Otonomy OTO-413 — Treatment of Hidden Hearing Loss

It would be better if they added measurements of tinnitus to an experimental arm in a future phase (like Frequency Therapeutics did) rather than have a whole separate trial which wouldn't get a treatment out quicker (and may even delay it).

The only reason to do a separate tinnitus trial would be to prove efficacy for insurance reasons, future marketing reasons (at release date) or if they were trying to get a corporate buy out of their drug and wanted to increase it's value.

If it works for tinnitus, it will be reported in places like this and used off label.

 

Good point. Well, hopefully it does well enough for a second arm and they include tinnitus patients as well.

 

Keyzilen: There is a difference between failing and being unable to prove efficacy. As there is currently no objective way to evaluate tinnitus distress, clinical trials rely on patient self-assessments (which are subjective to bias). Higher placebo response is also a factor (due to patients' foreknowledge of the trial they are entering). This can lead to a trial failing. Auris Medical believes that their drug works, but don't have the financial means to carry out another phase III trial and are therefore planning to execute a future trial via another entity that can supply the necessary funding (with the condition that the other party will get part of the future revenue stream should Keyzilen hit the market at some point).

 

Holy shit, I just found out one of the trial locations is right near me and I fit the criteria almost perfectly, I’m going to call them tomorrow and see what they say.

 

Did you end up calling them and have you received a reply yet?

Also are the results still being released in Q4/2020 or is this clinical trial also delayed?

 

Turns out you have to be 21 to be in the trial, so I didn’t end up calling. I’ll be 21 in December, so if god forbid they do delay, I’ll call then.

 

I think they've said they are still on track to release Phase 1/2 results in Q4/2020.

 

Oh wow I didn’t realise you had to be 21 to be in the trials. I thought most clinical trials would be 18 and up.

 

You are right, for most trials you need to be 18, but for Otonomy you have to be 21. For me it kind of feels like a win win in a way. If the trial ends before I am 21, we’ll finally get some data. If it doesn’t, well I can call them and see if they’ll take me. I’m pretty sure I fit the rest of the requirements.

 

Sick of the long waits for all this crap. I need it now. FDA can stick it.

 

So do I. I think that while the wait is unfortunate, it is going to be beneficial in the long term. I feel that there will be very positive results from these medications even though it is going to take time.

 

I just hope something comes out for hyperacusis. I can live with tinnitus, but painful ears and sound distortions aren’t possible to habituate to.

 

There seems to be a clear enthusiasm gap between OTO-413 and FX-322. That may be partly because OTO-413 hasn't proven itself, but even before FX-322's Phase I/II study, I had heard a lot about the company and the drug. Searching through the Facebook hearing-loss/tinnitus groups I'm in, I've found basically nothing on OTO-413. It doesn't seem to be on anyone's radar. And Otonomy has made some pretty interesting claims about OTO-413:

That's pretty compelling. Their internal OTO-313 studies seem to have been right, and I bet their internal studies on OTO-413 are right too. Though I should say that even though I'm optimistic, I don't believe in them enough to buy their stock. But I am hopeful that there's a nice surprise coming our way in a month or so when the Phase I/II results come in.

 

For me, I'm looking forward to reading these results but there isn't as much data to speculate back and forth about. However, if they are not delayed, results should be a few months away and there will be plenty to discuss then.

 

I have definitely seen stuff about Otonomy on other websites.

However, the discussion about OTO-413/Otonomy is usually pretty much limited to one of these three reasons:

- People asking about what OTO-413 does.

- How it is different from FX-322.

- Someone explaining why you might need a synapse medication instead of FX-322 or why you may need both a synapse and also a hair cell medicine together.

I absolutely agree with FGG's reasoning as to why there isn't much discussion about Otonomy and OTO-413 specifically.

 

Been lurking here for a while, as I've built a rather large position in Otonomy and always interested in learning more about the company along with public perception.

Earlier today there was a good Q & A at the Cantor Virtual Healthcare Conference, which is currently being archived for viewing:

https://investors.otonomy.com/events/event-details/cantor-virtual-global-healthcare-conference

Would love to hear views on this if you have some time to take a look.

Obviously anything can happen with their pipeline, but their Weber is definitely saying all the right things, and seems like things are going in the right direction, which has given me confidence to continue to build my position.

 

Very few of our esteemed hearing care professionals even recognize synaptopathy to begin with. FX-322 addresses the form of SNHL that everybody in that world knows about and agrees on.

With that being said I am pulling hard for both Otonomy and Frequency Therapeutics, the more players in regenerative medicine the better.

Pure BDNF seems like a wonderfully simple fix for broken synapses.

