Frequency Therapeutics — Hearing Loss Regeneration

Discussion in 'Research News' started by RB2014, Dec 8, 2016.

    1. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

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      Yep. They did a perilymph study in Germany with cochlear implant patients (so they could test the fluid at the time of surgery after the IT injection) concurrent with this phase and showed that it did.
       
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    2. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

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      I went into this a lot more in the Novartis thread but I really think if they did better patient selection (e.g., very severe vs profound), they wouldn't have had the problem they likely did with flat epithelial (which doesn't transduce with the genes used) and probably would have got better results.

      Also, viral vectored therapies have to be directly infused surgically into the cochlea and cochleostomy is a destructive surgical procedure and can produce enough inflammation (it's sometimes quite pronounced, which is why Hough Ear Institute is testing their pill for "cochlear implant trauma") where they can actually do more harm than good.

      Akouos is a lot more promising as far as viral vectors therapies go but they are starting with genetic deafness (for now, they are pre-clinical for hair cell regeneration) and, as I recall, have developed their own surgical technique. Even canalostomy, a relatively newer surgical technique would have very likely produced better results imo.

      Viral vectored therapies still have a lot of potential and may ultimately be the best way to treat the very severe to profound hearing loss (once they get the right genes, they could maybe even transduce fibroblasts) some people have where they lack support cells. Once they get the surgery right anyway.
       
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    3. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
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      This makes good sense and is also helpful info.
      As an Australian myself, I have learnt over time from researching and travelling that often the costs of non-PBS treatments (for those non-Australians, non-PBS means the cost of a pharma treatment not covered by the government) are often quite a lot higher than they cost in other countries. Furthermore medicines generally can be quite expensive even from an Australian pricing perspective.

      One of the reasons I think that this happens is because like with most other things sold in Australia, Australians are rightly or wrongly seen to have the ability to pay a higher amount for stuff. Just look at things like the cost of food and utilities for example, when compared to many other places. The same thing happens with both the government subsidised and non-government subsidised medications. For example a packet of antibiotics costs $9.60 in Australia whereas in the Philippines it costs about $2 or $3.

      I think that the unfortunate reality is that FX-322 is going to be around the $5,000 price point for two main reasons.

      Firstly, this cost is comparable to the alternative treatment of a hearing aid. As a result Frequency Therapeutics know that people potentially will pay this sort of price for this treatment and therefore they can comfortably charge this.

      Secondly, FX-322 will be under patent. Therefore firms like Frequency Therapeutics can usually charge what they want within reason, as they effectively have a monopoly on a treatment for the patent's duration. The reality is that Frequency Therapeutics is going to ensure that they are profitable from selling FX-322, as it is one of the two key aims of a pharmaceutical company (along with producing good treatments) and thus the price will reflect this aim.

      However, Frequency Therapeutics also needs to recover all medicine development expenses first to enable it to turn a profit. As a result the medicine needs to be sold at a price which enables it to recover both development costs and also turn a profit in a relatively speedy manner. The main way pharma companies such as Frequency Therapeutics can do this is by following the new mobile phone pricing model just like how Samsung does when they release a new Galaxy Phone for example.

      People want the new Galaxy immediately for a number of reasons such as the phone's look and better features. Therefore they will pay more money to get their hands on it earlier because they want the new technology and new product now. Samsung takes advantage of this by charging the maximum price that they know people will pay for this phone and holds the phone at that price until they have recovered enough money from sales to not only cover the costs of the phone's development but also to allow them to maximise profit from it. After the phone has been out for a while and Samsung feels that it has maximised benefit from it, Samsung will reduce its price.

      The same scenario should play out with how Frequency Therapeutics prices FX-322.

      However, instead of reducing the price per unit for individual customers (patented medicine holds its value for the duration of the patent, unless some superior medicine comes out), Frequency Therapeutics may be willing to enter into bulk buying discounts with pharmacy store groups or with governments so the treatment can be provided at a reduced cost. This happens regularly in Australia with many medicines and is the most likely way which we would be able to buy FX-322 at a discount.

