Otonomy OTO-6XX — Hair Cell Regeneration

Discussion in 'Research News' started by patorjk, Oct 2, 2020.

    1. AUTHOR
      AUTHOR
      patorjk

      patorjk Member Benefactor

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Several reasons
      OTO-313 is currently in Phase II trials. From what I gather online, Hough Ear Institute's pill hasn't entered Phase II:

      https://houghear.org/tinnitus-study

      This means OTO-313 is closer. I'm left with several questions though:
      • Has it been demonstrated that the Hough Ear Institute's pill can cure tinnitus in humans? They say as much on that landing page, but looking closer all I see is a pre-clinical study they did on rats. Where is the data from this study?
      • Why are they crowdfunding this? They could move things along a lot quicker if they got some investors. It seems almost scam-y to make big promises and raise money from people suffering from the condition. The only reason I see to do it this way is that they own their company completely when they go to market - but if there product works, they'll be rich no matter what, so there's no reason not to get investors if their product works.
      • The Hough Ear Institute pill is a synaptopathy drug. If it works for tinnitus, why didn't Otonomy see any tinnitus improvement in their Phase I study of OTO-413?
      There is real data behind OTO-313. Even though it's not a cure for the underlying cause, it's way more exciting as has solid science backing up its efficacy.

      Little is known about OTO-6XX at the moment. Otonomy has 2 investor conferences this month, maybe they'll talk a little more at those but I don't know.
       
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    2. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      - To be rational when it comes to the Hough Ear Institute pill, the initial trial was done with people who indicated that they did not have tinnitus etc. Essentially this demonstrates that it was not possible to determine whether the medicine had any benefit or not for tinnitus.

      - Also wasn't it the case that the Otonomy OTO-413 trial did not test for tinnitus?

      - Also to note that the trial outcomes from the recent work done by Hough Ear Institute has not been completed due to them apparently needing funding for the certification phase of this work.

      - The biggest issue for Hough Ear Institute is the funding/finance raising. Really to date they have been very confusing and unclear with what they are trying to do with the funds raised, as well as why they need to fund through this manner. Most reasonable investors would not be interested in investing even if their work is positive because their case behind why people need to invest is unclear. There is most certainly something missing when it comes to the business side of their operations and if there isn't, there is something that needs urgent rectification.
       
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    3. AUTHOR
      AUTHOR
      patorjk

      patorjk Member Benefactor

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Several reasons
      In a recent Tinnitus Talk Podcast @Hazel asked Dr. Webber and Dr. Foster if anyone reported any improvement in their tinnitus. They said no.

      33% (1 in 3) of the trial's patients had tinnitus. 10 people got the full dose of the drug, 21 people got various smaller doses, and 8 people got the placebo. Yes, this is a small sample size, but I feel like someone would have said something if there was some kind of effect.
       
    4. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      Thanks. I had not seen that tinnitus was commented on in the original trial results.

      Can you show me where in the transcript it says this as I cannot see any mention of tinnitus in the OTO-413 section?
       
    5. AUTHOR
      AUTHOR
      patorjk

      patorjk Member Benefactor

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Several reasons
      Here's the text from the transcript: (page 21)

      Hazel: Were there, so far that you are aware of any anecdotes amongst patients regarding tinnitus or maybe hyperacusis?
      Alan: So no, and again, it was a fairly small study population, but no, we didn't receive any anecdotes of that kind. I think in the patient population, we had maybe one in three actually reported to some degree of tinnitus, so it was a fairly small number, so we wouldn't really expect to learn much from that.​
       
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    6. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      Looking at the comments from Otonomy, it seems like they aren't able to comment and/or determine whether the medicine has any impact on tinnitus or not at this point.
       
    7. AUTHOR
      AUTHOR
      patorjk

      patorjk Member Benefactor

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Several reasons
      I quoted the numbers for the study above. 31 people were dosed with various levels of OTO-413. ~10 of these people had tinnitus and none of them reported back to their ENT that their tinnitus improved. FX-322 had a similarly small study and there were anecdotes of improved tinnitus. Obviously this isn't definitive, but it's 10 data points and that's interesting.

      Now to go into speculation territory, Otonomy has this interesting chart in their corporate presentation that shows Inner Hair Cell loss and Auditory Nerve Fiber loss (synapse loss) as we age:

      otonomy.png

      They also state that evidence suggests that cochlear synaptopathy occurs earlier than hair cell loss. Most older people don't have tinnitus, but they do have hearing loss. This leads me to think that cochlear synaptopathy is probably not a reason for tinnitus, otherwise a lot more people would have it.

