Otonomy OTO-413 — Treatment of Hidden Hearing Loss

[tequilaman69]

Some news from Otonomy regarding Otividex enrollment. Obviously not specifically OTO-413 related, but thought I'd share.

https://investors.otonomy.com/news-...es-patient-enrollment-phase-3-trial-otividexr

 

[Frédéric]

Just a note on the partnership with Kyoto's for OTO-6XX. There was actually an announcement about this in August. As a result of this announcement, I can reasonably assume that there is going to be something further happening with this treatment in the near future as it is incredibly unlikely that an official announcement like this would have been made otherwise.

Otonomy Announces Exclusive License Agreement with Kyorin for Novel Compound in OTO-6XX Hearing Loss Program

I don't think this has been recalled, but Kyorin was already involved in hearing loss treatment:

KRP-209 (Neramexane) By Kyorin

Edit 1: a specific OTO-6XX thread needs to be created if we want to continue on this subject (in order to avoid confusion).

Edit 2: history shows that we must keep evidence (screenshots) because companies' pipelines sometimes change drastically.

 

[patorjk]

I don't think this has been recalled, but Kyorin was already involved in hearing loss treatment:

KRP-209 (Neramexane) By Kyorin

Edit 1: a specific OTO-6XX thread needs to be created if we want to continue on this subject (in order to avoid confusion).

Edit 2: history shows that we must keep evidence (screenshots) because companies' pipelines sometimes change drastically.

I'll make one. I do think there'll be some overlap, but I think you're right that their needs to be a separate thread, as OTO-6XX will probably take over the discussion once we know more about it.

Otonomy OTO-6XX — Hair Cell Regeneration

 

[tommyd87]

Not relevant to OTO-413 per say, but it seems Otonomy has now completed enrollment for Meniere's disease OTIVIDEX/OTO-104 phase 3 trial. This tends to look quite promising from not only the perspective of probably providing relief to people with Meniere's but it is also actually going to mean that they can proceed to the other trials too.

Otonomy Completes Patient Enrollment for Phase 3 Trial of OTIVIDEX® in Ménière's Disease

 

[Lucifer]

Any idea when OTO-413 Phase 1/2 clinical trial results come out?

 

[FGG]

Any idea when OTO-413 Phase 1/2 clinical trial results come out?

4th quarter this year originally and, as far as I know, that's still the case.

 

[Lucifer]

4th quarter this year originally and, as far as I know, that's still the case.

I hope the results are positive and they don't delay.

 

[Paulmanlike]

4th quarter this year originally and, as far as I know, that's still the case.

How many patients were in the trial? Phase 1/2, so that's safety and efficacy?! I wonder if OTO-313 for tinnitus will become obsolete. I see OTO-313 had okay results, however I was hugely concerned with a member who had permanent worsening of tinnitus (@ChrisBoyMonkey). Looking at those results, those with worsening all received the placebo. It didn't give me too much confidence that a placebo would do that from a company specializing in ear disorders! Anybody else notice that?

 

[FGG]

How many patients were in the trial? Phase 1/2, so that's safety and efficacy?! I wonder if OTO-313 for tinnitus will become obsolete. I see OTO-313 had okay results, however I was hugely concerned with a member who had permanent worsening of tinnitus (@ChrisBoyMonkey). Looking at those results, those with worsening all received the placebo. It didn't give me too much confidence that a placebo would do that from a company specializing in ear disorders! Anybody else notice that?

About 40:

https://www.clinicaltrials.gov/ct2/show/NCT04129775

And yes, it's phase 1/2 and they will be looking at both.

And yes, that's super weird about placebo and adverse events but I'm not sure all the adverse events were tinnitus worsenings. Some could have been "dizziness," "migraine" etc. I would love to find the breakdown of what these events were.

 

[Lucifer]

About 40:

https://www.clinicaltrials.gov/ct2/show/NCT04129775

And yes, it's phase 1/2 and they will be looking at both.

And yes, that's super weird about placebo and adverse events but I'm not sure all the adverse events were tinnitus worsenings. Some could have been "dizziness," "migraine" etc. I would love to find the breakdown of what these events were.

Would there be a possibility that they will have one more phase after this before they can release OTO-413?

 

[tommyd87]

How many patients were in the trial? Phase 1/2, so that's safety and efficacy?! I wonder if OTO-313 for tinnitus will become obsolete. I see OTO-313 had okay results ,however I was hugely concerned with a member who had permanent worsening of tinnitus (@ChrisBoyMonkey). Looking at those results, those with worsening all received the placebo. It didn't give me too much confidence that a placebo would do that from a company specializing in ear disorders! Anybody else notice that?

Based off of below, I think that Otonomy is wanting to utilise the big dose in future trials and also in practice. I get this feeling from the fact that they have made this group the big participant group.

