Otonomy OTO-413 — Treatment of Hidden Hearing Loss

[FGG]

Otonomy may have put themselves in a cannibalization scenario with OTO-313 for tinnitus. If it turns out OTO-413 treats tinnitus as a symptom of synaptopathy; it reduces the need for a OTO-313 which might be a problem.

One might hypothesize that if FX-322 does indeed produce a significant reduction in TFI by creating new hair cells and thereby improving hearing; it's pretty likely that reconnecting synapses and improving hearing may also have a noticeable affect in tinnitus.

Just one theory.

From their press release:

"We believe that gacyclidine can reduce the severity of tinnitus symptoms following cochlear injury by decreasing the over-activation of damaged auditory nerve fibers in the cochlea and their connections."​

With that in mind, yes OTO-413 would treat AN underlying cause of what they are trying to address with OTO-313. But they didn't select for synaptopathy in their trial so clearly they don't believe it would only work for cases where synaptopathy is the cause of the over-excitation.

Here was their inclusion criteria:

• Subject's tinnitus is likely of cochlear origin, e.g., associated with sensorineural hearing loss; acute hearing loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma); age-related hearing loss; resolved otitis media; ototoxic drug exposure.

 

[Lucifer]

Do we know when Otonomy will start Phase 2a clinical trials for OTO-413?

 

[Philip83]

Otonomy may have put themselves in a cannibalization scenario with OTO-313 for tinnitus. If it turns out OTO-413 treats tinnitus as a symptom of synaptopathy; it reduces the need for a OTO-313 which might be a problem.

Maybe they could get both approved and then bring them to market as a cocktail injection?

 

[frpp]

Nice problem to have.

My thoughts exactly, that's one too many tinnitus solutions, better shut it all down.

Someone better call Frequency Therapeutics to and let them know.

 

[tommyd87]

Do we know when Otonomy will start Phase 2a clinical trials for OTO-413?

It hasn't been stated yet as obviously there is a whole lot of procedural stuff that they need to do first for the subsequent trial such as lodging stuff with the FDA.

From what we have seen from Otonomy, it would be fairly soon since they have indicated that they are keen to progress quickly.

Also an actual good example of Otonomy's keenness to progress is their actions with the OTO-313 trial. They were very keen to proceed with the Phase 2 trial instantly, they just needed to wait until they attained FDA approval to do so before getting it done.

I definitely do think that they'll try to proceed with the Phase 2 trial next year.

 

[Aaron91]

Otonomy may have put themselves in a cannibalization scenario with OTO-313 for tinnitus. If it turns out OTO-413 treats tinnitus as a symptom of synaptopathy; it reduces the need for a OTO-313 which might be a problem.

One might hypothesize that if FX-322 does indeed produce a significant reduction in TFI by creating new hair cells and thereby improving hearing; it's pretty likely that reconnecting synapses and improving hearing may also have a noticeable affect in tinnitus.

Just one theory.

Even if they have put themselves in a cannibalization scenario I don't think they would lose much sleep over it. I would only see this being a problem if OTO-313 had already hit the market as a tinnitus treatment. As we all already know, biotech is notoriously volatile, so I would hazard a guess that the main reason why Otonomy have so many different drugs in the pipeline is more a case of them hedging their bets than attempting to maximise profits (a happy bonus) as they can't guarantee success for any of these drugs in clinical trials.

Early OTO-313 results look average at best and didn't one of their Meniere's drugs initially flop before going to re-trial?

 

[Philip83]

The report says "activity also observed for other exploratory endpoints and doses".

I wonder what those other endpoints were...?

 

[tommyd87]

Even if they have put themselves in a cannibalization scenario I don't think they would lose much sleep over it. I would only see this being a problem if OTO-313 had already hit the market as a tinnitus treatment. As we all already know, biotech is notoriously volatile, so I would hazard a guess that the main reason why Otonomy have so many different drugs in the pipeline is more a case of them hedging their bets than attempting to maximise profits (a happy bonus) as they can't guarantee success for any of these drugs in clinical trials.

Early OTO-313 results look average at best and didn't one of their Meniere's drugs initially flop before going to re-trial?

OTO-313 had mixed results, however this was in the safety trial and the outcomes overall were favourable. Thus why Otonomy is looking at expanding the scope of the participation and also looking at utilising a bigger volume for the dose too.

