Otonomy OTO-6XX — Hair Cell Regeneration

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

    1. patorjk

      patorjk Member

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      This thread is for discussion of OTO-6XX, a drug being developed by Otonomy to regenerate hair cells in the ear. At the time of this posting, very little is known about the drug. Here's what I'm aware of at the moment:

      * It's been in development for several years.
      * As of August 2020, Otonomy entered into a licensing agreement with KYORIN Pharmaceutical for "exclusive worldwide rights to develop, manufacture and commercialize a novel compound for the treatment of sensorineural hearing loss. Under the terms of the agreement, Otonomy will make an upfront payment to Kyorin as well as success-based milestone payments and royalties on worldwide net sales of a product containing the patent-protected compound. Otonomy is formulating the compound utilizing the company’s proprietary technology to provide sustained drug exposure in the inner ear following a single local administration." [1]
      * Attached to this post is a slide from Otonomy's September 2020 presentation which shows OTO-6XX regrowing hair cells. [2]
      * This drug will most likely act as a compliment to OTO-413 (ribbon synapse repair), if that drug is successful.

      [1] https://investors.otonomy.com/news-...nces-exclusive-license-agreement-kyorin-novel
      [2] https://investors.otonomy.com/static-files/5d9cb779-996b-49b3-b162-8285d00b6e71

      6xx.png
       
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    2. frpp

      frpp Member

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      It almost looks as if there are more inner hair cells after treatment than the original.
       
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    3. tommyd87

      tommyd87 Member

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      That would be excellent if that happened.
       
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    4. weab00
      Alone

      weab00 Member Benefactor

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      The diagram looks like it isn’t a perfect reconstruction. Still amazing, but it looks cobbled together. Why is this?
       
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    5. Croaker
      Haunting

      Croaker Member

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      Yeah the “repaired” cells look nasty what the heck :depressed:
       
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    6. tommyd87

      tommyd87 Member

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      The heading at the top of the picture says "Damage and OTO-6XX".

      I would assume that this means one of two things:

      1. The treatment dosing used in the picture might only have been a partial course. It wouldn't surprise me if this was done deliberately because it is actually demonstrating how the medicine works to repair damage and clearly shows the after-effects of treatment.

      I therefore feel that the benefit might be bigger with further treatment.

      2. This is how the regrown cells form. From what I can see, it doesn't appear to be neat like the original. However the most important outcome is the hair cell regrowth and as a result how it looks doesn't matter if it is functional.

      At this stage I am going to go with point number one because showing the difference after some treatment is obtained gives a better indication and understanding that the treatment is working because it shows the change before and after the use of OTO-6XX.
       
    7. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

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      Morphologically it does look a bit off, though the IHC row goes from non existent to at least semi decent (the OHC rows look like a bit of a mess though).

      I wonder if that's part of why they have indicated their drug is for "severe hearing loss" because in terms of "after" the IHC row would provide much more hearing.

      Personally, I would try to repair my OHCs with FX-322 first as much as possible before trying this drug but this is based on such little info about OTO-6xx.

      Too many hair cells produced is not ideal ("supernummery cells"). You ideally want the same number you had.
       
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    8. GBB

      GBB Member

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      Any time you introduce entropy to a structure and then try to reassemble it, expect entropy.
       
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    9. frpp

      frpp Member

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      Why would supernummery cells be bad?
       
    10. tommyd87

      tommyd87 Member

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      I think that if this entropy thing actually happens then this won't matter or worry anyone as long as it provides positive treatment lol :).
       
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    11. FGG
      No Mood

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      If there were enough of them it seems that they could impede function as a space occupying entity (outer hair cells need to move to function) and would be unlikely to make the correct neural connections stack on top of one another.

      And if it was truly uncontrolled, that would be a cancer risk.

      This may not be a problem with this drug in vivo though, I was responding to @tommyd87's comment that supernummery cells would be a good thing and I think it would be a negative.
       
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    12. tommyd87

      tommyd87 Member

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      Only a good thing if they function correctly :D.

      Apparently an actual outcome of some of the synapse treatments such as the Hough Pill is to restore a more than normal number of synapses however. So not sure if there is a difference between extra numbers of hair cells regrowing and an extra number of synapses growing, however the extra numbers of synapses make no difference to their functionality so not sure if the same outcome would happen with hair cells.
       
