Otonomy OTO-413 — Treatment of Hidden Hearing Loss

Discussion in 'Research News' started by Michael Larsen, Jan 9, 2018.

    1. Diesel

      Diesel Member Benefactor Ambassador Hall of Fame Advocate

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      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.
       
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    2. AfroSnowman
      Balanced

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      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.
       
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    3. Hazel
      Dreaming

      Hazel Director Staff Podcast Patron Benefactor Hall of Fame Advocate

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      Good news: We have now published our interview with Otonomy as the next episode of the Tinnitus Talk Podcast! We had already released a video version of the discussion for supporters of the podcast only, but now the audio version is freely available to all!

      Behind the scenes, this episode was particularly challenging to record, coordinating with two busy executives, changing locations due to COVID-19 restrictions, and an unusual number of technical challenges. We think the end result was worth the wait though and we hope you agree!

      We hope you will find the episode informative; let us know!

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      If you enjoy this episode and appreciate our efforts, please consider becoming a supporter of the podcast. As a token of our gratitude, we offer video versions of select interviews only to our supporters, as well as early access to new episodes and some other bonus content.

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      You can also support us by sharing this and our other episodes on your social media, so more people can find us and benefit from our work.

      Thank you all for your kindness. Our next episode will be with Prof. Dirk De Ridder - you can look forward to that in June!
       
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    4. Philip83
      Jaded

      Philip83 Member Podcast Patron Benefactor

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      So mid-2022 is our next chance to be disappointed :ROFL:

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

      OptimusPrimed Member Benefactor

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

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      Yes as long as they keep trying, we have to roll with the punches.
       
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    7. Philip83
      Jaded

      Philip83 Member Podcast Patron Benefactor

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    8. Street Novelist
      Depressed

      Street Novelist Member

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

      patorjk Member Benefactor

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      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:

      45318-3d3718d58cdca351fdff07e93bbdfbb0.png

      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.
       

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    10. Matchbox
      Wishful

      Matchbox Member

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      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.
       
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    11. Brian Newman

      Brian Newman Member

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    12. star-affinity
      Gloomy

      star-affinity Member Benefactor

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      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. :)
       
    13. Lukee

      Lukee Member Podcast Patron Benefactor Ambassador

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      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.
       
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    14. tommyd87

      tommyd87 Member

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      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).
       
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    15. patorjk

      patorjk Member Benefactor

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      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.
       
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    16. serendipity1996
      No Mood

      serendipity1996 Member Podcast Patron Hall of Fame

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      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.
       
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    17. Joeseph Stope
      Innocent

      Joeseph Stope Member

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      noise? infection? negative stress? other?
      Move over Frequency Therapeutics. Time to go Hough Ear Institute. OTO-413 is the new FX-322.

      :bag:
       
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    18. tommyd87

      tommyd87 Member

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      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?
       
    19. ThomasRobert

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    20. Abacab

      Abacab Member

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    21. Matchbox
      Wishful

      Matchbox Member

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      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.
       
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    22. Diesel

      Diesel Member Benefactor Ambassador Hall of Fame Advocate

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      “Bothersome subjective tinnitus” does not mean all tinnitus sufferers.
       
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    23. Street Novelist
      Depressed

      Street Novelist Member

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

      Matchbox Member

      Location:
      BC Canada
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      August 2020
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      Yeah... I know doesn't bode super well.
       
    25. Diesel

      Diesel Member Benefactor Ambassador Hall of Fame Advocate

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      How so? It’s a Phase 1/2. Why would they open to a ton of locations?
       
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    26. weab00
      Gloomy

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      I hope not.
       
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    27. RichieTheKid
      Question it

      RichieTheKid Member

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

      Diesel Member Benefactor Ambassador Hall of Fame Advocate

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      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
       
    29. Piney

      Piney Member

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      Why would they kick anyone out of the trial for having formal musical training?
       
    30. tommyd87

      tommyd87 Member

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      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.
       
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