Otonomy OTO-413 — Treatment of Hidden Hearing Loss

[FGG]

Can you maybe provide me some sources for this? So far I have not found any clear statement for it (I did not find any so far - except for the podcast), so I would really like to get a more in depth answer...

Here is something on the neurite outgrowth caused by the drug:

http://otologicpharma.com/the-science/

I remember that the neurites did reportedly synapse and the rodents were tested for this weeks later. @HootOwl, do you remember where that info is by any chance?

 

[spacehunter]

Here is something on the neurite outgrowth caused by the drug:

http://otologicpharma.com/the-science/

I remember that the neurites did reportedly synapse and the rodents were tested for this weeks later. @HootOwl, do you remember where that info is by any chance?

Thank you very much for the reply!

I really like how they show the comparison between BDNF (OTO-413) and HPN-07. If HPN-07 (+NAC) really has the same effectiveness (provided the concentration is adapted correctly) as BDNF, this great news.

 

[Street Novelist]

So, OTO-413 could restore hearing, even if it doesn't regrow the hair cells? Might simply repairing the synapses be enough?

 

[FGG]

So, OTO-413 could restore hearing, even if it doesn't regrow the hair cells? Might simply repairing the synapses be enough?

Synapses are a component of hearing, most involved in "speech in noise" hearing. The "whether that's enough" likely depends on the individual.

 

[Jim Vasilakis]

How can someone find out if they have hidden hearing loss?

 

[FGG]

How can someone find out if they have hidden hearing loss?

There isn't a good audiological test for synaptopathy, unfortunately. If you have it widespread enough in the most important speech frequencies, however, you will have difficulty hearing in noisy places (aka "speech in noise difficulty").

 

[Justin Mills]

According to the latest research it is not so much the destruction of sound receptor hair cells, rather it is damage to cochlear synapses (which in turns causes progressive auditory nerve degeneration) that is the most significant cause of both tinnitus and loss of sound clarity perception.



The only regenerative therapy I've seen targeting auditory synapses is OTO-413. The problem is Otonomy appears to be specifically trying to exclude tinnitus from its endpoints.

See:

OTO-413 in Subjects With Speech-in-Noise Hearing Impairment

"Exclusion Criteria: Subject self-reports bothersome, subjective tinnitus and is consistently aware of their tinnitus throughout much of the waking day."

It's like Otonomy despite having so many neurotology experts doesn't realized that hearing loss and tinnitus are integrally connected. We know that tinnitus is usually caused by auditory damage from external sources such as noise or drugs. Reversing the damage through regenerative treatments would thus also reverse the tinnitus. Yet it appears they are excluding the group that would most be helped by OTO-413, people who are "consistently aware of their tinnitus" all day.

Perhaps if OTO-413 is approved for "hidden" hearing loss, it can nonetheless less be used off-label for tinnitus. It would've been better however seeing them state up front that it's for both tinnitus and hearing loss.

Another note, it would be great to see companies begin trying a treatment that includes both regeneration of the synapses and hair cells. All of the drugs in being studied either focus only on restoring hair cells (FX-322 progenitor cell stimulating small molecule) or regenerating synapses, OTO-413. It seems self evident that doing both would be the most effective. Such an approach is also more likely to get approved as a treatment because it would most likely yield clinically significant improvements.

 

[Tezcatlipoca]

All of the drugs in being studied either focus only on restoring hair cells (FX-322 progenitor cell stimulating small molecule) or regenerating synapses, OTO-413. It seems self evident that doing both would be the most effective. Such an approach is also more likely to get approved as a treatment because it would most likely yield clinically significant improvements

First, they'd need to find a drug that does both well. IMO this is a non-issue.

If the drugs get approved, we can get both. If they don't, well then the whole argument is a moot point because we wouldn't be able to get them anyway.

 

[serendipity1996]

According to the latest research it is not so much the destruction of sound receptor hair cells, rather it is damage to cochlear synapses (which in turns causes progressive auditory nerve degeneration) that is the most significant cause of both tinnitus and loss of sound clarity perception.