      Australian Government deals with pharma companies to get discounted medicines. It already happens with medicines like the flu shot and also a number of heart medicines. Heart medicines are probably the best example because they have been able to eliminate the need for people to have more expensive heart surgeries in many instances. This is because the medicine works just as well as, if not better than the surgery in a number of cases and yet is significantly cheaper. If FX-322 can demonstrate that it can provide a significant benefit to people which would reduce hearing aid use then it probably would be subsidised. The interest from Frequency Therapeutics at looking at age-related hearing loss (which is probably not much different to the hearing loss FX-322 is looking at currently) is probably the most relevant case as the government would certainly subsidise this since they already have hearing aid programs now which they fund. So just like in the case of the heart medicine, this would mean that FX-322 would be better than the current option. Thus the government would be much more likely to pay for it also.

      Given that FX-322 is a novel treatment with seemingly high demand, I cannot see Frequency Therapeutics reducing the cost of it at all initially under any circumstance.

      Furthermore, it is blatantly obvious that there are a significant number of factors which indicate FX-322 will be relatively expensive as highlighted above.

      This sucks as it is going to mean a significant outlay of money to purchase FX-322, however I strongly feel that all the data and all the analysis points to the fact that people will pay a substantial amount for FX-322 and both customers and Frequency Therapeutics know this. Thus it will be priced accordingly.
       
    4. GregCA
      Jaded

      GregCA Member Benefactor Hall of Fame

      Tinnitus Since:
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      Otosclerosis
      The cochlea is quite a delicate organ! For stapedotomies/stapedectomies a hole is drilled into it to insert the piston, and it is known to be one of the risky parts of this procedure. Mine was done with laser, which is also traumatic, but other methods do include a drill (which makes me queasy just to think about it). I've lost some high frequency sensorineural hearing from that surgery and I can't help but think it could be due to this, since the "drilling" happens "close to the high frequencies".
       
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    5. Lucifer

      Lucifer Member Podcast Patron Benefactor

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    6. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      This is now giving me more confidence that FX-322 is actually going to be successful.

      Seems Frequency Therapeutics has now demonstrated FX-322 has met the three key criteria required for this medicine to be successful, being

      - FX-322 can break the barrier in the cochlea

      - FX-322 delivers positive treatment results when consumed

      - The benefits provided from treatment with FX-322 are maintained a long time after the dosing.

      This tells me that the work of Frequency Therapeutics and the creation of FX-322 is not only wonderful, but it is also a mega miracle.

      I feel that now FX-322 has achieved the three criteria listed above, it is now just a matter of making the medicine more effective. This does of course rely upon the achievements seen thus far being maintained in future trials .

      I hope FX-322 can be made more effective so it provides broader treatment. However, I am fairly confident this can happen. Frequency Therapeutics have shown time and time again that they are keen on doing the work needed to get the best possible treatment that they can and that they are fully focused on achieving this.

      I somehow think that this leads me to believe that there will be positive times ahead.
       
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    7. tomytl
      Grumpy

      tomytl Member Benefactor

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      So is Frequency Therapeutics allowed to change their formula of FX-322, let‘s say for a Phase 2b, or would this start again at Phase 1/2 if they modified something? Or do they use always the same formula all the way to Phase 3 but with different dosing and concentration?

      What are they allowed to change to optimize the treatment?
       
      • Good Question Good Question x 2
    8. patorjk

      patorjk Member

      Tinnitus Since:
      2008
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      Several reasons
      This quote from that statement answers a question I'd had about whether the people who saw the 10 dB improvement were the same that had the WR score improvement:
      Although it seems obvious to assume it, it's nice that they spelled it out. I kind of wonder how big an effect the person doing the injection has. I've never had an intratympanic injection, but they can't all be equal, right? It'd be interesting to know if the same person did all of the injections for Phase I.

      Also, I wonder if their WR score improvements were due more to the improvements at 8000Hz than the improvements at 8000Hz+.

      Lastly, it's nice to see that the pure tone improvements were maintained (and possibly improved? In the announcement they say 10-15dB improvements, but originally they just said there was just a 10dB improvement).
      The fact that a 71% increase isn't statistically significant seems really odd to me. How can a 71% increase not be statistically significant? This makes their choice to avoid mild cases from Phase 2a make a lot of sense.
       
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    9. Lucifer

      Lucifer Member Podcast Patron Benefactor

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      If they can optimize the delivery method to target all frequencies in the ear, FX-322 will be a game-changer to all those who have hearing loss in all frequencies.

