Otonomy OTO-413 — Treatment of Hidden Hearing Loss

Its more about defining the specific patient population that the drug will show the most consistent/predictable improvements.

Once that patient population is clearly defined, or the population that should be excluded is defined; they effectively de-risk the chance of failing the Phase 2.

I think they understand that going to a Phase 2 where they are broadly accepting participants that may not show enough improvement could put releasing the drug at risk.

The goal of drug development in clinical trials is all about finding that specific population of patients and having them show significant improvements at at least 1 endpoint. When that is successful, the drug can be produced so everyone can get it.

 

I don't know, but I imagine that they hope they can do an Expansion Study ASAP, and then have a much better picture of how to best do a successful Phase 2 trial. I mean, their goal is to bring a product to market and make money, so I don't think they are doing anything intentionally to slow down the process.

 

So mid-2022 is our next chance to be disappointed

But seriously, great interview and great to hear people are hard at work in our favor!

 

Eventually someone is going to make a big breakthrough. That’s how science works, progressive failures which lead to discoveries and breakthroughs.

 

Yes as long as they keep trying, we have to roll with the punches.

 

Otonomy Initiates Expansion of Phase 1/2 Clinical Trial for OTO-413 in Hearing Loss

 

Any idea when and where Otonomy are planning to roll this next Phase out?

 

Very informative podcast! My only concern was how far away OTO-6XX seems to be, but I've recently started wondering if hair cells have been over hyped.

I wanted to share the below chart, which is found in Otonomy's latest slide deck:



I found this incredibly interesting. This is saying that most 80 year olds still have ~80% of their IHCs, but only around 40% of their synapses. Since FX-322 seems to target IHCs, this may be why that drug has been floundering in its latest studies. Additionally, this chart leaves me with the impression that hearing loss in old age is mostly due to synapse loss - however, this chart lacks OHCs, so maybe those play strong roll in hearing loss in old age?

I was curious if OTO-413 would regrow ANFs or just fix the synaptic connection, so I reached out to Otonomy for clarification and they responded:

In preclinical studies, BDNF has shown the ability to both regrow auditory nerve fibers and repair or re-establish their synapses with inner hair cells. As such, OTO-413 has the potential to restore auditory nerve fibers and their connections to inner hair cells in an 80 year old that has 40% remaining auditory nerve fibers to bring them back towards the normal level and improve hearing function.​

That sounds really exciting to me. I also reached out to them about information regarding the audiograms of the patients in phase 1/2, since pig studies showed an 11dB improvement. They responded:

Thanks for the question. We are still doing standard audiograms as part of the safety assessment. For preclinical studies, we used auditory brainstem response (ABR’s) because that’s the only way to measure hearing function in animals. Since the primary mechanism of action of OTO-413 (BDNF) is repair of the neuronal connection, this is best assessed by evaluating speech-in-noise tests. That is why we focused on these tests in reporting a therapeutic effect in our proof-of-concept trial and why we are focusing on these tests going forward. We will report the audiogram results from a safety perspective.​

I understand that audiograms are better for measuring OHCs and that they probably didn't see the needle move much here, but these systems all impact each other so part of me thinks we may see some improvement in this area. It'll be interesting to see what they report next summer.

 

I truly believe this is what actually causes the majority of issues. It isn't our resolution, it's our bandwidth that's screwed and, if overloaded, more nerves die similar to running 10 amps in a 20 gauge vs 10 gauge wire. Guess which one won't melt? Why would nerves and free radical formation from overfiring be any different?
More nerves to handle the Glutamate release close enough to react and mop it up... Better bandwidth and can handle the current instead of a few damaged survivors getting smashed over and over and over.

 

Yeah I think the synapse restoration would help me a lot.

 

Interesting, thanks for sharing!

So if my audiogram shows I have a hearing loss in some of the high frequencies, it's likely that it's mainly my OHCs are damaged and therefore OTO-413 probably won't be of much help in this case?

Would be nice to get rid of both the tinnitus and hearing loss in one go, but if only of them can be fixed it'll make me happy (happier...) too.

 

Brian, given all your symptoms, I think you may have a more “physical” issue. You should definitely investigate PLF and/or CSF leak.

That said, I think in general anyone with tinnitus should benefit from synapse restoration as @Matchbox mentioned above.

 

Probably the only way which you could conclusively tell whether it is your inner or outer hair cells which are stuffed would be to have a hearing test and then complete a word recognition test also at an appropriate volume. If you perform well on the word recognition test with the correct volume being given to you then it is likely you have an OHC issue. If you perform badly it is likely you have an inner hair cell issue (and potentially an OHC issue too).

 

I believe I read elsewhere on this forum that a hair cell can survive even if all its synapses die. So theoretically this could improve hearing by reconnecting OHCs that have lost all of their synapses. If 60% of our synapses are gone at age 80, I have to imagine that there are a lot of isolated hair cells.

We'll know more next summer though when the the study finishes. If there are audiogram improvements (even small ones) I'll be extremely excited. And actually, just thinking out loud, we may know more in the next month or two since Pipeline Therapeutics's PIPE-505 Phase 1/2 trial results are due. That drug is very similar, though it does some hair cell regeneration along with regenerating synapses, so it's not exactly the same.

 

The synapses that are involved in synaptopathy are the Type 1s which connect onto the inner hair cells. Nothing to do with the outer hair cells. In fact, it was recently shown that the number of Type 2 ribbon synapses actually *increases* in response to acoustic trauma, in contrast to Type 1s, where there is a loss/decrease.

 

Move over Frequency Therapeutics. Time to go Hough Ear Institute. OTO-413 is the new FX-322.

 

I could be wrong but aren't OTO-413 and the Hough Ear Institute pill ultimately ending up doing the same thing with their medicines by treating synapses and just utilising different methods to achieve the same outcomes?

 

Recruiting:

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

 

Tinnitus sufferers are excluded from recruitment, sadly.

 

Not really if it isn't "bothersome." I think that's just to keep desperate people from applying and faking the words-in-noise screening.

@roy1159 & @__nico__, if you guys have issues hearing in noise, this smells like a ticket.

I, unfortunately for this study's requirements, can hear perfectly well in noise. Just crazy tinnitus, so I doubt I'd get in.

 

“Bothersome subjective tinnitus” does not mean all tinnitus sufferers.

 

70 recruits? And only hitting Florida and Utah... my goodness.

 

Yeah... I know doesn't bode super well.

 

How so? It’s a Phase 1/2. Why would they open to a ton of locations?

 

I hope not.

 

How can non-US citizens participate in the OTO-413 trial? Is there any realistic chance I could get this drug?

 

Are you a resident in the US living near one of the trial sites? You would need to commit to the treatment appointment plus each follow-up visit. So, ideally you'd need to be reliably on US soil during that time + have reasonable residency + reliable transportation. That's a 90-plus day timeframe, so I'd have a hard time seeing "just travel and stay in the US for 90-plus days" due to passport restrictions in the US.

I'm no expert, so I'd suggest contacting one of the trial sites and asking.

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

 

Why would they kick anyone out of the trial for having formal musical training?

 

Probably because Otonomy is trying to avoid testing people who have had noise induced hearing loss from sources where they are likely to have acquired speech in noise issues.