Otonomy OTO-413 — Treatment of Hidden Hearing Loss

[hopes]

So i have read some pages from this topic and if I am right, OTO-413 seems to only target acute hidden hearing loss, not chronic?

 

[Eliot Martin]

OTO-413 seems to only target acute hidden hearing loss, not chronic?

Where have you read that?

 

[aorelia]

So i have read some pages from this topic and if I am right, OTO-413 seems to only target acute hidden hearing loss, not chronic?

I believe OTO-313 was initially targeting acute tinnitus. Have not seen that with OTO-413.

 

[hopes]

OTO-313: early onset tinnitus
OTO-413: having tinnitus is exclusion criteria

 

[Eliot Martin]

OTO-313: early onset tinnitus
OTO-413: having tinnitus is exclusion criteria

The exclusion criteria for OTO-413 is because some patients might not notice the improvement in hearing due to their LOUD tinnitus. Nothing more.

 

[Survivor234]

The exclusion criteria for OTO-413 is because some patients might not notice the improvement in hearing due to their LOUD tinnitus. Nothing more.

Isn't OTO-413 designed to repair hair cells? If so, why is tinnitus excluded, considering noise-induced tinnitus is caused by bent or damaged hair cells?

 

[d'Wooluf]

isn't OTO-413 designed to repair hair cells? If so, why is tinnitus excluded, considering noise-induced tinnitus is caused by bent or damaged hair cells?

Answered in the post above yours. It's about getting a clean result in a clinical trial. It's not about equity.

 

[Survivor234]

Answered in the post above yours. It's about getting a clean result in a clinical trial. It's not about equity.

You don't understand. If OTO-413 repaired damage to hair cells, then those with noise-induced tinnitus should be a shoo-in for the treatment because success could also be measured by a reduction in tinnitus.

 

[d'Wooluf]

They're taking a hearing loss treatment to the FDA, not a tinnitus treatment. Any improvement in tinnitus would be a flow-on result of improvement in hearing. Improved hearing is the primary outcome.

In any case, tinnitus is notoriously difficult to measure. If including tinnitus sufferers muddies the waters when it comes to measuring hearing, where's the upside in including them? It makes getting FDA approval a little less likely.

 

[Justin Mills]

You don't understand. If OTO-413 repaired damage to hair cells, then those with noise-induced tinnitus should be a shoo-in for the treatment because success could also be measured by a reduction in tinnitus.

OTO-413 doesn't work by repairing hair cells. It works by regenerating cochlear synapses.

 

[ColinUK]

They're taking a hearing loss treatment to the FDA, not a tinnitus treatment. Any improvement in tinnitus would be a flow-on result of improvement in hearing. Improved hearing is the primary outcome.

In any case, tinnitus is notoriously difficult to measure. If including tinnitus sufferers muddies the waters when it comes to measuring hearing, where's the upside in including them? It makes getting FDA approval a little less likely.

Unless it actually worked, I think it wouldn't be too hard to measure if people said "ooh, I don't have tinnitus anymore." I do think with a lot of these drugs it's a shame there's not a scatter gun approach at the start. Get a large group of people with different issues then narrow stuff down. With the ears it's all guesswork and theory at the moment. What if restoring the synapse does nothing on its own for hearing, but it could work for tinnitus or ear pain / sensitivity? They could be onto a winner but we will never know.

I mean I hope that some of these drugs do something for someone and they can make it to market so people can try, but with how many different issues are caused by ear damage, it would be really great to know if any of these drugs have potential to relieve any of them.

 

[Matchbox]

They're taking a hearing loss treatment to the FDA, not a tinnitus treatment. Any improvement in tinnitus would be a flow-on result of improvement in hearing. Improved hearing is the primary outcome.

In any case, tinnitus is notoriously difficult to measure. If including tinnitus sufferers muddies the waters when it comes to measuring hearing, where's the upside in including them? It makes getting FDA approval a little less likely.

They are one in the same man.

 

[Survivor234]

OTO-413 doesn't work by repairing hair cells. It works by regenerating cochlear synapses.

