Frequency Therapeutics — Hearing Loss Regeneration
- Thread starter RB2014
- Start date
MemberIf the severe hearing loss trial shows meaningful improvements in word scores and audiograms, FX-322 shouldn't be delayed further by repeating Phase 2 again. How long do we have to wait before FX-322 comes out in the market?
This could help millions of people right now who suffer from hearing loss, tinnitus and hyperacusis.
All they have to do is show the FDA drug efficacy to get approved for use. In my opinion they should have played it safer for Phase 2. Say it's only for high-frequency hearing loss, get approval for that, we can try it off-label. Meanwhile, they can work on improving the drug's delivery method.
Street Novelist
Member
- Apr 2, 2018
- 290
- Tinnitus Since
- February 2018
- Cause of Tinnitus
- Listening to loud music through headphones
We also don't know how well it works when doses are adequately spaced apart. Get a shot, wait a month, and get another shot. Maybe your hearing improves more with the second shot, when spaced far enough after the first one.
- Sep 21, 2016
- 1,051
- Tinnitus Since
- 2011 - T, 2016- H, relapsed 2019
- Cause of Tinnitus
- noise-induced
We all want this to come out ASAP but to be honest I think it's wishful thinking at this point to think they'll be able to skip a Phase 2 repeat.
They got too greedy. They should have continued with the single dosing but have a separate trial for multi dosing. Now they have fucked with the timeline and we are now waiting even longer to get treated. Fuck my life.
I didnt' notice a difference when it went from 70 dB back to 50 dB. I could definitely tell when it went from 25 dB to 50 dB though. At 25 dB loss I could still hear birds chirping on that side. Now instead of stereo I only hear them in mono. It's super weird walking outside and hearing birds but not being able to tell where they are. Only having one normal ear really blows.
Were you in the military as well? I didn't realise Howard Leight were a shit brand, I thought the orange pairs provide the best protection out of all the earplugs.
Forever hopeful
Member
- Sep 5, 2015
- 718
- Tinnitus Since
- 2015 resolved, 4/20 L ear, increase 2/21
- Cause of Tinnitus
- 2015,noise,2020-21 SNHL
Sorry. Getting rid of tinnitus wasn't my point in my response to the other poster. I was responding more to a post about audiograms and the variability of one's performance on them.
However, to your point, my tinnitus got worse when when I had a change in hearing at one frequency where I went from 10 dB to 25 dB. Which according to my ENT is still normal hearing. After Prednisone that frequency returned to 10 dB. Sadly, my tinnitus has not improved. But it has only been a month and a half. Perhaps in time.
If there is sufficient evidence of WR improvement and there are a certain number of anecdotes of PTA improvement, FX-322 will go on the market.
In that case, the indication might be "SNHL" rather than "WR deterioration".
In that case, there is a possibility that insurance will be applied even for "PTA deterioration".
If FX-322 goes on the market, I don't think reinjection is prohibited after a certain period of time. It may be accepted as a second, third, fourth..."single injection".
Are you down 10 dB at 8 kHz? If you are down 10 dB at 8 kHz and you only need 10 dB to get back to baseline, you might actually be one of the few people that FX-322 could help with, based on what we know up to this point.
My theory has always been if you can get back to baseline on all frequencies... 0 dB... then you can get rid of tinnitus.
Temporary threshold shifts (reversible) in OHCs often simultaneously occur with permanent synapse loss (synaptopathy).
And synaptopathy, like IHC loss and OHC loss is associated with tinnitus.
I can pull up papers if anyone is interested.
No military service. Just avid sport shooter and hunter; well at least I used to be. Only takes once to ruin your ears in some cases I guess. Dumb.
- Feb 14, 2020
- 1,630
- Tinnitus Since
- 1-2019
- Cause of Tinnitus
- 20+ Years of Live Music, Motorcycles, and Power Tools
- Aug 5, 2019
- 1,852
- Tinnitus Since
- 05/2019
- Cause of Tinnitus
- Autoimmune hyperacusis from Sjogren's Syndrome
Not dumb, you were doing something you loved, it's just a shame it happened. It's not your fault.
