Otonomy OTO-313 — Treatment of Tinnitus

[AxEars]

Looking back at OTO-313's history - it seems it never had a high probability for success.

SPI-1005 and Frequency Therapeutics' re-trial seem to have a higher probability for success.

No cure, just treatments. We'll take it.

 

[Nick47]

SPI-1005 and Frequency Therapeutics' re-trial seem to have a higher probability for success.

Why do they have a higher probability of success?

 

[Wrfortiscue]

This became real dark real fast lol.

I know. I'm usually not this pessimistic but I really do feel for some folks here.

 

[ThomasF]

Why do they have a higher probability of success?

SPI-1005 is already at Phase 3 with a long time of refining behind it. Frequency Therapeutics is trying to replace damaged hair cells through notch therapy. Which is old science but is also very promising. OTO-313 was tested in a way that was prone to manipulation so the placebo effect was too strong.

 

[Nick47]

@ThomasF, yes I get that SP-1005 is in Phase 3 (when is this due to start), however, isn't it for Meniere's disease and tinnitus as a result of Meniere's disease? A lot of people have tinnitus that's noise induced so no use.

I disagree that Frequency Therapeutics is promising. Very little evidence and lots of failed trials. Or am I missing something?

 

[ThomasF]

@ThomasF, yes I get that SP-1005 is in Phase 3 (when is this due to start), however, isn't it for Meniere's disease and tinnitus as a result of Meniere's disease? A lot of people have tinnitus that's noise induced so no use.

SPI-1005 is believed to have efficacy for noise induced tinnitus as well. So I've been told, though only for the frequencies associated with Meniere's.

 

[Nick47]

SPI-1005 is believed to have efficacy for noise induced tinnitus as well. So I've been told, though only for the frequencies associated with Meniere's.

Tinnitus from low frequency hearing loss, which excludes most, however not all on here.

 

[serendipity1996]

Frequency Therapeutics is trying to replace damaged hair cells through notch therapy. Which is old science but is also very promising.

Frequency are not using notch therapy - they are doing Progenitor Cell Activation. Completely different things.

 

[ThomasF]

Frequency are not using notch therapy - they are doing Progenitor Cell Activation. Completely different things.

Isn't notch therapy where the protein that stops progenitor cells is stopped or inhibited so the described process can occur? Leading to the creation of new hair cells.

 

[ZFire]

Getting caught up with the unfortunate news here. Noob question but are there any reliable ways to measure tinnitus loudness and severity? These clinical trials need to be geared towards chronic tinnitus people. Acute people are in a better position to improve with time alone and so that muddles the water and makes it real difficult to ascertain if the drugs are producing the desired results.

 

[ThomasF]

Getting caught up with the unfortunate news here. Noob question but are there any reliable ways to measure tinnitus loudness and severity? These clinical trials need to be geared towards chronic tinnitus people. Acute people are in a better position to improve with time alone and so that muddles the water and makes it real difficult to ascertain if the drugs are producing the desired results.

There's been studies done that have found certain chemicals lacking in tinnitus sufferers' brains compared to normal brains. BDNF being one that seems to be lower in people suffering from hearing damage. That is as close to anything objective AFAIK.

 

[Nick47]

BDNF being one that seems to be lower in people suffering from hearing damage. That is as close to anything objective AFAIK.

Interesting as that is what they are using in OTO-413.

 

[UKBloke]

Getting caught up with the unfortunate news here. Noob question but are there any reliable ways to measure tinnitus loudness and severity? These clinical trials need to be geared towards chronic tinnitus people. Acute people are in a better position to improve with time alone and so that muddles the water and makes it real difficult to ascertain if the drugs are producing the desired results.

The only organisation I'm aware of that is actively working towards an objective measurement of tinnitus volume and severity is, The Bionics Institute, in Australia.

Early onset/placebo-control (or lack thereof)/psychological-based subjective reporting, are the absolute bane of developing a treatment for our condition in my view.

The sooner we're able to hold the various tinnitus research projects to account by being able to objectively measure their results, the better. Until then tinnitus research just seems like a parade of circles and roundabouts to me, where us long-termers grit our teeth and battle through each day.

 

[ThomasF]

Interesting as that is what they are using in OTO-413.

BDNF is something your brain produces on its own. The ability for it to reach the cochlea and all the nerve lines leading to the brain can change. It doesn't do much for hair cells themselves but it helps nourish and repair nerve tissue so that's why OTO-413 is being targeted toward hidden hearing loss. In the Guinea pig test from a few years ago they found that the BDNF exposed ears gained back 11 dB more of hearing. In the notes for the experiment the possibility of multiple doses, larger doses, as well as extended exposure to BDNF were mentioned. Otonomy is following a similar course with OTO-413 which will be interesting to see the results of. There is also a potential aid in the gene therapy direction with correcting the genes responsible for producing the BDNF.