      I do hope by targeting all frequencies can help get rid of tinnitus, pain and loudness hyperacusis.
       
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    10. Lucifer

      Lucifer Member Podcast Patron Benefactor

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      Yes, I was shocked too that they said 71% increase is not statistically significant. 71% is a lot but maybe their terminology of statistically significant for hearing is different to what we think is statistically significant.
       
    11. Lucifer

      Lucifer Member Podcast Patron Benefactor

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      D9D6FB4A-AEF3-460F-B112-7536E262A010.jpeg

      The CEO of Frequency Therapeutics, David Lucchino, retweeted this on Twitter.

      This shows he’s really keen for FX-322 to come out to the market ASAP.
       
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    12. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

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      They can't change the formulation (e.g. the drug or the vehicle) but they can change the dose.
       
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    13. Cernuto

      Cernuto Member

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      2010
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      Noise Induced
      10 dB means it improves hearing two-fold, though mostly the higher frequencies? And they are seeing continued improvement many weeks after delivery?

      Sounds too good to be true for my skeptical mind, but I'm down for injection!
       
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    14. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

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      Good catch. They are confirmed to be the same patients after all.

      And 10-15dB improvements does mean that some patients continued to see improvements after the original study completion, which is exciting.

      Makes me wonder if the neuro connections are what takes additional time to regenerate after the hair cells have reformed.
       
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    15. tomytl
      Grumpy

      tomytl Member Benefactor

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      OK, so in Phase 2A participants are already given 4 shots and Frequency Therapeutics might already know about the improvements.

      I hope with 4 doses or more, they can reach deeper areas in the cochlea.

      Or how could they optimize it better in this trial if they can't change the vehicle or formulation?
       
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    16. d'Wooluf

      d'Wooluf Member

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      2010
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      Carl LeBel all but said that they wouldn't/couldn't in the recent panel discussion.
      A study result is statistically significant if the chances of that result happening by chance are below a pre-defined threshold. 0.05 is a number that is often used. They do some maths, come out with a number which is the probability that their results were due to random chance. If that number is less than 0.05, the results are said to be statistically significant.
       
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    17. Koz
      Dreaming

      Koz Member

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      Loud Music via headphones + loud concerts no earplugs
      I am hoping this is something they can look at again perhaps after releasing the first version of FX-322 on the market. Weren't they hiring experts in delivery/vehicle method not long ago though?

      Also, just seen they stated this in their latest press release:

      If that's the case then I will probably be taking a break from reading about this until summer 2021. Although I respect all of you for continuing to discuss and raise good questions, valid points and meaningful discourse, I find that the hypothesizing and uncertainty doesn't do my mental health any good. Sometimes perhaps as much (or more so) than tinnitus and hearing loss itself.
       
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    18. Koz
      Dreaming

      Koz Member

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      Unrelated but - he responded to me the other day, which surprised me. It's good that he's seeing what this means to the patient community.

      Screenshot_20200914-023845_Messenger.jpg
       
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    19. GBB

      GBB Member

      Location:
      NYC
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      2020
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      Microsuction / Additional Acoustic Trauma in Close Proximity
      Is there compelling evidence that if you fix the ear the tinnitus will just go away, as opposed to being internalized by the brain? This has always been my big worry with regenerative treatments. I feel like in the absence of Frequency Therapeutics giving detailed feedback on tinnitus decreases in their trials, we are all banking on a big assumption.
       
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    20. weab00
      Alone

      weab00 Member Benefactor

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      Were the 4 documented patients given just one injection? If so, that makes me very hopeful. Imagine how much more it could achieve with 3-4 spaced out injections.
       
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    21. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

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      Frequency Therapeutics will document the effects after this trial as tinnitus has been added to their experimental end points after receiving testimonials that it did lower tinnitus in phase 1.

      I would listen to the Tinnitus Talk Podcast interview with Frequency Therapeutics if you haven't already.

      Other evidence is the fact that cochlear implant studies have shown a reduction in tinnitus and hearing from CIs is extremely crude compared to regenerated natural hearing.

      In addition to that, when you can treat the underlying cause, the tinnitus responds. Sound Pharmaceuticals found a reduction in tinnitus with their Meniere's treatment because they were treating the cochlear cause (hydrops) which means it's not "stuck in the brain." Other treatable causes of tinnitus (e.g., ETD, TMJ) similarly respond.