Nice picture... This thread was created for anyone to talk about anything they want, related to Frequency Therapeutics, and cats are just as good. You can talk stock price, voice your opinions... Good or bad... Tell us your story and let the "experts" help or anything else you want. It is a great way for all of us to vent and discuss.
It hasn't exactly gone the way we wanted, but progress is being made and this thread is a great way for all of us to communicate.
Sure! Here is one on temporary threshold shifts and synaptopathy:
Hearing Loss: Reestablish the Neural Plasticity in Regenerated Spiral Ganglion Neurons and Sensory Hair Cells
But there are a ton of papers on this topic. A lot of cochlear synaptopathy papers mention the temporary audiogram changes despite permanent synapse loss. Just search "cochlear synaptopathy" in PubMed.
Interestingly, it's more established in rodents that cochlear synaptopathy itself can commonly cause tinnitus on its own. A few papers suspect this is "uncommon" for people but temporary thresholds shifts are less common in people so synaptopathy would be the result (usually) of a more gradual and less severe loss than in experimental rodent studies.
Some studies suggest IHC damage itself and not synaptopathy would be the more common cause in normal audiogram people:
Assessment of Hidden Hearing Loss in Normal Hearing Individuals with and Without Tinnitus
I'm not sure where I stand as far as synaptopathy generating tinnitus from the more gradual, cumulative age-related loss but I don't see why we would be different from rodents after a more substantial loss causing a temporary threshold shift, which suggests a lot more synapse damage.
It's not possible IIRC. The human cochlea is very fragile, now imagine a tiny mouse cochlea.
There are a lot of different schools of thought on this but my personal "unified theory of tinnitus" that I have tried to piece together goes something like this (this is ignoring middle ear and somatic causes and to keep it simple):
You have an acute trauma to the ear which causes cochlear inflammation which may or may not result in permanent damage. This involves excess Glutamate release to the local NMDA receptors which causes neuronal hyperexcitabilty which then gets propagated through the brainstem and up to the brain.
This acute phase tends to settle somewhat except in cases where there is continued cochlear inflammation.
In addition to that, permanent disruption of the auditory pathway (when it occurs) causes maladaptive plasticity due to "phantom cochlea".
This is less clear to me in terms of exact mechanics but it appears to me that in this case the brain then attempts to force a signal to match its predictions through ion channel mediated neural responses. And what ends up happening is excess Glutamate/hyperexcitabilty centrally as part of this maladaptive neuroplasticity (there is also some cytokine mediated inflammation too that may play a role but trying to keep it simple...)
Glutamate isn't just involved in "hyperexcitabilty", it's the neurotransmitter you need to propagate the sound signal at the IHC/SGN synapse level as well as centrally (you couldn't hear without it but it can become unbalanced with trauma). So when the signal doesn't get through, my impression is it's more or less pushed centrally in a sense.
So, to my understanding, you have acute hyperexcitabilty locally and eventually central hyperexcitabilty from "phantom cochlea". But some people's tinnitus might involve less central neuroplastic change and may settle a bit with time especially without continued NMDA stimulation which contributed to their acute local hyperexcitabilty.
Basically acutely, tinnitus presence and severity seems to be a combination of both local and central hyperexcitabilty but chronically it's more central unless you have a reason for continued local cochlear NMDA receptor stimulation. That reason could be as simple as secondary effects of things like TMJ which can cause abnormal intracochlear pressure etc. Really absolutely anything that can perpetuate local cochlear inflammation.
And here is also where stress really might be more related too than just "mind set" and psychobabble.
In addition to promoting a less favorable Glutamate/GABA ratio, chronic severe stress causes the axons in your inner ear to release peptides called "dynorphins" which sensitize your NMDA receptor to glutamate. This means potentially less noise can perpetuate local cochlear inflammation. This might be a reason that tinnitus can be subject to the placebo effect among other things but also why, for some people, tinnitus gets a lot better, in actual volume I mean. While for others, it's less correlated (just to complicate things further people can also do things like clinch their jaw when stressed).
