Sound Pharmaceuticals (SPI-5557 & SPI-1005)

Does anyone have info when Sound Pharmaceuticals will be starting their phase 3 Meniere's trials or are they blowing that off for COVID-19 trials?

 

They haven't started recruiting yet, so the info isn't on clinicaltrials.gov yet. I don't think the COVID-19 trials are delaying that though.

 

I'm not sure either but I've never found anything to say that type II's can become desensitized again.

'Selective activation of P2Y receptors increased type II afferent excitability by the closure of KCNQ-type potassium channels, a potential mechanism for the painful hypersensitivity (that we term “noxacusis” to distinguish from hyperacusis without pain) that can accompany hearing loss. Exposure to the KCNQ channel activator retigabine suppressed the type II fiber’s response to hair cell damage.'

The 'activation' part of the above quote makes me think that once its activated, its activated for good. Also what convinces me more that it is permanent is the fact that no matter how well a noxacusis sufferer seems to recover, they are always at risk of relapse. I put this down to those type II's being permanently sensitized. (And the trigeminal nerve for that matter).

Just as aside, it's been suggested that if someone really wanted to, Hough Ear Institute Pill and SPI-1005 could be made independently in a lab. Could a Xenon or RL-81 style KCNQ activator be 'made' by someone at their own cost? (Or is it a secret formula compared to Hough Ear Institute Pill and SPI-1005)?

 

This makes sense to me - from my own experience, even though I have achieved what could be called 'recovery' before, I always knew I was susceptible to a setback versus someone with healthy ears. The key question to me is whether repairing the underlying cause/damage of hair-cell death could possibly desensitize our Type 2s back to the level of a healthy cochlea? Since, currently, even if we achieve superficial 'recovery' we're still walking around with damaged cochleas at the end of the day.

To be honest, I'm also hoping that regenerative drugs will work for us just because I don't really fancy the idea of having to take a powerful anti-epileptic drug potentially every day - and we don't even know what the side effects would be.

 

Perhaps this is wishful thinking, but I'm not convinced that once the fibres are activated then that is it. Without a doubt, cochlea damage has an element of permanence about it (at least until regenerative medicine hits the market), but from my little understanding of molecular biology and neurology, this has to do with upregulation of pain receptors - although it seems to be more commonly referred to as activation of pain fibres.

We know that ATP is actually required for a P2X purinoreceptor to be activated. So this is what is being activated (or upregulated) - the P2X purinoreceptor. But we also know that pain receptors can be upregulated or downregulated. To quote you @100Hz from a different thread, we also know that sensitivity to ATP is reduced in type II afferents after the onset of hearing (this is very interesting to me). But we also know that "sensitivity" - presumably P2X activation - increases after "noise exposure", which clearly, at first glance, seems to contradict the previous statement, and so therefore raises some important questions regarding the pathology of hyperacusis and ear pain in general.

My question therefore is whether the body has natural self-correcting mechanisms to turn off (downregulate) pain receptors once a particular area has healed. The only instance I am aware of where people still experience pain after the initial injury has "healed" is amputees who suffer from phantom limb pain.

Perhaps there are others as well, but generally speaking it seems that one of two things happen when peripheral damage in the body heals: either our pain receptors in those areas become downregulated or some kind of neuroplastic changes happen in the brain in recognition that that area is no longer in danger. It is for this reason I believe that a drug like FX-322 may not only enable physiological changes in the cochlea, but the increased input to the brain will cause neuroplastic changes that will help those who are not cured directly from the peripheral treatment that the drug is primarily designed for.

There have been arguments made that some types of pain can become centralised, raising the question then as to whether the pain will continue once the peripheral damage has been treated. As @serendipity1996 has pointed out to me and others on here previously, and who also drew my attention to this article, patients who undergo a hip replacement always see a complete resolution of their hip pain, regardless of how bad or how long they had their hip pain previously, suggesting therefore that centralised pain either doesn't occur in these types of patients or is in fact reversible due to the brain's ability to adapt.

I will be the first to admit that some of the above may be wishful thinking. I hope someone more qualified in this area can shed some additional light.