      I could be wrong, and future studies (especially Otonomy's extended Phase I/II OTO-413 study due out next summer) will be able to shed more light on this, but as things stand right now I'm very skeptical on cochlear synaptopathy drugs helping tinnitus - and thus skeptical on the Hough Ear Institute Pill.
       
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    8. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      I have seen indications which suggest the opposite when it comes to tinnitus that it is often present in older people.

      The Hough Ear Institute Pill is interesting. It apparently just doesn't solely have medicine for synapses alone according to what they have put out and while I think that there will be benefit from synapse regeneration, I don't think it will be as effective as a medicine like an FX-322 or similar which works with both.
       
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    9. star-affinity
      Wishful

      star-affinity Member Podcast Patron Benefactor

      Tinnitus Since:
      1993, increase in 2020, then new in 2021
      Cause of Tinnitus:
      Maybe during a soundcheck – sudden sound from speaker
      :confused:
      Maybe not for everyone, but for some?

      Tinnitus is definitely triggered in conjunction without hearing loss for some people. I’m one example of that – seems my pitch of tinnitus corresponds approximately to the hearing loss frequency. I actually heard the onset happen. My ear did a two, three second “warped chirp” that then immediately faded into to a high-pitched hiss/sizzle that’s been going on for 4.5 months now.

      Maybe there’s also a difference to how the brain reacts to the synaptopathy if the synapse disconnects/dies gracefully of old age compared to if it’s damaged or “disconnected somewhat” from auditory overstimulation?

      Just a thought...

      But I also hear from ENTs that there are people who hear the tones in a hearing test where their tinnitus is at, i.e. they don’t have hearing loss (in a classical audiogram test), but do have tinnitus (like how my right ear seems to behave). It sure is confusing... :confused:
       
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    10. Tau
      In pain

      Tau Member

      Location:
      Europe
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      2019-Concert, 2021-headphones/acoustic trauma at 110dB,16kHz
      My case is like that. No threshold shifts larger than 10 dB, but I have cochlear neuropathy and blaring tinnitus sounds. I can hear all tones up to 18 kHz with my right ear and up to 16 kHz with my left ear. I do think synaptogenesis would help in this case.
       
    11. Gb3

      Gb3 Member

      Tinnitus Since:
      12/19
      Cause of Tinnitus:
      Sshl
      You just have hearing loss that a standard audiogram can’t detect.
       
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    12. Silvio Sabo
      Pooptoast

      Silvio Sabo Member Benefactor

      Location:
      Gothenburg, Sweden
      Tinnitus Since:
      05/2006
      Cause of Tinnitus:
      Noise - I think
      I think most who consider tinnitus to be disconnected from hearing loss use an audiogram and think "I have no hearing loss, but I have tinnitus. Therefore tinnitus is not connected to hearing loss".

      However it's not as simple as that. Audiograms are really blunt tools and hearing loss comes in many forms. Even when you have hearing loss in a certain frequency it's not 0% or 100%. It's gradual. People who have hearing loss in certain frequencies are seldom completely unable to hear sound in that frequency. If the sound is loud enough they will probably be able to hear it. So it's not just frequency. It's frequency AND volume. So you might be able to hear 20 db sounds at 4 kHz but it takes at least 60 db at 12 kHz for you to pick up the sound.

      I strongly believe that tinnitus is connected to hearing loss in probably 99% of the cases. It's just that the hearing loss might be so slight or of a different kind that doesn't affect the ability to pick up pure tones and is therefore not picked up by an audiogram.

      Oh, and most audiograms only go up to 8 kHz which is not even remotely close to the 20 kHz that the human hearing organ is normally capable of.
       
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    13. Tau
      In pain

      Tau Member

      Location:
      Europe
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      2019-Concert, 2021-headphones/acoustic trauma at 110dB,16kHz
      My extended audiograms are fine. I literally hear 16 kHz at 0-5 dB. It's synapses - I am not saying I don't have hearing loss, I do, I hear stupid beeping sounds over everyday noise and music sounds like trash, but I do hear all the instruments. Auditory brainstem response test show that I have neuropathy/synaptopathy. Maybe there's a dead hair cell here and there, but I don't have big threshold shifts. So I am hoping that BDNF or NT-3 injections can help.
       
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    14. star-affinity
      Wishful

      star-affinity Member Podcast Patron Benefactor

      Tinnitus Since:
      1993, increase in 2020, then new in 2021
      Cause of Tinnitus:
      Maybe during a soundcheck – sudden sound from speaker
      Wow, can you conduct a test to figure out if you have synaptopathy? I didn't know that. Would be interesting to know how I fare on that.
       