      And understanding neuroplasticity, it's not a switch that gets stuck in one direction because that would imply the brain has a preference for tinnitus (and it doesn't, brains are dumb in that sense and just respond to the input they are given).
       
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    22. Lucifer

      Lucifer Member Podcast Patron Benefactor

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      I gotta hand it to you. I would not have personally messaged the CEO on Facebook but props to you for doing that.
       
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    23. Koz
      Dreaming

      Koz Member

      Tinnitus Since:
      2009
      Cause of Tinnitus:
      Loud Music via headphones + loud concerts no earplugs
      I thought it wouldn't hurt to try, certainly better than moaning at them. The more they see what this means to us the more they can hopefully keep pushing forward with intent.
       
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    24. Lucifer

      Lucifer Member Podcast Patron Benefactor

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      2017
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      Ear Infection
      True, they are probably sick and tired of us moaning but we are just glad that so far Frequency Therapeutics have been getting positive results in their current clinical trials for FX-322.
       
    25. Billy_Shears

      Billy_Shears Member Benefactor

      Location:
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      Pink Floyd
      I totally agree. At the risk of advancing to an optimistic plateau on the thought of FX-322 being the potential cure, yes cure, I believe we have finally reached 'the light at the end of the tunnel' whereas through modifications along the way we may be witnessing the beginning of the end of sensorineural hearing loss and associated tinnitus.

      The signal that Frequency Therapeutics has reached is quite phenomenal. The needed capital investment is not only there but this company's primary sole existence is for this shining moment to occur. Remember, Carl came out of retirement with a true belief that this is within reach. One day within sight this medical procedure from an ENT physician will become routine.

      It's worth noting that a stock purchase in FREQ would probably pay for the treatment. Again, I am being optimistic but for good reason.
       
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    26. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      I agree with you about improving and optimising the delivery method. What we have seen to date with the results doesn't necessarily tell us the full picture. Although FX-322 has delivered improvements to date, I think that we have only seen a small improvement due to the small size of the dose used in the inaugural trial.

      Frequency Therapeutics have discovered in the lab that their treatment works throughout the whole ear. Therefore we now know that FX-322 isn't the problem, but rather the reason we haven't seen more extensive growth in ears is to do with the dosing factors.

      Therefore I think that there are three things that should be noted about the dosing of FX-322:

      1. We have only seen the benefits of one dose of FX-322 in people. The results from this one dose have been nothing short of remarkable, especially with the gains seen in all patients (both those deemed to be statistically insignificant and those deemed statistically significant).

      2. If the evidence and research is true which suggests doing multiple doses, spread out a week apart to achieve better results, I think there will be better outcomes. This could include not only a larger improvement in decibels but also increased word recognition scores too.

      My hypothesis (I could be completely wrong) is that those who had worse improvement in the inaugural trial (ie: those with statistically insignificant improvement) were the people with the worse hearing losses. Therefore I believe that based off of how FX-322 operates (by targeting the stuffed cells till it has been all used), more of the medicine would have had to get used in the very high frequencies with the higher hearing losses. This in turn has led to the lower word recognition improvement and the no measured decibel improvement, because their gain was not widespread enough to demonstrate benefit.

      Therefore I think that more dosing does seem like a highly likely method to improve the outcomes from treatment with FX-322. This is because the methodology does indicate that this will lead to a better outcome.

      3. Frequency Therapeutics needs to redesign the dose in order to deliver FX-322 to all areas of the cochlear. It is already known that Frequency Therapeutics is redesigning the delivery method and/or reformulating the dose of FX-322 in order to make it work better.

      It is inevitable that this will happen, as from what we know Frequency Therapeutics was hiring someone to work through this. Furthermore we know that the issue is not with FX-322 but rather it is with getting the medicine to all parts in the ear. We have seen FX-322 provide complete regrowth in a lab setting and as a result there is no real reason why this cannot be replicated in an ear. Therefore I reckon that this is an excellent area to focus on in order to get improved benefit from FX-322 in terms of treatment.
      I asked someone I know well who works as a data analyst why there could be a large percentage increase (like the one you referred to) and he indicated that there tends to be a number of mathematical rules around this that he said can be complicated. He said that there was no real point in going into the nuts and bolts of it all. Basically he said that the reason it wasn't classified as statistically significant is probably solely due to a technical reason, like complying with the rules of statistics.

