn't recover at least 30 dB across the board, people would still call it "clinically insignificant".

 

[GBB]

I genuinely wonder why an 11 dB gain across all frequencies is deemed clinically insignificant. Personally I'm 10005% sure I'd notice that much of a gain with everything sounding 2x louder, same thing with FX-322 and people gaining 10-15 dB at 8 kHz and who knows what it did at the frequencies above that.

It feels to me like if something doesn't recover at least 30 dB across the board, people would still call it "clinically insignificant".

Same - if tinnitus can be reversed by restoring hearing, this would likely cure me.

 

[Diesel]

I genuinely wonder why an 11 dB gain across all frequencies is deemed clinically insignificant. Personally I'm 10005% sure I'd notice that much of a gain with everything sounding 2x louder, same thing with FX-322 and people gaining 10-15 dB at 8 kHz and who knows what it did at the frequencies above that.

It feels to me like if something doesn't recover at least 30 dB across the board, people would still call it "clinically insignificant".

I do agree for most, a 10 dB improvement should be perceived as about a 3x improvement in clarity to the human ear.

I think one problem I have with the 10 dB gain being significant or not is considering the baseline and endpoint. Decibels are measure of power on a logarithmic scale.

So, an increase from 10 dB to 20 dB requires 10x the sound power. 10 dB to 30 dB requires 100x the sound power. And so on.

From this we know that on the low end of the spectrum, improving from a 20 dB loss to 10 dB is a very small improvement in energy reception at the ear; probably insignificant. Compared to say 40 dB to 30 dB; this is significant as the power needed to generate sound is much less on a logarithmic scale.

This is why I hope Otonomy and Frequency Therapeutics can show how the aggregate of their participants improved from a hearing loss baseline to a lower decibel level.

 

[Pre55ure]

From this we know that on the low end of the spectrum, improving from a 20 dB loss to 10 dB is a very small improvement in energy reception at the ear; probably insignificant. Compared to say 40 dB to 30 dB; this is significant as the power needed to generate sound is much less on a logarithmic scale.

This is why I hope Otonomy and Frequency Therapeutics can show how the aggregate of their participants improved from a hearing loss baseline to a lower decibel level.

Can you clarify this part? I'd like to understand what you are saying here but I'm confused by how this is worded.

 

[GBB]

Can you clarify this part? I'd like to understand what you are saying here but I'm confused by how this is worded.

Decibels are a logarithmic measure of energy, meaning the jump from 40 dB to 30 dB is much greater than the jump from 20 dB to 10 dB, even though they are nominally both 10 dB of improvement. Therefore to move your hearing from 40 dB to 30 dB is much harder than going from 20 dB to 10 dB, because you're bridging a greater gap.

 

[Pre55ure]

Decibels are a logarithmic measure of energy, meaning the jump from 40 dB to 30 dB is much greater than the jump from 20 dB to 10 dB, even though they are nominally both 10 dB of improvement. Therefore to move your hearing from 40 dB to 30 dB is much harder than going from 20 dB to 10 dB, because you're bridging a greater gap.

Thanks for the explanation. That was a very clear and concise way to put it. That isn't the part that I found hard to follow though. (I actually work designing audio equipment so dB's and logarithmic scales aren't the part I was having trouble with). Rereading the post, I think it's just more an issue of the word choice and how it was phrased that makes the second half confusing to me? But no matter. 10 dB of improvement is potentially very significant.

 

[GBB]

Thanks for the explanation. That was a very clear and concise way to put it. That isn't the part that I found hard to follow though. (I actually work designing audio equipment so dB's and logarithmic scales aren't the part I was having trouble with). Rereading the post, I think it's just more an issue of the word choice and how it was phrased that makes the second half confusing to me? But no matter. 10 dB of improvement is potentially very significant.

I suppose the second part is saying if the average improvement is 10 dB, and assuming they have a diverse group with different levels of hearing deficit, it would implicitly include both people going from 40 dB to 30 dB and 20 dB to 10 dB, and therefore you could feel more assured the medication works effectively for a wide range of hearing loss.

 

[tommyd87]

No, that's not it. I'm starting to doubt myself on this one, as I spent a few hours last night searching around and found nothing stating that the durability wasn't good. I remember reading these studies:

• Brain-Derived Nerve Growth Factor in the Treatment of Sensorineural Hearing Loss
• Brain-derived nerve growth factor in the cochlea – a reproducibility study

Neither says anything about durability. I could have sworn I read something that said that many of the new synapses didn't last - maybe I'm wrong though.

Those pig studies are encouraging though. One states that there was an 11dB gain across all frequency bands, but that it wasn't enough to be clinically significant. However, I'm not so sure, especially if the synapses aid in words-in-noise type hearing (and the fact that OTO-413 is extended release should increase the benefit too).