 

[Sentinel]

BDNF is something your brain produces on its own. The ability for it to reach the cochlea and all the nerve lines leading to the brain can change. It doesn't do much for hair cells themselves but it helps nourish and repair nerve tissue so that's why OTO-413 is being targeted toward hidden hearing loss. In the Guinea pig test from a few years ago they found that the BDNF exposed ears gained back 11 dB more of hearing. In the notes for the experiment the possibility of multiple doses, larger doses, as well as extended exposure to BDNF were mentioned. Otonomy is following a similar course with OTO-413 which will be interesting to see the results of. There is also a potential aid in the gene therapy direction with correcting the genes responsible for producing the BDNF.

I have slightly more confidence in OTO-413, simply because I think that hearing tests are probably more conclusive than self-reported TFI changes if it does go right.

 

[hopes]

Well, Phase 1 OTO-313 results were positive but didn't look so fantastic, so I didn't have a lot of hope in this. But, at least, the trial was aiming for tinnitus cure as the goal. And indeed, there are few studies that aim for that.

Most the stuff about Kv7, OTO-413 and even regenerative medicine etc don't specify tinnitus cure or treatment as the goal. So it's really disappointing.

I don't trust Dr. Susan Shore. I think we need big artillery stuff like Deep Brain Stimulation to get rid of tinnitus. Or the next generation of regenerative/healing ear but it will be a long ride...

 

[SmallRonnie]

Well, Phase 1 OTO-313 results were positive but didn't look so fantastic, so I didn't have a lot of hope in this. But, at least, the trial was aiming for tinnitus cure as the goal. And indeed, there are few studies that aim for that.

Most the stuff about Kv7, OTO-413 and even regenerative medicine etc don't specify tinnitus cure or treatment as the goal. So it's really disappointing.

I don't trust Dr. Susan Shore. I think we need big artillery stuff like Deep Brain Stimulation to get rid of tinnitus. Or the next generation of regenerative/healing ear but it will be a long ride...

DBS really seems like it would work amazingly well but probably a very long way off getting there.

The method of measuring tinnitus is so important. So difficult to measure when it's so subjective and so many people just "heal" naturally over time anyway, like most people do heal, so placebo results will naturally always be high.

 

[EkkoMusic]

The only organisation I'm aware of that is actively working towards an objective measurement of tinnitus volume and severity is, The Bionics Institute, in Australia.

I wonder in a decade, when this objective measuring is hopefully widespread (from the Bionics Institute or elsewhere), if some kind of retrial of OTO-313 can be done just to see objectively if it was doing something or not. I doubt it would happen, but I'd be so curious.

I think it would be important though in really refining if the drug was doing something or not, so that other companies know what of OTO-313 worked and what didn't in developing their own treatments. At the moment, it all seems murky still, and I worry if that ambiguity doesn't actually move us forward much.

 

[DimLeb]

I wonder in a decade, when this objective measuring is hopefully widespread (from the Bionics Institute or elsewhere), if some kind of retrial of OTO-313 can be done just to see objectively if it was doing something or not. I doubt it would happen, but I'd be so curious.

I think it would be important though in really refining if the drug was doing something or not, so that other companies know what of OTO-313 worked and what didn't in developing their own treatments. At the moment, it all seems murky still, and I worry if that ambiguity doesn't actually move us forward much.

I believe the heterogeneity of tinnitus is so vast that it's almost pointless to look into a failed drug such as OTO-313. Even if it did something, it did very little and to a tiny portion of tinnitus sufferers and that wouldn't benefit a satisfying amount of patients. So, real-world clinics wouldn't care to use it and it wouldn't be worth for the companies to keep producing it.

It keeps coming back to the absence of objective measuring, its million causes, the duration of the disorder, its unknown mechanisms, the subjectivity of each patient etc etc. If researchers don't come across a substance/device/technique/drug etc that is actually very effective against most tinnitus categories, then the same story will happen again and again.

The discovery must be a real breakthrough. Small, mediocre stuff can't cut through as it seems.

 

[Diesel]

I wonder in a decade, when this objective measuring is hopefully widespread (from the Bionics Institute or elsewhere), if some kind of retrial of OTO-313 can be done just to see objectively if it was doing something or not. I doubt it would happen, but I'd be so curious.

I think it would be important though in really refining if the drug was doing something or not, so that other companies know what of OTO-313 worked and what didn't in developing their own treatments. At the moment, it all seems murky still, and I worry if that ambiguity doesn't actually move us forward much.

It does happen. Firms sell IP to larger entities (corporations, universities, governments) that have the resources to re-trial / re-formulate / re-study.