      He thinks Frequency Therapeutics has probably been mandated to report results in this way. If Frequency Therapeutics doesn't comply with these rules, it could lead to them getting in trouble for delivering misleading and wrong info.

      He suggested to look at the data from a real world perspective and interpret it accordingly. As a result he hinted that if you see something which looks like it is a good gain or good improvement for what it is then treat it as such and actually ignore what was reported.

      So I agree with you that 71% is a large improvement, significant and also a good result.
       
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    27. tommyd87

      tommyd87 Member

      Tinnitus Since:
      1999
      Cause of Tinnitus:
      tmj music
      I think I am like you. I am optimistic, however I won't be fully satisfied until the day this medicine is completed and usable LOL.

      I think that your analysis that we may be reaching the "end of the tunnel" is accurate, as I think that FX-322 has achieved the titanic breakthrough needed to get treatment that works in the ear. Even if FX-322 isn't the best treatment over time (I think it will possibly be), the amount of unbelievable work Frequency Therapeutics has completed has set the foundation for the future of ear medicine up wonderfully well.

      I think that Frequency Therapeutics certainly reflect the quality of the people who are working to develop both FX-322 and the company. Carl LeBel appears to be a very decent operator. He has been very direct in his comments and he has not done anything that could jeopardise Frequency Therapeutics or FX-322. I believe the fact that Carl had faith in this for the reasons you stated, is an excellent sign too.

      While it isn't finished yet, I have a feeling FX-322 will provide quite positive benefit to a number of people.
       
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    28. Thuan

      Thuan Member

      Location:
      California
      Tinnitus Since:
      05/2018
      Cause of Tinnitus:
      Ear infection
      So with Frequency Therapeutics' recent press release, this related article popped up in my news feed:

      https://www.wbur.org/commonhealth/2020/09/13/frequency-therapeutics-regenerate-hearing-drug

      And from the article's quotes regarding pure tone testing:

      An improvement of 10 decibels at 8000 hertz is also almost a negligible gain, adds University of Iowa's Gantz, "within test, retest variability of an audiogram," he says.​

      I do agree that current equipment to test hearing is not great but is 10 dB really so small that it can be attributed to testing variability? Decibels are measured in logarithmic terms so anyone going from 10 dB to 20 dB hearing loss is ten times less sensitive to sounds, not just two times less sensitive (correct me if I'm wrong).
       
    29. FGG
      No Mood

      FGG Member Podcast Patron Benefactor Hall of Fame Advocate

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      I get the impression that most of the ENTs interviewed haven't read much beyond a few press releases. The reason I say that is this quote:

      "But Dr. Alan Cheng, an otolaryngologist at Stanford University who did not work on the study, says there isn't enough evidence to show the drug is truly regenerating sensory hair cells. While Frequency scientists have shown that FX-322 can regenerate sensory hair cells in mice and in the lab, he says there’s still a long road ahead to demonstrate it works in living human beings."

      And maybe he means the human cochlear explants are considered "in a lab" vs living human beings but when you consider that they *did* grow hair cells in intact human cochleas removed before nearby tumor removal surgery and then also showed in their German perilymph study, that the drug could reach their target in "living human beings" it seems misinformed and it's likely due to the fact that Frequency Therapeutics didn't release many press releases on the perilymph studies and most ENTs don't have incentive to keep up with the progress of the drug until phase 3.

      It's an easy way to avoid having to take time to discuss it with patients before they can offer the drug commercially.
       
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    30. Kendra

      Kendra Member

      Tinnitus Since:
      08/2017
      Cause of Tinnitus:
      SSNHL/ Acoustic Trauma
      10 dB is definitely significant for anyone who has hearing loss and tinnitus. I had a sudden drop of 15 dB which caused tinnitus and diplacusis. And my ENT essentially said it wasn’t statistically significant. Not enough to cause concern to do anything.

      Without real life experience I just don’t think ENTs or other physicians really comprehend how much “just” 10 dB can mean when it comes to the difference in real life to people and ear function.
       
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