Then why are they excluding people with tinnitus? Aren't some forms of tinnitus caused by dead or broken synapses?

Furthermore, why did Otonomy state that OTO-413 repairs the ear rather than regenerates?

 

[AfroSnowman]

Then why are they excluding people with tinnitus? Aren't some forms of tinnitus caused by dead or broken synapses?

Furthermore, why did Otonomy state that OTO-413 repairs the ear rather than regenerates?

I think tinnitus is just another layer of complexity for a study looking at hearing restoration.

 

[Lucifer]

I think tinnitus is just another layer of complexity for a study looking at hearing restoration.

But can't they list tinnitus as a secondary outcome?

 

[AfroSnowman]

But can't they list tinnitus as a secondary outcome?

Nope, only hearing.

 

[OptimusPrimed]

Nope, only hearing.

I don't think this is the drug we're waiting for. They said on the Tinnitus Talk Podcast that there were no reports of tinnitus improving with the usage of the drug in the trials. Maybe the drug would have an application as an adjunct therapy with Dr. Susan Shore's device or something; but outside of that I remain skeptical.

 

[Survivor234]

OTO-413 doesn't work by repairing hair cells. It works by regenerating cochlear synapses.

How is that different from regenerating hair cells?

 

[Diesel]

I don't think this is the drug we're waiting for. They said on the Tinnitus Talk Podcast that there were no reports of tinnitus improving with the usage of the drug in the trials. Maybe the drug would have an application as an adjunct therapy with Dr. Susan Shore's device or something; but outside of that I remain skeptical.

They also are excluding patients with bothersome tinnitus from the trial. So, chances are, if someone did have tinnitus that wasn't "bothersome," any improvement wouldn't be significant on a TFI anyway.

 

[OptimusPrimed]

They also are excluding patients with bothersome tinnitus from the trial. So, chances are, if someone did have tinnitus that wasn't "bothersome," any improvement wouldn't be significant on a TFI anyway.

Upon further investigation, many experts in the field are theorizing that cochlear synaptopathy may in fact be responsible for some tinnitus and hyperacusis. Check out this quote from Dr. Charles Liberman. There may be a benefit of such drugs for those suffering from tinnitus or hyperacusis.

In Conversation with Professor Charles Liberman

Since acoustic overexposure is the most reliable way to produce tinnitus and hyperacusis in humans, and since both perceptual anomalies can occur without audiometric shifts, and since auditory-nerve synapses are the most vulnerable elements in noise damage, it was natural to hypothesise that synaptopathy might be a key elicitor of tinnitus and hyperacusis. There is now evidence from animal models that this type of peripheral neural loss is transformed into hyperactivity (both spontaneous and sound-evoked) throughout the central auditory pathways, as central neuronal circuits rebalance the excitatory and inhibitory inputs in response to decreasing ascending signals. It's intriguing that, in some cochlear implant users, simply turning on the implant, and thereby restoring spontaneous activity to heretofore silent auditory nerve fibres, can attenuate the tinnitus percept. It suggests that reconnecting silenced spiral ganglion neurons to hair cells could also be a treatment for tinnitus. It might also be a cure for some types of hyperacusis, but see below.

 

[Justin Mills]

They also are excluding patients with bothersome tinnitus from the trial. So, chances are, if someone did have tinnitus that wasn't "bothersome," any improvement wouldn't be significant on a TFI anyway.

The difference is synapses are more vulnerable and take the brunt of the damage.

@OptimusPrimed is spot on, that is the primary underlying cause for tinnitus and hyperacusis. I fully believe that regenerating the cochlear synapses will be the most effective way possible to reverse tinnitus. All the lost sensory input that is causing the overstimulation of neurons and ringing sounds would be restored.

 

[UKBloke]

The difference is synapses are more vulnerable and take the brunt of the damage.

@OptimusPrimed is spot on, that is the primary underlying cause for tinnitus and hyperacusis. I fully believe that regenerating the cochlear synapses will be the most effective way possible to reverse tinnitus. All the lost sensory input that is causing the overstimulation of neurons and ringing sounds would be restored.