OTO-413 Phase 1/2 clinical trial in hearing loss: patient enrollment is ongoing with results expected in the fourth quarter of 2020. This is an ascending single dose safety and exploratory efficacy study for OTO-413, a sustained exposure formulation of brain-derived neurotrophic factor (BDNF). We have successfully escalated through three dose levels totaling 24 patients and recently initiated enrollment for the high dose cohort. We expect to enroll approximately 16 patients in this cohort, randomized 3:1 for a single intratympanic injection of OTO-413 or placebo. Patients enrolled in this trial have a speech-in-noise hearing deficit measured at baseline and can have normal up to moderately-severe hearing loss by conventional testing. Following treatment, patients undergo repeated testing for safety and exploratory efficacy over 3 months. We expect to announce results from this trial in the fourth quarter of 2020.

The issue with the placebo may actually have been basically unknown to Otonomy. I am well aware of people who have gotten tinnitus through things such as saline solution and water in their ear. Essentially this tells me that this was potentially just a very isolated case of a negative reaction to whatever was being used as the placebo.

I'm interested in whether OTO-413 would make OTO-313 obsolete as well. I have looked at what OTO-413 is doing and at this stage if it is functional in the same manner as the Hough Ear Institute Pill is which is to regrow nerve ends/synapses and apparently also eliminate tinnitus then there is a very good chance that OTO-413 might end up with the same result as the Hough Ear Institute Pill then. The only way which OTO-413 wouldn't end up with the same results as the Hough Pill is if the compounds used in the Hough Ear Institute Pill have some sort of unique effect in treating tinnitus, though I don't think that this is likely.

I believe that there could be positive tinnitus outcomes with OTO-413 because from what we have come to know, you can have nerve end/synapse damage and tinnitus while having no hearing loss. Thus this can indicate that the nerve ends and/or synapses getting busted is what causes tinnitus. Therefore if the nerve ends/synapses got treated then this theoretically would resolve the tinnitus.

Therefore I also would not have been at all surprised if Otonomy had deferred their phase 2 OTO-313 trial to see what the OTO-413 outcomes are first. This would make total sense because there's totally no point in continuing with investing in a medicine which works but doesn't work as well as a medicine making improvements to the underlying issue. Thus I think that it is likely that OTO-313 may be obsolete unless it helps in some manner with the other types of tinnitus that wouldn't be fixed through nerve end/synapse regrowth such as jaw induced tinnitus.

 

[tommyd87]

About 40:

https://www.clinicaltrials.gov/ct2/show/NCT04129775

And yes, it's phase 1/2 and they will be looking at both.

And yes, that's super weird about placebo and adverse events but I'm not sure all the adverse events were tinnitus worsenings. Some could have been "dizziness," "migraine" etc. I would love to find the breakdown of what these events were.

I haven't heard how anyone got any worse effects from the actual treatment, I have only heard about the negative placebo case. Have there been some who got OTO-313 and had bad side effects from the actual treatment, not just placebo?

Would there be a possibility that they will have one more phase after this before they can release OTO-413?

I know that Otonomy are very keen in getting their treatments out to people ASAP, although they also do this in a manner which is inevitably going to yield the most appropriate and the best results. The best example of this is what they have done with Otividex by making sure that this treatment passes the trials in a meaningful way.

What I think is more likely is that due to the far shorter time required for treatment with OTO-413 than compared to hair cell treatments, they will likely run a phase 2 or phase 2a trial next followed by a phase 3 trial. I say this because if the first trial hypothetically results in OTO-413 being identified as working best with the big dose then they would be logical to next try to confirm this size dose works with a bigger cohort across the different hearing loss groups. Then they can confirm the overall suitability of the treatment sufficiently to the regulators before release. If OTO-413 was to get released after the second phase then I could only see this being done under compassionate use access, however if Otonomy can rip through the trials quickly they could consequently be done around the same time or just after the current FX-322 trial is done which isn't too far away.

 

[Mentos]

How many patients were in the trial? Phase 1/2, so that's safety and efficacy?! I wonder if OTO-313 for tinnitus will become obsolete. I see OTO-313 had okay results, however I was hugely concerned with a member who had permanent worsening of tinnitus (@ChrisBoyMonkey). Looking at those results, those with worsening all received the placebo. It didn't give me too much confidence that a placebo would do that from a company specializing in ear disorders! Anybody else notice that?

They don't even test OTO-413 with an indication for tinnitus, only for speech in noise improvement. Hence they will not even know if it works for tinnitus once the drug hits the market, unless they intend to include tinnitus in their measures in the subsequent testing phases.

 

[tommyd87]

They don't even test OTO-413 with an indication for tinnitus, only for speech in noise improvement. Hence they will not even know if it works for tinnitus once the drug hits the market, unless they intend to include tinnitus in their measures in the subsequent testing phases.