 

[Damocles]

The only organisation I'm aware of that is actively working towards an objective measurement of tinnitus volume and severity is, The Bionics Institute, in Australia.

Early onset/placebo-control (or lack thereof)/psychological-based subjective reporting, are the absolute bane of developing a treatment for our condition in my view.

The sooner we're able to hold the various tinnitus research projects to account by being able to objectively measure their results, the better. Until then tinnitus research just seems like a parade of circles and roundabouts to me, where us long-termers grit our teeth and battle through each day.

^ This.

The adage horse before cart (or vice versa), comes to mind in relation to all treatments being explored for tinnitus at the moment.

As long as we continue to rely on archaic methods such as word recognition tests and (current) audiograms, for measurement of efficacy, we will continue to produce flawed trials with unreliable results.

Like trying to stitch a wound in the dark, our physicians (researchers) can't even see the extent of damage they're attempting to fix, and so likewise, once "remedied", are unable to tell what extent of healthy tissue they've managed to save/restore. Financial incentive drives them to conclude: well, it seemed to do something. But ultimately it's a hospital where patients tell the doctors if they think they're better or not.

Imagine a cardiologist asking a patient whether the open heart surgery they had performed on them earlier that month might have averted their risk of future heart failure. That's where we are right now.

TL;DR: We need better technology for objective detection of tinnitus and hearing loss, and until the day we do, we will keep hitting this same dead end.

 

[SmallRonnie]

^ This.

The adage horse before cart (or vice versa), comes to mind in relation to all treatments being explored for tinnitus at the moment.

As long as we continue to rely on archaic methods such as word recognition tests and (current) audiograms, for measurement of efficacy, we will continue to produce flawed trials with unreliable results.

Like trying to stitch a wound in the dark, our physicians (researchers) can't even see the extent of damage they're attempting to fix, and so likewise, once "remedied", are unable to tell what extent of healthy tissue they've managed to save/restore. Financial incentive drives them to conclude: well, it seemed to do something. But ultimately it's a hospital where patients tell the doctors if they think they're better or not.

Imagine a cardiologist asking a patient whether the open heart surgery they had performed on them earlier that month might have averted their risk of future heart failure. That's where we are right now.

TL;DR: We need better technology for objective detection of tinnitus and hearing loss, and until the day we do, we will keep hitting this same dead end.

I saw a study recently that was able to measure the amount of exosomes in the ear. The idea is that the more hair cells, the more exosomes that will be in the ear. It doesn't directly measure tinnitus of course since some people have no issues with hair cells but it could work well in a lot of cases to measure the efficacy of certain treatments.

 

[in_LA]

^ This.

The adage horse before cart (or vice versa), comes to mind in relation to all treatments being explored for tinnitus at the moment.

As long as we continue to rely on archaic methods such as word recognition tests and (current) audiograms, for measurement of efficacy, we will continue to produce flawed trials with unreliable results.

Like trying to stitch a wound in the dark, our physicians (researchers) can't even see the extent of damage they're attempting to fix, and so likewise, once "remedied", are unable to tell what extent of healthy tissue they've managed to save/restore. Financial incentive drives them to conclude: well, it seemed to do something. But ultimately it's a hospital where patients tell the doctors if they think they're better or not.

Imagine a cardiologist asking a patient whether the open heart surgery they had performed on them earlier that month might have averted their risk of future heart failure. That's where we are right now.

TL;DR: We need better technology for objective detection of tinnitus and hearing loss, and until the day we do, we will keep hitting this same dead end.

Agreed, I have ADHD and my word recognition is not always accurate.

 

[UKBloke]

^ This.

The adage horse before cart (or vice versa), comes to mind in relation to all treatments being explored for tinnitus at the moment.

As long as we continue to rely on archaic methods such as word recognition tests and (current) audiograms, for measurement of efficacy, we will continue to produce flawed trials with unreliable results.

Like trying to stitch a wound in the dark, our physicians (researchers) can't even see the extent of damage they're attempting to fix, and so likewise, once "remedied", are unable to tell what extent of healthy tissue they've managed to save/restore. Financial incentive drives them to conclude: well, it seemed to do something. But ultimately it's a hospital where patients tell the doctors if they think they're better or not.

Imagine a cardiologist asking a patient whether the open heart surgery they had performed on them earlier that month might have averted their risk of future heart failure. That's where we are right now.

TL;DR: We need better technology for objective detection of tinnitus and hearing loss, and until the day we do, we will keep hitting this same dead end.

It's my third year here on Tinnitus Talk (I think). When I joined it was mainly to comment on Lenire that wasn't that far away from commercial launch at that point.