The only regenerative therapy I've seen targeting auditory synapses is OTO-413. The problem is Otonomy appears to be specifically trying to exclude tinnitus from its endpoints.

See:

OTO-413 in Subjects With Speech-in-Noise Hearing Impairment

"Exclusion Criteria: Subject self-reports bothersome, subjective tinnitus and is consistently aware of their tinnitus throughout much of the waking day."

It's like Otonomy despite having so many neurotology experts doesn't realized that hearing loss and tinnitus are integrally connected. We know that tinnitus is usually caused by auditory damage from external sources such as noise or drugs. Reversing the damage through regenerative treatments would thus also reverse the tinnitus. Yet it appears they are excluding the group that would most be helped by OTO-413, people who are "consistently aware of their tinnitus" all day.

Perhaps if OTO-413 is approved for "hidden" hearing loss, it can nonetheless less be used off-label for tinnitus. It would've been better however seeing them state up front that it's for both tinnitus and hearing loss.

Another note, it would be great to see companies begin trying a treatment that includes both regeneration of the synapses and hair cells. All of the drugs in being studied either focus only on restoring hair cells (FX-322 progenitor cell stimulating small molecule) or regenerating synapses, OTO-413. It seems self evident that doing both would be the most effective. Such an approach is also more likely to get approved as a treatment because it would most likely yield clinically significant improvements.

Otonomy is not the only company working on synapse regeneration - Pipeline Therapeutics also has a drug in clinical trials targeting this.

Otonomy also has a hair cell drug in development - I assume it will be a few years at least until they advance to clinical but they are working on both.

Regarding targeting both, I am not sure what you mean - do you mean a single drug that does both at the same time? Frequency Therapeutics have demonstrated that when you regenerate a hair cell, it automatically then synapses to the auditory nerve. Robert Jackler from the Stanford Initiative to Cure Hearing Loss also demonstrated this back in 2012. Also, many people have synaptopathy without corresponding hair cell loss so a treatment targeting solely synaptopathy will be greatly valuable.

Also, thanks for linking the talk! Gonna watch it.

 

[Street Novelist]

PIPE-505 regrows synapses as well. Don't forget about that one. Their results come out next month.

 

[Diesel]

According to the latest research it is not so much the destruction of sound receptor hair cells, rather it is damage to cochlear synapses (which in turns causes progressive auditory nerve degeneration) that is the most significant cause of both tinnitus and loss of sound clarity perception.

The only regenerative therapy I've seen targeting auditory synapses is OTO-413. The problem is Otonomy appears to be specifically trying to exclude tinnitus from its endpoints.

See:

OTO-413 in Subjects With Speech-in-Noise Hearing Impairment

"Exclusion Criteria: Subject self-reports bothersome, subjective tinnitus and is consistently aware of their tinnitus throughout much of the waking day."

It's like Otonomy despite having so many neurotology experts doesn't realized that hearing loss and tinnitus are integrally connected. We know that tinnitus is usually caused by auditory damage from external sources such as noise or drugs. Reversing the damage through regenerative treatments would thus also reverse the tinnitus. Yet it appears they are excluding the group that would most be helped by OTO-413, people who are "consistently aware of their tinnitus" all day.

Perhaps if OTO-413 is approved for "hidden" hearing loss, it can nonetheless less be used off-label for tinnitus. It would've been better however seeing them state up front that it's for both tinnitus and hearing loss.

Another note, it would be great to see companies begin trying a treatment that includes both regeneration of the synapses and hair cells. All of the drugs in being studied either focus only on restoring hair cells (FX-322 progenitor cell stimulating small molecule) or regenerating synapses, OTO-413. It seems self evident that doing both would be the most effective. Such an approach is also more likely to get approved as a treatment because it would most likely yield clinically significant improvements.

I found 27:30 on to be extremely interesting, and telling... Especially that part about the audiogram...