There are also somatic factors that sometimes improve like middle ear muscle dysfunction after acoustic trauma that can resolve, etc.
You've mentioned "super responders" quite a bit, but I'm not sure they exist.
During Phase I, a few participants who received FX-322 significantly improved word scores. There was a tremendous amount riding on them, and a great deal of hope, not only among participants but also audiologists evaluating them. It's possible unconscious (and conscious) bias skewed results, along with X factors we can never know. Maybe the participants had better night sleeps before the 2nd evaluation. Maybe they had more coffee. Maybe the evaluators made it easier for them, somehow. Maybe the focus on safety meant results were treated more casually. That doesn't mean participants were liars or the results were fraudulent. It means that it was a Phase I safety study with a handful of humans, evaluated by humans, with a great deal riding on them.
If 50% of the almost 100 participants in Phase II showed meaningful word score increases, that would be huge. But 50% of 6 people during Phase I just doesn't tell us all that much (which is why drug trials proceed to ever larger and more meaningful Phase II and Phase III studies).
- Dec 21, 2019
- 319
- Tinnitus Since
- 2014, 10/2019
- Cause of Tinnitus
- School Band, Noxious Car Radio
Thanks! I think my case is pretty similar to these rat studies (one major, short, trauma with temporary but pretty intense threshold shift) so they're helpful in trying to understand my situation.
Hopefully my SGNs stay in good order while I wait for treatment to roll around some day, but I won't hold my breathe... I really want a regenerative drug on the market so we can start seeing better testing developed.
- Aug 5, 2019
- 1,852
- Tinnitus Since
- 05/2019
- Cause of Tinnitus
- Autoimmune hyperacusis from Sjogren's Syndrome
I'm a little confused, since I've been saying the same things. When I say "super responders," (at the time this post is written, without more data) I really mean super improvers.
My belief is that clearly something is describing these doublings. All of the points you made are valid considerations. I've been insisting that Phase 2 efficacy matters so much more because the recruiting is biased towards finding responders.
Do I think it's possible that at least 1 of those 3 people had a super response to the drug? Absolutely. Do I think the "evidence is there," so everyone should invest their soul into this drug? Absolutely not.
I think you are misrepresenting my positions. I have admitted that my assumption, prior to the Phase 2 results, that the something was definitely the drug, has not been proven.
Agreed. I'm not sure it's helpful to vilify participants who joined the trial at real risk to themselves, or speculate that they're "liars." It's also possible other factors influenced improvements across both treated and placebo groups. It could be that after receiving the treatments, everyone was just super focused in their post-treatment evaluations, swept up in the potentially life-altering process, with evaluators similarly, subtly, pulling for the participants, all with the expectation scores would improve.
That aside, let's assume, for the sake of argument, some participants artificially deflated pre-treatment word scores. Thing is, I'm not sure that undermines the results.
Since no one knew if they were to receive FX-322 or a placebo, artificially deflated scores would be evenly distributed across both placebo and treatment groups. Subsequent score boosts would therefore also be evenly distributed, rather than aggregate only around the placebos. For example, let's say artificially deflating pre-treatment scores gives you, just to pick a number, an extra 10 points in the end. Those 10 points would occur evenly among all groups (as they actually did – all groups, placebo and treated, showed similar word score improvements).
However, if FX-322 actually worked, the trial design flaw cancels itself out, and you would see an additional response, above and beyond the artificial response, among the treated group (10 fake points across all groups + actual improvements for participants treated with FX-322).
I'm not arguing that FX-322 doesn't work, I'm arguing that the trial design flaw doesn't by itself explain the lack of results.
Humans have different SGNs than rodents and ours do not degrade for decades to maybe even never. Neuronal damage in humans is usually more immune mediated (MS, GBS etc) and I believe that's Rinri Therapeutics' target population as well.
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