I think if people are going to post anecdotal reports that the use of OTO-413 has led to improving their tinnitus then Otonomy will probably put this as a secondary measure in their later trials.

 

[Paulmanlike]

You'd think if they are claiming to repair synapses and, hearing loss being the cause of tinnitus, they'd have tinnitus as an outcome measure.

 

[tommyd87]

You'd think if they are claiming to repair synapses and, hearing loss being the cause of tinnitus, they'd have tinnitus as an outcome measure.

The theory that I have with Otonomy is that they are actually focused on three things in the first OTO-413 clinical trial. They are focused on demonstrating the treatment is safe. They want to see which dosing actually works best, essentially hoping that the big dose gets approved and can be used. They want to show that OTO-413 actually is going to regrow synapses.

Subsequently if Otonomy is successful in achieving these three outcomes out of the initial OTO-413 trial then the thought would be that they would then get given anecdotal accounts about the other benefits that people got from it such as tinnitus lowering. As a result really it would be quite likely that Otonomy would then add these measures in as secondary measures into their phase 2 trial (or whatever it is called) and test these benefit.

Frequency Therapeutics did not make the tinnitus claims with FX-322 in its initial trials, nor did they test for tinnitus either, simply because tinnitus treatment was not the main purpose of the treatment. I am also pretty sure that there was no guarantee that tinnitus would be improved or would get treated by FX-322 either at that stage. Therefore looking at the benefits of tinnitus only became relevant when there were anecdotal accounts made about FX-322's positive outcomes on tinnitus.

I therefore think that Otonomy will do what we saw Frequency Therapeutics do in their current trials by simply adding secondary measures in their second trial if they get positive accounts of other benefits. This is because Otonomy can consequently keep the trial on track by sticking to the requirements of the inaugural trial being safety and speech in noise and gaining the necessary outcomes to proceed with the trials further.

I also believe that adding these additional measures into the second trial will assist in proving the benefits of the OTO-413 if Otonomy wishes to release it early should they be granted Fast Track status and/or Compassionate Use allowance too. While obviously the main requirement would be for Otonomy to demonstrate that OTO-413 works well with restoring synapses since this is its primary function, I am quite positive that the FDA would take into account any other benefits which it may provide when determining whether to allow its early release.

Thus I wouldn't be surprised if Otonomy went with a much more widely focused phase 2 trial that tested more benefits and also as a result released OTO-413 after this phase if the outcomes allowed them to do so.

 

[patorjk]

Out of curiosity, what are everyone's expectations of this drug? And do you think there will be positive results in a few weeks, or that it will flop?

I have combed my Facebook hearing loss/tinnitus groups, Twitter, and the broader internet, and I can find almost nothing on OTO-413. It seems like no one is talking about it, and based on Facebook, no one is even aware of it.*

The pig studies I dug up a few weeks ago really piqued my interest. I dug a little bit deeper into another link [1] someone shared here and found this bit of info kind of compelling:

In our previous studies, BDNF was administered to the round window membrane by intra-tympanic injection of a thermosensitive sustained-exposure formulation, in a rat model of noise-induced hearing loss and found to provide significant structural and functional amelioration of cochlear synaptopathy

So it looks like there's promise here, though what the will translate to seems to be unknown.

*This opposed to FX-322, where I can find quite a bit of discussion.

[1] https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224022

 

[tommyd87]

Out of curiosity, what are everyone's expectations of this drug? And do you think there will be positive results in a few weeks, or that it will flop?

I have combed my Facebook hearing loss/tinnitus groups, Twitter, and the broader internet, and I can find almost nothing on OTO-413. It seems like no one is talking about it, and based on Facebook, no one is even aware of it.*

The pig studies I dug up a few weeks ago really piqued my interest. I dug a little bit deeper into another link [1] someone shared here and found this bit of info kind of compelling:

So it looks like there's promise here, though what the will translate to seems to be unknown.

*This opposed to FX-322, where I can find quite a bit of discussion.

[1] https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224022

I think that the discussion around Otonomy's synapse medicine has been somewhat quiet because I think that there isn't as much known about it by many.

My feeling is that a lot of people simply don't know what its benefit might be or how it will help them. Then there is also the fact that Otonomy have been quietly working away in the background.

 

[Diesel]

I think that the discussion around Otonomy's synapse medicine has been somewhat quiet because I think that there isn't as much known about it by many.

My feeling is that a lot of people simply don't know what its benefit might be or how it will help them. Then there is also the fact that Otonomy have been quietly working away in the background.

I think educating the general populace on what OTO-413 is exactly doing to recover hearing isn't as easy to do and immediately obvious. Otonomy isn't nearly as invested in marketing and comms as Frequency Therapeutics is about FX-322.