Didn't part of the problem with the OTO-104 trial come from the trial though and the doctors pushing patients into the trials, and not necessarily from the medicine itself? I know @FGG is versed on this.

 

[FGG]

Even if they have put themselves in a cannibalization scenario I don't think they would lose much sleep over it. I would only see this being a problem if OTO-313 had already hit the market as a tinnitus treatment. As we all already know, biotech is notoriously volatile, so I would hazard a guess that the main reason why Otonomy have so many different drugs in the pipeline is more a case of them hedging their bets than attempting to maximise profits (a happy bonus) as they can't guarantee success for any of these drugs in clinical trials.

Early OTO-313 results look average at best and didn't one of their Meniere's drugs initially flop before going to re-trial?

Their Meniere's drug didn't at all flop. It's kind of a unique situation.

It was effective in earlier trials and ENTs were shoving their refractory vertigo patients into the nearest trial centers with so much enthusiasm that it actual increased the placebo responses as well. After the "post mortem" on this and after interviewing participants when they figured out what happened, the FDA let them restart with much more careful recruiting.

Meniere's vestibular attacks definitely can related to stress levels and placebo effects are a much bigger factor, than say in testing hearing.

 

[Aaron91]

Their Meniere's drug didn't at all flop. It's kind of a unique situation.

It was effective in earlier trials and ENTs were shoving their refractory vertigo patients into the nearest trial centers with so much enthusiasm that it actual increased the placebo responses as well. After the "post mortem" on this and after interviewing participants when they figured out what happened, the FDA let them restart with much more careful recruiting.

Meniere's vestibular attacks definitely can related to stress levels and placebo effects are a much bigger factor, than say in testing hearing.

Yes, you're right, and on reflection I realise I chose my words poorly.

What I meant by flop wasn't that the drug itself flopped but that the process of it being approved (an inherent risk in biotech) flopped. My wider point from my initial comment was that they're trying to treat all sorts of conditions related to the ears with no guarantee that any of their drugs will ever hit the market - for whatever reasons may arise during clinical trials/approval process. Indeed the Meniere's one was a very unique situation and I'm sure it's a big relief for those sufferers that this treatment should eventually be available to them.

 

[paul mclean]

Right now I'd like them to hurry the F up and confirm that tinnitus is impacted by these drugs.

I know there was some anecdotal evidence on the FX-322, but right now I think we are all assuming, not without reason, that restoring lost hearing will make the tinnitus decrease or go away. A not insignificant part of me is afraid that while these drugs may restore hearing they may not be particularly effective in making my brain stop screeching.

My tinnitus is definitely hearing loss related. I fell asleep with headphones on loud for 13 hours and woke up with tinnitus and cochlear synaptopathy. I'm more excited for hearing restoration as not understanding speech in noise bugs me much more than my tinnitus does.

That being said if it stops or at least alleviates the tinnitus to some extent, I'll be happy.

Either way I'm beyond excited for these drugs to be available!

 

[Mentos]

My tinnitus is definitely hearing loss related. I fell asleep with headphones on loud for 13 hours and woke up with tinnitus and cochlear synaptopathy. I'm more excited for hearing restoration as not understanding speech in noise bugs me much more than my tinnitus does.

That being said if it stops or at least alleviates the tinnitus to some extent, I'll be happy.

Either way I'm beyond excited for these drugs to be available!

Your case is proof one should be able to sleep easily even with severe tinnitus. You had earphones blasting music on loud for 13 hours before you woke up, unbelievable.

 

[NewLionel]

Your case is proof one should be able to sleep easily even with severe tinnitus. You had earphones blasting music on loud for 13 hours before you woke up, unbelievable.

I think this happened to the guy from My Bloody Valentine.

 

[Kam75]

Why is there suddenly hype around OTO-413?

Is it because they announced that they are going to start Phase II?

 

[Philip83]

Why is there suddenly hype around OTO-413?

Is it because they announced that they are going to start Phase II?

Results for Phase 1 are out and they are looking promising.

 

[weab00]

Your case is proof one should be able to sleep easily even with severe tinnitus. You had earphones blasting music on loud for 13 hours before you woke up, unbelievable.

Eh not really. There's a difference between playing loud music and having a shrill unescapable 17 kHz tone piercing through your skull.