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    13. FGG
      No Mood

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      Extra synapses should not impair function the way extra hair cells would.
       
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    14. tommyd87

      tommyd87 Member

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      So therefore we will need further clarity from Otonomy to explain why the picture with the regrowth looks like it does. It is incredibly possible that this picture looks exactly the way which @GBB claimed it does from entropy and actually also won't have any impact on the operation of the regrown cells.
       
    15. FGG
      No Mood

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      I'm sure more information would be provided around the time of a phase 1. A lot can happen in culture that wouldn't happen in vivo.
       
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    16. paul mclean

      paul mclean Member

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      A good question I reckon is if you have hearing loss that is from both cochlear synaptopathy and the loss of inner hair cells, which order of drug treatment would you have?

      Repair the synapses first and then regrow more hair cells or regrow more hair cells and then repair synapses afterwards?
       
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    17. frpp

      frpp Member

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      That probably depends on what your audiogram looks like, if it's showing significant dB loss, hair cell regeneration would likely be the best route both for tinnitus and quality of life but, if the extended audiogram looks pretty good, synapse regeneration would be the way to go.
       
    18. Indra

      Indra Member

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      Yes what order should we do it in?
      This it's a good question and I also think about what other things we should do or not do during the treatment and healing phase after. For instance I'm thinking of supplements to take or not to take, exercise, get extra sleep, drink extra water, all of that.

      Also there was this paper on cochlear pumping where they were able to get medicine deep in the cochlea just by using some kind of pressure waves in the ears, now I don't know if those waves would mess with people like us but it seemed to really easy way to get a medicine in.

      I'm really hoping insurance will cover these things I have a really good one and would do everything I can. Ready to try multiple courses of all of them at the moment lol but this one and frequency and Hough are the main ones I'm thinking of, although this and Hough seem to do similar, yeah?
       
    19. paul mclean

      paul mclean Member

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      Studies are leaning towards people getting cochlear synaptopathy/synapse damage before they actually lose the inner hair cells.

      So my question is if you have both hair cell damage and cochlear synaptopathy, which order would be best suited?
       
    20. tommyd87

      tommyd87 Member

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      I'm not an expert, however I have had a very strong feeling that it would be better to regrow the synapses and nerve ends first and then regrow the hair cells.

      There are three reasons why I would do the nerve ends and synapses first:

      1. The medicine for synapses is much easier to dose and also faster to treat than the medicine for hair cells is. It appears that most synapse medications are single dose and only take 90 days to complete treatment. This is opposed to hair cell treatments that tend to be varied and there seems to be no accurate guide yet on how to treat people due to the fact that there is a lot more variance.

      2. Treating the synapses first will mean that those who utilise hearing aids are going to get big benefits from them in the time between receiving synapse treatment and completing hair cell treatment. This is because by having the synapses and nerve ends repaired first, you can actually benefit brilliantly from having some improved hearing volume and also from having had normal abilities to hear in background noises restored.

      3. It is better to have the nerve end and synapse treatment first because this will give those treating you a better indication of what your hair cell issue is likely to be. Based off of indications in research work, we know that there is approximately a 15 dB improvement in hearing volume from a synapse treatment. Furthermore by treating the synapses and nerve ends, we know that these will be regular at the time of the hair cell treatment. Therefore it is incredibly likely that this then will improve your hair cell treatment because everything is connected correctly. Thus if you then add additional hair cells it is likely that you will be getting a true reflection of what your current hearing level is and not a distorted indication due to things not being fully connected up correctly.
       
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    21. paul mclean

      paul mclean Member

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      For sure that all does make sense. As for treatment availability it seems like hair cell regeneration will be available first before synapse repair though. Guaranteed I'll be getting FX-322 as soon as it comes out and then maybe PIPE-505 when that comes out too.
       
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    22. tommyd87

      tommyd87 Member

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      I reckon OTO-413 will come out before PIPE-505.

      It is actually possible for OTO-413 to even beat FX-322 if successful. Supposedly Otonomy has proceeded straight to the multi dosing of OTO-413 in their phase 1/2 trial and thus will have a good idea about any issues relating to dosing size. Furthermore with the treatment time being a lot faster than FX-322 I could see Otonomy proceeding to a phase 2a or even their final trial in a fairly short time if it is successful because their trial candidate suitability is a lot broader than it is for FX-322.