Now I'm confused. Do we assume OTO-413 may be the treatment we're looking for or not?

 

[AfroSnowman]

Do we assume OTO-413 may be the treatment we're looking for or not?

Could be but we have yet to get any evidence at all that regenerative medicine impacts tinnitus. I'm waiting for the first hint of evidence that it will help, right now it is all just theory. That being said it makes sense to me.

 

[Geatly]

By the way guys, Otonomy is recruiting people for their Phase 2 clinical trial.

To find out more, go to this link. There are numbers and email contacts as well as locations of the clinical studies:

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

 

[Joeseph Stope]

Could be but we have yet to get any evidence at all that regenerative medicine impacts tinnitus. I'm waiting for the first hint of evidence that it will help, right now it is all just theory. That being said it makes sense to me.

When I first joined up here I thought tinnitus was all about damaged or missing hair cells.

If there's one thing I've learned since then is that there are a lot more "moving parts" in the inner ear.

 

[Diesel]

Upon further investigation, many experts in the field are theorizing that cochlear synaptopathy may in fact be responsible for some tinnitus and hyperacusis. Check out this quote from Dr. Charles Liberman. There may be a benefit of such drugs for those suffering from tinnitus or hyperacusis.

In Conversation with Professor Charles Liberman

Since acoustic overexposure is the most reliable way to produce tinnitus and hyperacusis in humans, and since both perceptual anomalies can occur without audiometric shifts, and since auditory-nerve synapses are the most vulnerable elements in noise damage, it was natural to hypothesise that synaptopathy might be a key elicitor of tinnitus and hyperacusis. There is now evidence from animal models that this type of peripheral neural loss is transformed into hyperactivity (both spontaneous and sound-evoked) throughout the central auditory pathways, as central neuronal circuits rebalance the excitatory and inhibitory inputs in response to decreasing ascending signals. It's intriguing that, in some cochlear implant users, simply turning on the implant, and thereby restoring spontaneous activity to heretofore silent auditory nerve fibres, can attenuate the tinnitus percept. It suggests that reconnecting silenced spiral ganglion neurons to hair cells could also be a treatment for tinnitus. It might also be a cure for some types of hyperacusis, but see below.

The difference is synapses are more vulnerable and take the brunt of the damage.

@OptimusPrimed is spot on, that is the primary underlying cause for tinnitus and hyperacusis. I fully believe that regenerating the cochlear synapses will be the most effective way possible to reverse tinnitus. All the lost sensory input that is causing the overstimulation of neurons and ringing sounds would be restored.

These are great points, and I am aware of and agree that synaptopathy may be one of the underlying conditions causing tinnitus and/or hyperacusis. As someone who had progressive synaptopathy issues for about a decade prior to getting "hear it all time" tinnitus, I can anecdotally say there may be a correlation.

However, that doesn't change that Otonomy isn't accepting patients with "bothersome tinnitus" into the OTO-413 trial, nor are they testing for it. So, within the scope of the Phase 2 in-progress, unfortunately they won't comment on tinnitus improvement or be able to provide any data/evidence that OTO-413 improves the tinnitus symptom vs placebo.

They will either add tinnitus to a Phase 3 / Pivotal as an experimental outcome, or we'll have to wait and see what the early tinnitus-having recipients of the drug say.

 

[Joeseph Stope]

These are great points, and I am aware of and agree that synaptopathy may be one of the underlying conditions causing tinnitus and/or hyperacusis. As someone who had progressive synaptopathy issues for about a decade prior to getting "hear it all time" tinnitus, I can anecdotally say there may be a correlation.

However, that doesn't change that Otonomy isn't accepting patients with "bothersome tinnitus" into the OTO-413 trial, nor are they testing for it. So, within the scope of the Phase 2 in-progress, unfortunately they won't comment on tinnitus improvement or be able to provide any data/evidence that OTO-413 improves the tinnitus symptom vs placebo.