    15. Tau
      In pain

      Tau Member

      Location:
      Europe
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      2019-Concert, 2021-headphones/acoustic trauma at 110dB,16kHz
      I probably have lost more synapses than the classic 'can't-hear-in-noise' person because I have clear sound distortions. After my initial trauma ABR showed nothing, a month after - clear neuropathy (with no additional trauma - strange). I am lucky to have an experienced otologist who ran custom ABR tests, not just a standard 2 kHz click, or whatever it is. After my MRI I have clearly lost even more synapses, but she did not want to do another ABR for fear it might cause more damage as I have moderate hyperacusis now. I will get retested before my stem cell secretome treatment to establish a baseline.

      To sum up, if you have speech-in-noise difficulty and that's it, an ABR test will most likely not show anything unless you do suprathreshold tests, but almost no otologist can do that.
       
    16. AUTHOR
      AUTHOR
      patorjk

      patorjk Member Benefactor

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Several reasons
      Can you explain what a suprathreshold test is? If it measures synaptopathy then it's kind of odd that Otonomy isn't using it. From my understanding the ABR test is like an audiogram test. A few months ago when I asked Otonomy about data from these tests (the preclinical and audiograms from Phase I), they told me:

      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.​
       
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    17. Tau
      In pain

      Tau Member

      Location:
      Europe
      Tinnitus Since:
      2019
      Cause of Tinnitus:
      2019-Concert, 2021-headphones/acoustic trauma at 110dB,16kHz
      @patorjk:

      Hidden hearing loss, a disorder with multiple etiologies and mechanisms

      "The auditory defects associated with HHL have been demonstrated in animal models by detection of changes in neural responses to sounds with intensities above hearing thresholds (suprathreshold sounds) in the absence of changes in sensitivity (threshold shifts). Early studies in mice indicated that moderate noise exposures that induce temporary threshold shifts (TTS) do not induce hair cell death, but rather result in decreased responses to suprathreshold sounds that persists after thresholds recover. The observation that the decreased amplitude in the response to suprathreshold sounds correlates with the loss of a subset of synaptic connections between IHCs and AN fibers in the cochlea led to the notion that noise-induced synaptopathy causes HHL (Kujawa and Liberman 2009)."

      Some info here, too:

      Hidden versus Not-so-Hidden Hearing Loss

      The problem is that none of these are completely reliable yet.
       
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    18. AUTHOR
      AUTHOR
      patorjk

      patorjk Member Benefactor

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Several reasons
      I'll have to dig into this deeper later on, thank you for the links! One interesting aside was this bit:

      However, more recent findings indicate that other causes of HHL exist, including cochlear demyelination (Wan and Corfas 2017, Choi, Seok et al. 2018) and possibly mild or persistent hair cell dysfunction (Hoben, Easow et al. 2017, Mulders, Chin et al. 2018)​

      So hidden hearing loss can be caused by more than just synapses dying off. Unless I'm reading something wrong there doesn't seem to be a way to tell synaptopathy from these other two types of damage. This isn't great news for Otonomy, though I'm guessing most HHL is due to synapse damage.

      Assuming OTO-413 works, next year we'll have a better idea on if repairing synapses does anything for tinnitus.
       
    19. evrmre
      Magical

      evrmre Member

      Location:
      Waterloo, Ontario
      Tinnitus Since:
      2018
      Cause of Tinnitus:
      music overdose
      @patorjk, although it would be great for Otonomy to treat most hearing loss, they really only need to demonstrate consistent reproducible results of hearing regeneration in a subset of hearing loss sufferers to be successful. If they can greatly improve hearing in people with hair cell dysfunction but not synapse damage, that will still be one of the greatest medical breakthroughs of the century and most certainly secure them more funding. They have plenty of time to investigate why their treatments succeed in some and fail in others. It's succeeding in anyone that is the first big step.
       
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    20. Diesel

      Diesel Member Benefactor Ambassador Hall of Fame Advocate

      Tinnitus Since:
      1-2019
      Cause of Tinnitus:
      20+ Years of Live Music, Motorcycles, and Power Tools
      Signed in just to give you a quick winner. Glad to see someone else on this forum "gets" how drugs come to market. Talk to you all later.
       
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    21. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      This isn't necessarily true. A lot of people have hearing loss from the audiogram perspective and no tinnitus.
       
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