      Thus there is every chance some synapse medicines may be available before FX-322 is.
       
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    23. tommyd87

      tommyd87 Member

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      So Frequency Therapeutics managers sell shares because this is how they end up getting paid the cash for the work they do, as Frequency Therapeutics has no cash reserves. Therefore I do not think that this has anything to do with headhunting.

      If Frequency Therapeutics was going to headhunt a staff member to handle something like customer liaison management for example, then they would likely end up paying them the same way as all other senior staff get paid which would be by giving them shares.

      Otonomy's value dropped drastically after their Meniere's treatment phase 3 trial failed the first time around. After Otonomy rejigged and reworked the medicine to make it much more effective, their share price started to appreciate once again. This is due to the Meniere's medicine now looking rather promising and that it is looking like it will comply with the phase 3 trial requirements. Furthermore Otonomy obviously has got three other treatments in the works now, which are all actually looking very promising and one treatment has already gone out to market.
       
    24. tommyd87

      tommyd87 Member

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      Just got an update from Otonomy's capital firm who manages investment related questions about the progress of OTO-6XX.

      They told me that they have no information about the timeline at this time, however they will be proceeding with the compound that has been licensed from Kyorin.
       
    25. FGG
      No Mood

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      Otonomy didn't change their drug.

      What happened was the drug was so effective that doctors were excitedly recruiting people and there was a powerful placebo effect.

      They were measuring vertigo days as their primary endpoint which can be very subject to placebo.

      After meeting with FDA, the trials were reviewed and they made some changes in terms of how people were recruited.
       
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    26. tommyd87

      tommyd87 Member

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      Thanks for correcting.
       
    27. paul mclean

      paul mclean Member

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      Any articles I can read about this?

      That's pretty big if you think they could beat Frequency Therapeutics. When I check Otonomy's website, it says they are still in phase 1 and that is a fair while away from being available to patients.
       
    28. tommyd87

      tommyd87 Member

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      No idea about articles. Otonomy is apparently going to complete phase 1/2 either early next year or by the end of this year and then they will move to phase 2 if they are successful.

      So the main difference between Otonomy and FX-322 is that Otonomy takes approximately a bit over 3 months to finish a trial while FX-322 takes 7 months. Therefore theoretically there is a fair chance Otonomy could move to a phase 2 trial early next year and if successful, the final trial soon afterwards. I think that unless there is a very bad failure with the medicine, Otonomy can proceed with this pretty quickly since they can use a lot broader criteria to get the medicine released, so they will not have any issues with candidate selection.
       
    29. paul mclean

      paul mclean Member

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      They are expecting to release their phase 1/2 results in the next 3 months.

      If their results are good, which it seems like they will be, then they could actually have phase 2 done by June/July next year if they are going quick.

      Seems like Otonomy and Frequency Therapeutics aren't messing around. My only worry with these clinical trials is phase 3 which is the longest phase, hopefully they can both get granted Breakthrough Drug designation and start treating people right away.

      I'm setting my sights for 2022. It seems that's when things will get really exciting.
       
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    30. tommyd87

      tommyd87 Member

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      Supposedly Frequency Therapeutics already has obtained the Breakthrough Therapy/Fast Track/Compassionate Use release approval from the FDA. I think that the issue is whether Frequency Therapeutics will grant this or not as once the FDA allows a company to go down this route it is up to the company and not the FDA at all.

      I can absolutely assume at least one (possibly two) global trials of FX-322 will get done due to the fact that Astellas and Frequency Therapeutics have an agreement where Frequency Therapeutics receives a cash payment for doing this. This will be highly valuable for Frequency Therapeutics and as a result they will most certainly be doing this.

      Otonomy could possibly get given Fast Track/Compassionate Use access allowances from the FDA as their medicines most likely will meet the criteria. Although I actually do not believe that there will be a massive hindrance or delay if it has to go through the phase 3 trial since it is likely that Otonomy will have a much bigger range of candidates that they can choose from and also the time taken to complete a phase 3 trial for the nerve end/synapse medicine will be fairly short compared to FX-322.

      The reason these organisations aren't mucking around is because they believe that they can achieve real results rather soon and actually want to help people.
       
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