 

[LAnative]

I want to put this out there in case any researcher is reading these posts, as well as for my tinnitus and hyperacusis comrades. This is my personal theory:

I shot a gun and went deaf for 10 seconds. Totally normal hearing and ear function for a week. One week after the shot, I woke up with a fullness feeling (likely my body's inflammation clearing away the dead hearing cells). At this point I got a hearing test showing a approximately 10 dB dip in my higher frequencies. I found myself turning up the treble in the car radio to balance the sounds. I did not have tinnitus or hyperacusis at this time. Zero tinnitus and hyperacusis.

One week after that (2 weeks after the gunshot) I felt weird all day. By the end of the day I had tinnitus and hyperacusis both at once (the fullness remained as well). Crumpling paper and children laughing brought me pain, and I couldn't sleep because of the ringing. I went to an ENT and they tested my hearing. I got a perfect score. The ENT said he could calibrate his audiometry test machine with my hearing.

My theory: I lost hearing cells (unsure if hair cells or synapses). My brain sensed the imbalance, and rebalanced my hearing by increasing the sensitivity of the high frequency areas. My brain "turned up the volume" on whatever hair cells I had left in my damaged areas, likely turning up the dead hair cells too. I believe that it's the "turning up" of the dead/damaged hair cells that causes the noise feedback (tinnitus) and pain/sensitivity (hyperacusis).

The brain rebalances. Remember the story of the guy who wore upside down glasses for a week, and his brain reversed the image and caused him to see normally? Then when he took the glasses off and was seeing upside down due to the brain's adjustment.

That being said, I truly believe that if a hearing loss reversal drug works to regrow the hair cells and synapses, the brain will rebalance the sensitivity again, causing an END to tinnitus and hyperacusis.

Have hope my friends. We are close.

 

[Diesel]

I want to put this out there in case any researcher is reading these posts, as well as for my tinnitus and hyperacusis comrades. This is my personal theory:

I shot a gun and went deaf for 10 seconds. Totally normal hearing and ear function for a week. One week after the shot, I woke up with a fullness feeling (likely my body's inflammation clearing away the dead hearing cells). At this point I got a hearing test showing a approximately 10 dB dip in my higher frequencies. I found myself turning up the treble in the car radio to balance the sounds. I did not have tinnitus or hyperacusis at this time. Zero tinnitus and hyperacusis.

One week after that (2 weeks after the gunshot) I felt weird all day. By the end of the day I had tinnitus and hyperacusis both at once (the fullness remained as well). Crumpling paper and children laughing brought me pain, and I couldn't sleep because of the ringing. I went to an ENT and they tested my hearing. I got a perfect score. The ENT said he could calibrate his audiometry test machine with my hearing.

My theory: I lost hearing cells (unsure if hair cells or synapses). My brain sensed the imbalance, and rebalanced my hearing by increasing the sensitivity of the high frequency areas. My brain "turned up the volume" on whatever hair cells I had left in my damaged areas, likely turning up the dead hair cells too. I believe that it's the "turning up" of the dead/damaged hair cells that causes the noise feedback (tinnitus) and pain/sensitivity (hyperacusis).

The brain rebalances. Remember the story of the guy who wore upside down glasses for a week, and his brain reversed the image and caused him to see normally? Then when he took the glasses off and was seeing upside down due to the brain's adjustment.

That being said, I truly believe that if a hearing loss reversal drug works to regrow the hair cells and synapses, the brain will rebalance the sensitivity again, causing an END to tinnitus and hyperacusis.

Have hope my friends. We are close.

Thank you for sharing this, and well said. My own experience was similar to yours.

I tend to agree with this theory. Restoring hearing signal to the brain with new cells that can provide the full range of signal at each location restored should reduce the sensation of whatever damage isn't recovered, if any.

I think the years of mis-directed research have led sufferers of tinnitus and hyperacusis from acquired SNHL to believe their symptoms are from a litany of partially correct reasons. Where, in reality, simply restoring the signal and giving the brain more high-quality information to work with should mitigate the symptoms of tinnitus and hyperacusis.

 

[ThomasC]

So Otonomy have now completed the first phase? I thought it was the second.

The results look good but it took 3 years to complete the first phase and there are two phases left.

 

[Lucifer]

So Otonomy have now completed the first phase? I thought it was the second.

The results look good but it took 3 years to complete the first phase and there are two phases left.

It may be quicker depending on how long they need to wait and review their patients.