The thing I really liked about Neuromod's approach to their trials was their patient recruitment policy; tinnitus >6 months <5 years. It was the 5 year bit that really got me because what I saw there was a company being realistic about attempting to treat patients who have clearly transitioned from the acute stage to chronic. I thought tinnitus research had suddenly gotten really serious.

I was that star-struck by all of this that I was willing to overlook the lack of placebo control (absolutely something that was within their control) and lack of objective tinnitus measurement metrics (to be fair, not really in their control - but they went with it anyway).

Evidently, the end result for Lenire and Neuromod has been extremely bloody strange to say the least. Fast-forward a few years and here were are; one bizarre dead-end after another like you say.

I do wonder whether we as a patient community have to finally pushback a little more formally against this research space and highlight (in a professional, polite yet firm manner) the obvious elephant in the room, which is cutting-edge scientists trying to develop cutting-edge technology by building it upon a foundation of subjective psychological reporting, which quite frankly, now seems so utterly farcical to me I can't quite believe it's happening.

I was racking my brains trying to think of a way to get the message out to a wider audience. One option I thought might work could be a thirty-second animation - kind of like an infommerical to highlight the absurdity of the situation. I mean, imagine trying to quantify something you can't measure???

Personally I'd rather there were a moritorium on tinnitus curative research until at least The Bionics Institute could get their device out to clinical end users and trials and give us some basic common-sense objective feedback to all this fancy science because until that happens it just seems like hubris to me where researchers in search of their next grant hurl sh*t at the wall hoping some of it will stick, which is fine but as you and I know we're talking about punctured eardrums, electroctuted trigeminals and munching on horse tranquiliser. It's about time we stood our fricking ground.

Anyhow man... sorry for taking this opportunity to rant (it's not directed at you - you know that). Hope you're having some good days.

PS - one of my analogies was - you'd never address a squeak on a car by covering the entire vehicle in oil.
PPS - I like your heart analogy better.

 

[beefling]

TL;DR: We need better technology for objective detection of tinnitus and hearing loss, and until the day we do, we will keep hitting this same dead end.

I do wonder whether we as a patient community have to finally pushback a little more formally against this research space and highlight (in a professional, polite yet firm manner) the obvious elephant in the room, which is cutting-edge scientists trying to develop cutting-edge technology by building it upon a foundation of subjective psychological reporting, which quite frankly, now seems so utterly farcical to me I can't quite believe it's happening.

To borrow a quote from one of the most famous scientists in human history:

 

[LostinTX]

I felt like a kick in the gut hearing the news about this.

@Sentinel, I also reached out to the clinic and the researcher there said they will un-blind and she will contact me when they send the information to her (she doesn't have a timeline yet).

I was hopeful that it would come to market and possibly more shots or more drug would be beneficial. I reported my experience months ago on this thread.

 

[Brian Newman]

I felt like a kick in the gut hearing the news about this.

@Sentinel, I also reached out to the clinic and the researcher there said they will un-blind and she will contact me when they send the information to her (she doesn't have a timeline yet).

I was hopeful that it would come to market and possibly more shots or more drug would be beneficial. I reported my experience months ago on this thread.

Did they give you and @Sentinel any rules to not discuss the trial with others? Like any written documents you had to sign, or did they not mention anything like it?

 

[LostinTX]

Did they give you and @Sentinel any rules to not discuss the trial with others? Like any written documents you had to sign, or did they not mention anything like it?

No they didn't, but I discussed it with the researcher letting her know I felt like not discussing it until recruitment or the trial was over because I had seen people swayed away from it on the thread. So, it was my personal decision to not post until recruiting was closed. I wouldn't want my experience to stop someone else from trying it.

 

[Sentinel]

@Sentinel, I also reached out to the clinic and the researcher there said they will un-blind and she will contact me when they send the information to her (she doesn't have a timeline yet).

Yeah they haven't gotten back to me yet but I'm sure this kind of thing takes time.

Did they give you and @Sentinel any rules to not discuss the trial with others? Like any written documents you had to sign, or did they not mention anything like it?

Nope, I specifically asked that at the start. Nothing like that.

If I had, you bet your sweet ass none of you would have heard about it until now or ever depending on the paperwork.

 

[Brian Newman]

No they didn't, but I discussed it with the researcher letting her know I felt like not discussing it until recruitment or the trial was over because I had seen people swayed away from it on the thread. So, it was my personal decision to not post until recruiting was closed. I wouldn't want my experience to stop someone else from trying it.

Interesting, thanks!

Nope, I specifically asked that at the start. Nothing like that.

If I had, you bet your sweet ass none of you would have heard about it until now or ever depending on the paperwork.

Do you think the trial was affected by placebo? Seems like they didn't care at all about people talking about it. Maybe the drug just is not as effective as they thought.