 

[Tezcatlipoca]

I found 27:30 on to be extremely interesting, and telling... Especially that part about the audiogram...

Scientists have begun acknowledging our "wild theories" about the audiogram.

Who would have thought a century old test was flawed...

 

[Diesel]

Scientists have begun acknowledging our "wild theories" about the audiogram.

Who would have thought a century old test was flawed...

LOL... the "wild theories" are based on scientific research findings that members read and relayed. I think it's more the members here that need to acknowledge the science behind hearing is more than 9 tones on a sheet.

It blows my mind that hearing assessments developed from 1940-1960 are considered "standard."

 

[Tezcatlipoca]

LOL... the "wild theories" are based on scientific research findings that members read and relayed. I think it's more the members here that need to acknowledge the science behind hearing is more than 9 tones on a sheet.

It blows my mind that hearing assessments developed from 1940-1960 are considered "standard."

Yeah it's definitely not "wild theories," I was just paraphrasing what some users have said.

I think it's akin to flat earth in a way, science is very complicated so people want to simplify it as much as they can so they feel like they "get it," and 9 tones on a piece of paper is pretty simple!

Now the real question is, does the FDA consider this "wild theories"? A lot of hearing loss drugs would have way better chances if the FDA reviewers took the audiogram with a grain (or maybe more like a pinch) of salt.

 

[OptimusPrimed]

I have a near perfect audiogram, ABR, conduction test, OHC etc... but have had very tinny, crackly distorted hearing in my right ear and moderate-severe tinnitus since a couple of gun sessions. I can't hear anything clearly in my right ear in restaurants, schools, loud places. Dishes, toilets, kids voices, shrill dog barks, shower faucets... all extremely distorted.

I highly suspect I suffer from cochlear synaptopathy and I am very hopeful that OTO-413 is successful. It could give some of us relief. Only if you live with hidden hearing loss, do you know the frustration of having to live with it daily and then having audiologists tell you "your audiogram is perfect, you don't have any hearing loss."

 

[GBB]

LOL... the "wild theories" are based on scientific research findings that members read and relayed. I think it's more the members here that need to acknowledge the science behind hearing is more than 9 tones on a sheet.

It blows my mind that hearing assessments developed from 1940-1960 are considered "standard."

I trust my ENT - he hits my knee with a little hammer and my leg kicks - means my nervous system is MINT. After that we did a high five and skipped the audiogram altogether. This is good old American healthcare just like what Patton got and by god I'm a patriot.

 

[Lukee]

I trust my ENT - he hits my knee with a little hammer and my leg kicks - means my nervous system is MINT. After that we did a high five and skipped the audiogram altogether. This is good old American healthcare just like what Patton got and by god I'm a patriot.

GBB: Americans have bad healthcare.

CANADA: Hold my beer...

 

[Diesel]

Anyone else had a look at their most recent deck? Nice new details on OTO-413.

https://investors.otonomy.com/static-files/83e92663-05d8-4033-b063-cfb180af8595

 

[OptimusPrimed]

Anyone else had a look at their most recent deck? Nice new details on OTO-413.

https://investors.otonomy.com/static-files/83e92663-05d8-4033-b063-cfb180af8595

 

[Tezcatlipoca]

2022 is going to be a make or break year for Otonomy.

 

[Rajin]

2022 is going to be a make or break year for Otonomy.

Why do you say that? Will they come thru?

 

[Diesel]

2022 is going to be a make or break year for Otonomy.

Big fan of this urgency & new entry we're seeing in the hearing space lately.

Breakthroughs are coming...

 

[Zugzug]

Anyone else had a look at their most recent deck? Nice new details on OTO-413.

https://investors.otonomy.com/static-files/83e92663-05d8-4033-b063-cfb180af8595

The graphs on page 8 of the OTO-313 performance are interesting. All of the placebos clearly lowered their TFI as well. The placebo effect is real, apparently.