With FX-322 clinical trial for Phase 2a they had to review patients up to 210 days which caused massive delays.

 

[Drachen]

Is there any hope of the TFI being used as a measure in this next trial? While it is true there is so far a lack of anecdotal evidence, they also excluded anyone with "bothersome" tinnitus. The TFI isn't exactly the most consistent or reliable measurement for determining efficacy of a product, but it's better than nothing, and nothing is what we have at the moment.

As I am somewhat new to reviewing clinical trials, I must ask: could this exclusion criteria also be revised or revoked?

 

[tommyd87]

Is there any hope of the TFI being used as a measure in this next trial? While it is true there is so far a lack of anecdotal evidence, they also excluded anyone with "bothersome" tinnitus. The TFI isn't exactly the most consistent or reliable measurement for determining efficacy of a product, but it's better than nothing, and nothing is what we have at the moment.

As I am somewhat new to reviewing clinical trials, I must ask: could this exclusion criteria also be revised or revoked?

I think that the same situation is in play here as with Frequency Therapeutics' outcome measures for FX-322. This is primarily a treatment for hearing loss and as a result tinnitus would be a secondary outcome measure if it is tested. Therefore there may actually end up being tinnitus added to the third trial if it is the case that the people running the trial and/or Otonomy receive anecdotal accounts about it benefiting tinnitus.

 

[Drachen]

Therefore there may actually end up being tinnitus added to the third trial if it is the case that the people running the trial and/or Otonomy receive anecdotal accounts about it benefiting tinnitus.

I hope so. In many ways, we are considering (or at the very least theorizing) this to be a solution for tinnitus caused by cochlear synaptopathy, and it would be really helpful for them to also study and proclaim that themselves.

 

[patorjk]

I've been anxiously following the OTIVIDEX trial, since Otonomy's future seems to depend on it. If OTIVIDEX fails, it's unclear to me what happens with OTO-413. I imagine they would sell it off to some other company, but that process would most likely delay its release by a year or two.

They last updated their clinical trial page for OTIVIDEX September 14th to state they were no longer recruiting:

https://clinicaltrials.gov/ct2/show/NCT03664674

The trial takes 3 months, which means it would have ended in mid-December. I would assume that would mean they not only have the data from it now, but they got it last month. Today they announced they were participating in a fireside chat at a conference in a week's time:

https://investors.otonomy.com/news-...icipate-hc-wainwright-bioconnect-2021-virtual

My thinking is that they wouldn't go forward with this if they got the data back and it was bad, so maybe this is a sign good news is on the way. Though on the other hand, I have no idea how long it takes to analyze this type of data, so maybe at this point they really don't have an indication of what the results are.

 

[Diesel]

I've been anxiously following the OTIVIDEX trial, since Otonomy's future seems to depend on it. If OTIVIDEX fails, it's unclear to me what happens with OTO-413. I imagine they would sell it off to some other company, but that process would most likely delay its release by a year or two.

They last updated their clinical trial page for OTIVIDEX September 14th to state they were no longer recruiting:

https://clinicaltrials.gov/ct2/show/NCT03664674

The trial takes 3 months, which means it would have ended in mid-December. I would assume that would mean they not only have the data from it now, but they got it last month. Today they announced they were participating in a fireside chat at a conference in a week's time:

https://investors.otonomy.com/news-...icipate-hc-wainwright-bioconnect-2021-virtual

My thinking is that they wouldn't go forward with this if they got the data back and it was bad, so maybe this is a sign good news is on the way. Though on the other hand, I have no idea how long it takes to analyze this type of data, so maybe at this point they really don't have an indication of what the results are.

They could also reiterate findings on OTO-413. I wouldn't count them out just because one drug fails to meet expectations. It's possible that they pivot and simply focus remaining resources/efforts on bringing OTO-313 and OTO-413 to market more quickly.

 

[twa]

I want to put this out there in case any researcher is reading these posts, as well as for my tinnitus and hyperacusis comrades. This is my personal theory:

I shot a gun and went deaf for 10 seconds. Totally normal hearing and ear function for a week. One week after the shot, I woke up with a fullness feeling (likely my body's inflammation clearing away the dead hearing cells). At this point I got a hearing test showing a approximately 10 dB dip in my higher frequencies. I found myself turning up the treble in the car radio to balance the sounds. I did not have tinnitus or hyperacusis at this time. Zero tinnitus and hyperacusis.