Synapses do provide some benefit to hearing from a volume perspective, as confirmed by multiple studies, however this is not in anyway the primary and main benefit they provide when it comes to hearing. The primary benefit of synapses is their ability at assisting speech in noise. This is entirely different as a function. From what I can see, it is irrelevant whether synapses help or even benefit volume hearing because this is not the benefit or function that is trying to be obtained.

 

[Diesel]

Thanks for the explanation. That was a very clear and concise way to put it. That isn't the part that I found hard to follow though. (I actually work designing audio equipment so dB's and logarithmic scales aren't the part I was having trouble with). Rereading the post, I think it's just more an issue of the word choice and how it was phrased that makes the second half confusing to me? But no matter. 10 dB of improvement is potentially very significant.

10 dB improvement is definitely significant in my opinion.

At a patient-level improvement, I suspect the improvement from a 40 dB threshold to a 30 dB threshold would be more significant than 30 dB threshold to 20 dB threshold. I think this because the reduction in sound power needed from 40 dB-30 dB is exponentially more than 30 dB-20 dB.

I would assume that patients with worse baselines would experience a more noticeable hearing improvement.

 

[tommyd87]

I genuinely wonder why an 11 dB gain across all frequencies is deemed clinically insignificant. Personally I'm 10005% sure I'd notice that much of a gain with everything sounding 2x louder, same thing with FX-322 and people gaining 10-15 dB at 8 kHz and who knows what it did at the frequencies above that.

It feels to me like if something doesn't recover at least 30 dB across the board, people would still call it "clinically insignificant".

Statistic rules get followed with clinical trials because this is a point of accuracy in results. Really the reality is even if something is or is not statistically significant, it does not have a bearing on whether somebody notices a gain or not. Now looking at the first FX-322 trial there tended to be some who claimed that the 10-15 dB improvement and/or the word recognition improvement is nothing fancy or significant, yet in reality those who benefited got real gains from the treatment and actually would have noticed this personally. This is why statistical analysis of certain things can be somewhat flawed and not representative of the actual benefits and improvements something can have on somebody.

 

[weab00]

The earlier question was never really answered. I'm aware that Otonomy is working on both OTO-313 and OTO-414 for acute and chronic hearing loss respectively, but I'm curious about the the mechanisms that physiologically differentiate the two from each other. Are there some different mechanics within a certain time frame?

@FGG?

 

[FGG]

The earlier question was never really answered. I'm aware that Otonomy is working on both OTO-313 and OTO-414 for acute and chronic hearing loss respectively, but I'm curious about the the mechanisms that physiologically differentiate the two from each other. Are there some different mechanics within a certain time frame?

@FGG?

OTO-313 is Gacyclidine in their extended release intratympanic gel. It's an NMDA receptor blocker, which is a specific glutaminergic receptor. The Glutamate surge happens relatively early during the tinnitus process before tinnitus becomes chronic. I suspect this could be useful in some cases more chronically (just like Ketamine and related compounds are for some people, which also antagonizes the NMDA receptor). BTW this is not blocking all of Glutamine's effects, just the NMDA receptor.

OTO-413 is intratympanic BDNF, which experimentally has shown to cause broken synapses in synaptopathy to reconnect. The reason I suspect they are testing it for chronic cases is just that they need evidence that are dealing with stable loss for testing purposes. You could likely use it acutely too.

 

[kingsfan]

Does anyone know if both the hair cell regeneration (FX-322, OTO-6xx) medicine can be taken alongside synaptic regeneration medicine (OTO-413)? I assume many of us may need repairs to both sites in order to reduce tinnitus. I also wonder what the cost of all of this would be. A big determining factor would probably be whether these medicines' effects are permanent or temporary.

 

[FGG]

Does anyone know if both the hair cell regeneration (FX-322, OTO-6xx) medicine can be taken alongside synaptic regeneration medicine (OTO-413)? I assume many of us may need repairs to both sites in order to reduce tinnitus. I also wonder what the cost of all of this would be. A big determining factor would probably be whether these medicines' effects are permanent or temporary.

Otonomy has said they anticipate OTO-413 to be used with OTO-6xx (not meaning at exactly the same time but they would have additive hearing effects).

 

[Orions Pain]

Does anyone know if both the hair cell regeneration (FX-322, OTO-6xx) medicine can be taken alongside synaptic regeneration medicine (OTO-413)? I assume many of us may need repairs to both sites in order to reduce tinnitus. I also wonder what the cost of all of this would be. A big determining factor would probably be whether these medicines' effects are permanent or temporary.