They will either add tinnitus to a Phase 3 / Pivotal as an experimental outcome, or we'll have to wait and see what the early tinnitus-having recipients of the drug say.

It's great to have someone who knows the jargon and puts an optimistic slant on it. Not much I can add with my limited knowledge of medicine or the auditory system other than to say that Otonomy is fighting its corner in Bureaucracy-land where the costs in time and money are very high and where hearing tests in a sample (PTA WIN etc) yield concrete results whereas tinnitus tests get kind of mixed up with mood and placebo and might vary over time.

So the way to get FDA approval is with concrete results.

Once the drug hits the market, well, we can try for ourselves once the good doctor prescribes it.

 

[Diesel]

It's great to have someone who knows the jargon and puts an optimistic slant on it. Not much I can add with my limited knowledge of medicine or the auditory system other than to say that Otonomy is fighting its corner in Bureaucracy-land where the costs in time and money are very high and where hearing tests in a sample (PTA WIN etc) yield concrete results whereas tinnitus tests get kind of mixed up with mood and placebo and might vary over time.

So the way to get FDA approval is with concrete results.

Once the drug hits the market, well, we can try for ourselves once the good doctor prescribes it.

I appreciate the comment, however I am but a simple liquid hydrocarbon.

The requirements to get a drug to product are simple: Identify a clear patient population, demonstrate that a drug is safe or with non-severe side effects on that population, demonstrate that it reliably performs better than placebo.

The more variables the trial adds, reduces the clarity on patient population. That puts the likelihood of this product (and the underlying work / knowledge) of ever reaching the final production state.

 

[Champ]

I appreciate the comment, however I am but a simple liquid hydrocarbon.

The requirements to get a drug to product are simple: Identify a clear patient population, demonstrate that a drug is safe or with non-severe side effects on that population, demonstrate that it reliably performs better than placebo.

The more variables the trial adds, reduces the clarity on patient population. That puts the likelihood of this product (and the underlying work / knowledge) of ever reaching the final production state.

Great points that everyone needs to understand. They're testing a drug to restore hearing. They don't want to have anyone with any conditions that could affect their maximum perception of improvement. It's why they exclude Meneire's and others. They want to show as large gains in hearing threshold in the trial as they can for information and marketing purposes and unfortunately for a lot that want to participate in the trial, that will be easier in people with only hearing loss and no other conditions.

It should still help tinnitus if hearing is regenerated as a result of it. There are 2 parts to this - regenerating the physical parts of the cochlea, and having the brain rewire itself to reconnect the signal processing back to those frequencies to bring the feedback loop to homeostasis and thus quiet the noise. I think most of us would be happy with any improvements we can get.

 

[Joeseph Stope]

Great points that everyone needs to understand. They're testing a drug to restore hearing. They don't want to have anyone with any conditions that could affect their maximum perception of improvement. It's why they exclude Meneire's and others. They want to show as large gains in hearing threshold in the trial as they can for information and marketing purposes and unfortunately for a lot that want to participate in the trial, that will be easier in people with only hearing loss and no other conditions.

It should still help tinnitus if hearing is regenerated as a result of it. There are 2 parts to this - regenerating the physical parts of the cochlea, and having the brain rewire itself to reconnect the signal processing back to those frequencies to bring the feedback loop to homeostasis and thus quiet the noise. I think most of us would be happy with any improvements we can get.

Forgive me for nit-picking your informative post -- which seems to have gained some resonance among readers here by the way -- but I'm apprehensive about the order in which these are carried out.

IMHO in my humble opinion, it would make sense to repair/reconstruct the cochlea first. Once that's running smoothly then would be the time to start re-wiring the brain.

Rewiring the brain on a faulty cochlea... and then fixing the cochlea??

Assembled multitude clamors: "Show us the data!"

We know so little sadly.

But this question might become more pressing in the months... or years ahead.

Should we be waiting for the regenerative medicine men to repair the synapses and hair cells before we sign up for Susan Shore's device or the other way around?

Boy, is life so technical.