Slide 11 also reveals a parallel to FX-322 concepts, which is that higher starting TFI help to reduce a floor effect.

I think OTO-313 could be a nice drug. It might actually help my problems some.

 

[Tezcatlipoca]

Big fan of this urgency & new entry we're seeing in the hearing space lately.

Breakthroughs are coming...

Definitely. They see the writing on the wall and know it's just a matter of time. Everyone is rushing to be the first to make the big break in the hearing space and make a ridiculous amount of money.

 

[Sentinel]

Pardon my ignorance. What's an expansion study and how does it factor into the phase system for clinical trials?

Google failed to yield anything I could understand.

 

[AfroSnowman]

Pardon my ignorance. What's an expansion study and how does it factor into the phase system for clinical trials?

Google failed to yield anything I could understand.

Expansion study is doing an expanded study (more people) under the same procedures as original study. For example, instead of creating new patient qualifications, new endgoals, new study structure, and potentially with new clinics they will just add a bunch more people to the original Phase 1/2 study that they already did. It is a way to potentially speed up the clinical study process.

 

[Pete88]

Expansion study is doing an expanded study (more people) under the same procedures as original study. For example, instead of creating new patient qualifications, new endgoals, new study structure, and potentially with new clinics they will just add a bunch more people to the original Phase 1/2 study that they already did. It is a way to potentially speed up the clinical study process.

How does this speed up clinical study process? Legit question because to my uneducated brain, it seems like a redo of a previously favorable Phase is just taking up more time.

 

[AfroSnowman]

How does this speed up clinical study process? Legit question because to my uneducated brain, it seems like a redo of a previously favorable Phase is just taking up more time.

I may have this wrong, but this is my understanding.

I think that the original Phase 1/2 had too few people to make broad assumptions about subtyping and overall effectiveness. So they showed it was safe and got some effect in a percentage of the 20 or fewer people that took part in that study. Rather than going through a somewhat lengthy process to design a new Phase 2 study using their best guesses for who to allow to participate (I'm not sure how this all works but I think that it needs study design, exclusion criteria, modified protocols, approvals and the like) which might take a year or more to get going, they can immediately recruit and start an already approved study with, let's say 80 or 100 subjects, and may be able to get enough data to start subtyping and finding more definitive results.

 

[Pete88]

I may have this wrong, but this is my understanding.

I think that the original Phase 1/2 had too few people to make broad assumptions about subtyping and overall effectiveness. So they showed it was safe and got some effect in a percentage of the 20 or fewer people that took part in that study. Rather than going through a somewhat lengthy process to design a new Phase 2 study using their best guesses for who to allow to participate (I'm not sure how this all works but I think that it needs study design, exclusion criteria, modified protocols, approvals and the like) which might take a year or more to get going, they can immediately recruit and start an already approved study with, let's say 80 or 100 subjects, and may be able to get enough data to start subtyping and finding more definitive results.

So you're saying it's kind of like a "slow and steady wins the race" kind of thing? Like "get good, then go fast?". Couldn't they just have done pretty much the same thing and call it Phase 2 and if it works out, they get another Phase out of the way and if it doesn't, they're at the same spot they'd be in had they done a Phase 1/2 Expansion study?

 

[Diesel]

I may have this wrong, but this is my understanding.

I think that the original Phase 1/2 had too few people to make broad assumptions about subtyping and overall effectiveness. So they showed it was safe and got some effect in a percentage of the 20 or fewer people that took part in that study. Rather than going through a somewhat lengthy process to design a new Phase 2 study using their best guesses for who to allow to participate (I'm not sure how this all works but I think that it needs study design, exclusion criteria, modified protocols, approvals and the like) which might take a year or more to get going, they can immediately recruit and start an already approved study with, let's say 80 or 100 subjects, and may be able to get enough data to start subtyping and finding more definitive results.

This is exactly the case. They also reduced the amount of endpoint tests required of the patients, which should make extended recruiting easier.