 

[weab00]

Otonomy isn't nearly as invested in marketing and comms as Frequency Therapeutics is about FX-322.

Why?

 

[tommyd87]

I think educating the general populace on what OTO-413 is exactly doing to recover hearing isn't as easy to do and immediately obvious. Otonomy isn't nearly as invested in marketing and comms as Frequency Therapeutics is about FX-322.

I agree with both points. I'm pretty sure that Otonomy is happy springing away in the background and actually not going out to sprout what they are doing. I don't know if this is because they see it as pointless or whether they want to go about hiding their work until they get good outcomes from the trials.

I also agree with educating people about OTO-413. I think that there are lots of people who have no clue on synapses. Also speech in noise doesn't get dealt with too much in testing. Therefore the theory I have is if it turns out that Otonomy gets good results in the trial for OTO-413 I think that not only will they start sprouting this but they will also articulate what OTO-413 does when you get treated with it. It is therefore very likely that they will also partner with a testing company or group who will work with the speech in noise testing to identify if OTO-413 can provide a benefit so they can set up a mutual system of referral.

I think Otonomy will certainly become more prominent to potential patients of their products but basically this won't get done till they actually have got something solid sorted first.

 

[Markku]

I think educating the general populace on what OTO-413 is exactly doing to recover hearing isn't as easy to do and immediately obvious. Otonomy isn't nearly as invested in marketing and comms as Frequency Therapeutics is about FX-322.

Why?

We've had good experiences with Otonomy. Back in 2017 I and Steve had a fruitful conference call with their team.

I've now (literally 5 minutes ago) invited them to the Tinnitus Talk Podcast. I'll keep you posted on any developments. It might take place not in the immediate future, depending on their wishes, but we'll see.

 

[tommyd87]

We've had good experiences with Otonomy. Back in 2017 I and Steve had a fruitful conference call with their team.

I've now (literally 5 minutes ago) invited them to the Tinnitus Talk Podcast. I'll keep you posted on any developments. It might take place not in the immediate future, depending on their wishes, but we'll see.

Hopefully they are not only successful but also come on board with wanting to do a podcast. Maybe they are too busy to do anything other than product work with all they got going on lol.

 

[Michael01]

I've now (literally 5 minutes ago) invited them to the Tinnitus Talk Podcast. I'll keep you posted on any developments. It might take place not in the immediate future, depending on their wishes, but we'll see.

I'm hopeful they accept your invite. I'd really like to hear from Otonomy on any insights or progress they feel like sharing on OTO-413 and its potential to fix tinnitus.

 

[Diesel]

So... we're in Q4 now... when do you all think we'll see the trial for this drug actually end? The more I learn about this drug, the more I'm interested in the outcomes from the Phase 1/2.

 

[tommyd87]

So... we're in Q4 now... when do you all think we'll see the trial for this drug actually end? The more I learn about this drug, the more I'm interested in the outcomes from the Phase 1/2.

Apparently according to the ClinicalTrials.gov information it is supposed to be done this month (October), however I remember seeing something suggesting that there has been a bit of a delay due to various factors such as COVID-19. Hence the information might get updated accordingly.

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

This treatment I believe will help relieve tinnitus, although the question will be how well since it is quite clear that this will be a complementary treatment to FX-322 or OTO-6XX. Therefore there tends to be the likelihood that there will be very varied and mixed results with this treatment at least until we get both treatments working because it is incredibly possible that some people will get a very good response from a synapse treatment due to having limited hair cell loss and vice versa.

 

[weab00]

Apparently according to the ClinicalTrials.gov information it is supposed to be done this month (October), however I remember seeing something suggesting that there has been a bit of a delay due to various factors such as COVID-19. Hence the information might get updated accordingly.

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

This treatment I believe will help relieve tinnitus, although the question will be how well since it is quite clear that this will be a complementary treatment to FX-322 or OTO-6XX. Therefore there tends to be the likelihood that there will be very varied and mixed results with this treatment at least until we get both treatments working because it is incredibly possible that some people will get a very good response from a synapse treatment due to having limited hair cell loss and vice versa.

Wish there was a way to tell which one you needed. For now it'll be trial and error.

 

[frpp]

5 years forward and most of us will be back to normal, reading books, playing music, sitting in silence, and living our best lives. LET'S DO ITTTTTT!!!!!

 

[weab00]

5 years forward and most of us will be back to normal, reading books, playing music, sitting in silence, and living our best lives. LET'S DO ITTTTTT!!!!!

It makes me excited even reading this. I fantasize about this shit every day. I will be playing music and drinking and laughing for sure once I get rid of this noxacusis shit.

 

[Piney]

I can't find one trial to enter for the severely deaf crowd with tinnitus. The criteria is too narrow, either within 6 months of onset or not within decibel range, etc.

Maybe the trials will move faster if they open up the criteria next phase.