 

The OTO-413 stuff starts at 27:08. I think it sounds interesting. The fact that he says it restored hearing function in animals is very interesting. I think I'd like to know more about how they know that. I did some googling and found a study done on guinea pigs [1]. It found:

So if it works in humans, it's probably not going to be some miracle drug. This may also be why Otonomy is focusing on speech-in-noise for their trial. It'll help with people hearing aids hear better. Also, since tinnitus is part of the exclusion criteria, so we won't know if it helps for that (I feel like it could - though with their focus on speech-in-noise, it makes sense from their perspective).

Honestly, I kind of wish Otonomy and Frequency Therapeutics would team up. From what the Otonomy CEO said, it sounds like they have the drug delivery part down (with a hydrogel the CEO claims is much better than anyone else's). Add that with OTO-413 and FX-322, and we'd possibly have something really amazing.

[1] https://journalotohns.biomedcentral.com/articles/10.1186/s40463-020-00432-7

 

The big advantage to their drug delivery is extended release. It "doesn't escape down the eustachian tube" as he pointed out which would cause more of a variability in drugs like FX-322 where some people are just going to be better at being still and not swallowing.

And it also means instead of getting four injections, you could get one and more sustained levels of drug. I wonder if this is the way, if any, Frequency Therapeutics would reformulate: FX-322XR.

 

I can't recall exactly where I read it but Liberman once stated that repairing the synapses is one of the most 'straightforward' mechanisms to repair. I will try and find the article this was from.

 

I think we will obviously have to wait and see what comes out with it when the clinical trials are done, however if OTO-413 provides positive benefits for synapses alone then it is incredible and it is going to be a winner. If it provides any additional benefit than solely synapse restoration then it is a bonus and it will also make this OTO-413 even more marvellous.

My view is that OTO-413 will be a winner as long as it provides benefit. The synapse benefit will likely be a winner within its own right. The current crop of hearing aids are absolutely useless when it comes to maximum speech in noise benefit. Thus just as you have stated, the benefits for hearing aid users will be immense. This will be because the devices can predominately be used for amplifying speech and actually not need to be used to eliminate background noise which they are largely poor at doing overall.

Obviously the hearing aid companies and also some audiologists are not going to like the success of synaptic based medication much like OTO-413. The predominant reason for this is that the hearing aids that tend to come with the background noise programs are premium devices that are usually in the more expensive end of the range ($4000-$5000 approximately.) Thus even without hair cell repair medicine, this is ultimately going to mean that the device costs could get cut in half.

Having a look at what we can get at the moment, you can find that the $1500-$2000 entry level products (which are usually fit by audiologists on people in places like nursing homes) which usually don't have the program functions required for speech in noise might now end up being super suitable for a lot of people too. This is because the entry level hearing aids are quite likely to meet the requirements of many users.

Therefore having a successful outcome with OTO-413 for synapse recovery would mean that the hearing aid companies could see a significant, sudden and deep drop in profitability. This would be because the additional benefits provided in the more expensive and higher end options could not be needed by most users too.

The partnership possibility between Otonomy and Frequency Therapeutics is quite plausible and also would be an excellent, logical also smart business decision, should both companies have success with OTO-413 and FX-322, respectively. The reality however (at least in the short-term/next few years) is that Frequency Therapeutics and Otonomy might not want to partner with each other due to their own benefits with their own medication. This is because both companies may see themselves as having the ability of maximising financial benefit through their own operations.

The reasons I believe that Frequency Therapeutics and Otonomy might wish to remain independent are as follow:

1. Although it is unlikely, both Otonomy and Frequency Therapeutics may possibly be able to provide full restoration with their own treatments.

Frequency Therapeutics is doing their own clinical trials around speech in noise benefit during the current phase 2a trial (as a secondary measure), while Otonomy obviously saw that there was benefit with more than just synapse repair in their lab experiments. Thus I cannot see either company being willing to collaborate until they have both eliminated full repair capabilities from their treatments.

2. Otonomy and Frequency Therapeutics may believe that they can maximise financial benefit from their products by remaining independent. This is because both companies may feel that if they simply go it alone, they can remain responsible for their own affairs like price setting and also the direction of their organisation.

Obviously there are financial and also business benefits by merging, such as only needing one set of operations and one manufacturing arm etc.

My opinion is that both companies could remain completely independent from each other from a management/operation perspective, however what they could do is link up in clinics and suggest people take each other's medications. For example patients might come in because they need FX-322 and then also discover that they would benefit from a synapse treatment. Maybe these clinics could then offer Otonomy's treatment as the preferred and/or recommended choice for this.