I'm wondering if we were to get FX-322 before a synapse drug, and a synapse drug is actually what is needed, will that influence how effective it is later on (having gotten FX-322 prior)?

I feel like at some point there was a discussion on this but it's probably buried deep in the thread.

 

[patorjk]

Does anyone know if both the hair cell regeneration (FX-322, OTO-6xx) medicine can be taken alongside synaptic regeneration medicine (OTO-413)? I assume many of us may need repairs to both sites in order to reduce tinnitus. I also wonder what the cost of all of this would be. A big determining factor would probably be whether these medicines' effects are permanent or temporary.

Otonomy has stated that OTO-413 and OTO-6XX will complement each other, so I'm assuming they see people getting both. Whether they can be mixed for one shot or if you have to go back and get the other drug separately, I'm not sure anyone knows yet.

 

[kingsfan]

I'm wondering if we were to get FX-322 before a synapse drug, and a synapse drug is actually what is needed, will that influence how effective it is later on (having gotten FX-322 prior)?

I feel like at some point there was a discussion on this but it's probably buried deep in the thread.

Yes I've been wondering/worried about this as well. I'm really wary of any treatments that will potentially affect the efficacy of these drugs. For example, I've been interested in trying the Ketamine treatments just see if it can hold me over until these better alternatives are released, but I'm worried it will create some sort of resistance to these drugs.

 

[Shizune]

I'm just worried about any sort of push back from ENTs. I know it's been discussed at some point before, but with so many uneducated about the alleged mechanisms behind hyperacusis or tinnitus I feel like they might just deny the whole thing or question you if you tell them "this might help me". Mixing both Otonomy drugs is one thing but the others...? Especially if it's not being formulated for tinnitus or hyperacusis specifically.

I'm just very used to doctors denying me medication. Am I being too jaded here?

 

[Born To Slay]

I'm wondering if we were to get FX-322 before a synapse drug, and a synapse drug is actually what is needed, will that influence how effective it is later on (having gotten FX-322 prior)?

I feel like at some point there was a discussion on this but it's probably buried deep in the thread.

I don't see how that would be an issue.

 

[Diesel]

I'm just worried about any sort of push back from ENTs. I know it's been discussed at some point before, but with so many uneducated about the alleged mechanisms behind hyperacusis or tinnitus I feel like they might just deny the whole thing or question you if you tell them "this might help me". Mixing both Otonomy drugs is one thing but the others...? Especially if it's not being formulated for tinnitus or hyperacusis specifically.

I'm just very used to doctors denying me medication. Am I being too jaded here?

Won't happen. The demand will be in the MILLIONS in the US alone if these drugs prove significant gains. That's enough for a "hearing restoration" industry to pop up if Audiologists/ENTs deny treatment.

Besides, doctors are held to an ethical standard in the US; if they are aware a treatment can help a patient, they're obligated to offer it and discuss the risks.

 

[kingsfan]

I'm just worried about any sort of push back from ENTs. I know it's been discussed at some point before, but with so many uneducated about the alleged mechanisms behind hyperacusis or tinnitus I feel like they might just deny the whole thing or question you if you tell them "this might help me". Mixing both Otonomy drugs is one thing but the others...? Especially if it's not being formulated for tinnitus or hyperacusis specifically.

I'm just very used to doctors denying me medication. Am I being too jaded here?

I would just continue trying different doctors until you find the one that will help you try these out. My GP advised me that University doctors are more 'academic' and opened minded to try new procedures more than ones in private medical groups.

 

[FGG]

I'm wondering if we were to get FX-322 before a synapse drug, and a synapse drug is actually what is needed, will that influence how effective it is later on (having gotten FX-322 prior)?

I feel like at some point there was a discussion on this but it's probably buried deep in the thread.

I also can't think of a reason the order would matter but that's something that maybe Otonomy could be asked when Tinnitus Talk gets them on the podcast since they also have a hair cell drug (OTO-6xx) in pre-clinical.

 

[Orions Pain]

I'm just worried about any sort of push back from ENTs. I know it's been discussed at some point before, but with so many uneducated about the alleged mechanisms behind hyperacusis or tinnitus I feel like they might just deny the whole thing or question you if you tell them "this might help me". Mixing both Otonomy drugs is one thing but the others...? Especially if it's not being formulated for tinnitus or hyperacusis specifically.

I'm just very used to doctors denying me medication. Am I being too jaded here?

If their trials show it's not very useful for tinnitus (which I doubt and I'm hopeful isn't the case) then we probably want the injection anyway right? As for synapse drugs, they'll probably follow in FX-322's footsteps and include a tinnitus outcome in their trials as well!

I doubt any ENT will deny treatment if there are cold hard facts backing up that the treatment would be effective! (More money in their pocket too).