One week after that (2 weeks after the gunshot) I felt weird all day. By the end of the day I had tinnitus and hyperacusis both at once (the fullness remained as well). Crumpling paper and children laughing brought me pain, and I couldn't sleep because of the ringing. I went to an ENT and they tested my hearing. I got a perfect score. The ENT said he could calibrate his audiometry test machine with my hearing.

My theory: I lost hearing cells (unsure if hair cells or synapses). My brain sensed the imbalance, and rebalanced my hearing by increasing the sensitivity of the high frequency areas. My brain "turned up the volume" on whatever hair cells I had left in my damaged areas, likely turning up the dead hair cells too. I believe that it's the "turning up" of the dead/damaged hair cells that causes the noise feedback (tinnitus) and pain/sensitivity (hyperacusis).

The brain rebalances. Remember the story of the guy who wore upside down glasses for a week, and his brain reversed the image and caused him to see normally? Then when he took the glasses off and was seeing upside down due to the brain's adjustment.

That being said, I truly believe that if a hearing loss reversal drug works to regrow the hair cells and synapses, the brain will rebalance the sensitivity again, causing an END to tinnitus and hyperacusis.

Have hope my friends. We are close.

I pray you are right!

 

[patorjk]

They could also reiterate findings on OTO-413. I wouldn't count them out just because one drug fails to meet expectations. It's possible that they pivot and simply focus remaining resources/efforts on bringing OTO-313 and OTO-413 to market more quickly.

It's not just OTIVIDEX. OTIPRIO has been a disappointment for them too. It passed its Phase 3 study and made it to market, but it only generates around $600k in revenue for them a year. According to their financial guidance, they have enough money to fund the company for 2 years. That's not really enough time to get OTO-313 and OTO-413 out the door. The only way that would work is if they completed a successful Phase 2 study for one of those drugs (probably OTO-313) and then raised more capital. I suppose this path would be a possibility, but it would put some serious strain on the company.

 

[twa]

It's not just OTIVIDEX. OTIPRIO has been a disappointment for them too. It passed its Phase 3 study and made it to market, but it only generates around $600k in revenue for them a year. According to their financial guidance, they have enough money to fund the company for 2 years. That's not really enough time to get OTO-313 and OTO-413 out the door. The only way that would work is if they completed a successful Phase 2 study for one of those drugs (probably OTO-313) and then raised more capital. I suppose this path would be a possibility, but it would put some serious strain on the company.

Are these treatments for hidden hearing loss?

 

[patorjk]

Are these treatments for hidden hearing loss?

No, only OTO-413 is for hidden hearing loss. They have another drug in the works though - OTO-6XX - which is for "severe hearing loss". It's thought to be something similar to FX-322.

• OTIVIDEX is for Ménière's disease / vertigo. It's the drug the company is currently most known for.
• OTIPRIO is "for the treatment of acute otitis externa in patients 6 months of age and older due to Pseudomonas aeruginosa and Staphylococcus aureus". I have no idea what that means. It's narrowness is probably why it doesn't make them much money.

You can see all of the drugs in their pipeline here:
https://www.otonomy.com/pipeline/

 

[FGG]

No, only OTO-413 is for hidden hearing loss. They have another drug in the works though - OTO-6XX - which is for "severe hearing loss". It's thought to be something similar to FX-322.

• OTIVIDEX is for Ménière's disease / vertigo. It's the drug the company is currently most known for.
• OTIPRIO is "for the treatment of acute otitis externa in patients 6 months of age and older due to Pseudomonas aeruginosa and Staphylococcus aureus". I have no idea what that means. It's narrowness is probably why it doesn't make them much money.

You can see all of the drugs in their pipeline here:
https://www.otonomy.com/pipeline/

OTIPRIO is a topical fluoroquinolone antibiotic.

It's for two indications: outer ear infections that are resistant to other antibiotics (pseudomonas is known for this as a bacterial species and staph can always be resistant).

Or for middle ear infections with effusion through tympanostomy tube (it's likely needed because purulent effusions produce a environment/pH that makes other antibiotics less effective--humans tend not to have this problem in outer ear infections like dogs do but can get it in the middle ear).

Regardless, neither are common enough problems for this to be a blockbuster drug but it's always good to show investors you have already gone through the approval process.