I think that the end result however would have to be financially beneficial for both companies to consider merging.

3. From what I have seen on Otonomy's website, they were also working on a hair cell treatment.

This is the biggest reason I can't see Frequency Therapeutics and Otonomy merging. If both entities are planning to offer the same treatment types, I cannot see them wanting to merge when Otonomy might feel that they are going to have a superior hair cell repair medicine. As a result Otonomy and Frequency Therapeutics might be competing for the same market share as a result.

Having said that, if Frequency Therapeutics is successful with their hair cell treatment and Otonomy doesn't feel they can do better with their equivalent, I think it would completely change the way both Otonomy and Frequency Therapeutics view a possible merger.

I think that ultimately a merger would be beneficial for both companies and also potential consumers if both Otonomy's OTO-413 and Frequency Therapeutics FX-322 were hugely successful treatments in their own right. I strongly believe that this would allow both companies to streamline operations not only from a business perspective but also to provide streamlined treatment for patients.

 

Why is Frequency Therapeutics' hydrogel inferior to Otonomy's?

 

It’s also worth noting they performed an intracochlear injection in this study, not an intratympanic injection. The paper also states they’ll be looking at multiple injections. I think there’s no way around that, regardless of the drug, as long as intracochlear/intratympanic injections are being used. Ideally you would use either pump to get a consistent and controlled flow of the drug to the cochlea or nanoparticles loaded with a drug that release in the cochlea.

 

I think that there's been some progress made with the pump delivery for cochlea. I read somewhere that something came out relating to this earlier in the year. I have said this previously, I have a strong feeling that companies focusing on drug delivery solutions will have increased interest in this now that there is an actual reason to work on it.

 

Frequency Therapeutics' isn't an extended release. This may not be a huge disadvantage clinically other than the need for multiple dosing (and the risk of swallowing some of the drug during the post procedure time). Phase 2a should provide more info on repeat dosing obviously.

 

Very interesting and thoughtful replies, this forum is such a valuable resource.

Not hearing related, but Otonomy updated its trial on OTO-104 for Meniere's yesterday:

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

 

They said recently that they are submitting for approval Q1/2021 for their Meniere's drug and expect release later that year (they have manufacturing ready).

I think OTO-104 has off label use potentially too since an extended release long acting Dexamethasone could help anyone with steroid responsive inflammation potentially.

 

I found this:
https://www.researchgate.net/public...n_the_Treatment_of_Sensorineural_Hearing_Loss

It's a different BDNF guinea pig study, but this time they say how they tested the hearing in the pigs:

This site (https://www.asha.org/public/hearing/Auditory-Brainstem-Response/) describes how ABR works:

So it sounds like the way they tested hearing in guinea pigs is legit. Now we just have to see if it works for humans and if Otonomy's hydrogel really can get to the lower frequencies.

However, even if it can, we're still only looking at a ~10dB improvement, so not amazing, but certainly a good step forward. Also, it's unclear to me if this type of medication has any durability, that could also be a problem here.

 

I’d be willing to bet 10 dB of improvement would help substantially cut through tinnitus.

 

There are three things that interest me about the hearing side of OTO-413.

Firstly, a 10 dB increase in low frequency hearing would be a good gain for many people.

Secondly, I wonder whether repeat dosing would provide an additional dB gain benefit if Otonomy could get OTO-413 into the low frequency ranges too? This would be something I would be interested in seeing since this would possibly alleviate the issues that FX-322 could have with getting their treatment into the lower frequency area as well.

Thirdly, when you refer to lasting benefit, I am pretty sure that there was research information that indicated that repaired synapses were stable once treated. However finding out whether the same results are replicated in people is certainly a different story.

The other thing that I would note is that the claims made by Otonomy about the treatment benefits of OTO-413 are identical to the claims that other firms are making about their synaptic repair treatments. I am pretty sure that Hough Ear Institute has stated their pill will not only restore more than the normal numbers of synapses, but that there would also be a 10-15 dB hearing improvement. Therefore I believe that Otonomy's claim about OTO-413 being able to provide dB hearing improvement in conjunction with synaptic improvement is highly merited. Furthermore the fact that other possible providers of synaptic restoration treatments believe that the dB gain they provide is going to be stable gives me further reason to believe that OTO-413 would have the same outcomes also.

This means that the only unknown with Otonomy's OTO-413 is whether there is going to be a tinnitus benefit from this? The question is whether the synapse repair is enough to assist tinnitus or whether whatever the additional property Hough Ear Institute is going to put in their pill is what gives it the tinnitus relief capability. Time will tell.