 

I couldn't agree more @serendipity1996. Ideally it would be fixed with a fully regenerative treatment. I was thinking the same thing today, its all good and well that say RL-81 now means no more noxacusis but what if there are nasty side effects for life from it? (I'd like to think that if I could get music back in my life, the side effects would be worth it though!)

I can still see how a combination of FX-322 and XEN / RL-81 might work together because if fixing up the cochlea would reduce the amount of excess / leaking ATP then that baseline for potential setbacks would hopefully be reduced, and then for loud noise exposure where the nociceptors were triggered again, the XEN / RL-81 could be taken.

Yes I do believe that the sensitivity of type II afferents are upregulated by their exposure to excess ATP. This rings true for all people who can still enjoy loud music even though they know its loud (all of us before we got noxacusis), who shrug it off and the ear gets over the overexposure. It happens again and again, maybe for many years but then for the unlucky few it eventually snaps, and something irreversible happens. I may be reading the research wrong but there appears to be a difference between a pain receptors sensitivity being upregulated vs. being fully sensitized. Its like a dimmer that gets finally jammed in the full 'on' position. I don't know though, it seems to be a very complex relationship between the excess ATP and whatever possible states the type II's may be in.

The centralized thing though I don't know what to make of because of how well the symptoms can recover naturally with enough care taken around noise. I still believe that as symptoms recover that it is a direct result of lessening inflammation, that lessening of inflammation in turn becomes less and less likely to aggravate the thing that is permanently broken (the sensitized type II's). When we appear recovered and then listen to something loud and have a setback, its generally never anything that would be loud enough to typically hurt a normal pair of ears so is that crucial difference between us and healthy hearing people the sensitized type II's? It is just a theory in end, and I'd love to see research to reveal whether type II's once sensitized, remain sensitized or not.

 

This is going to be interesting to see if it does do this, I really hope this is what happens once we finally get to test and see what it does indeed fix for noxacusis.

 

I really hope this is not the case.

 

I think our lack of knowledge on this really owes more to the fact that this is, ultimately, a super niche and rare disorder. It was only 5 years ago that they determined that the type 2 fibres behave like pain fibres so it's all very new. The Fuchs lab at Johns Hopkins are studying the role of the Type 2s and inflammation so I am assuming further research will emerge in the next few years that should hopefully answer these questions. Fingers crossed.

 

At the end of the day this is all just speculation on some forum. I appreciate the fact that they use scientific papers to back their assertions up, but when it comes down to it we simply don't know. FX-322 will probably be out before any study concluding whether the fibers are permanently sensitized, so I try to rest easy knowing that these drugs will give us our lives back when they come. That's enough to think about on its own.

 

My dad did get his hip done. Definitely doesn't have any issues with walking, with moving or any pain problems whatsoever and this was done almost 20 years ago. As a result I think that it is fairly reasonable to conclude that there totally could be a situation where if you correct an injury it is going to result in normality. I think in fact that you can even go much more simpler than that and also again look at a cut on the finger for example which is sore and painful while the injury is present and then things tend to return to normal when it heals.

I think that the thing we should also evaluate is the fact that something like this has never been done before either. Essentially I think that there could be some surprising outcomes out of cochlear regeneration if it is to happen and I also actually think that you cannot rule anything out or in until it gets done. There seems to be a situation at present when it comes to ear stuff whereby research previously put forward one theory about something and then as further research got done or as things were then discovered we then found out that the previous research was not entirely reflective of the current situation. So I think that this area tends to be not something which we should look at as the research being hard and fast.

I am also actually not going to be considering making my own Hough Pill or SPI-1005 no matter how easy this is because of the cost and risk behind doing it lol .

The research outcomes are often behind the outcomes we see from trials. I think that there is a real possibility that the medicine will actually show some of these research outcomes are wrong and also that it will answer the questions about some of these theories that have been put forward about things.

 

Yeah - I'm inclined to agree and I reckon that even if you picked the brains of the top researchers like Charles Liberman, even they probably couldn't give us a definitive answer at this point in time. But it's reassuring to know that it's being actively worked on.

 

One of the things that has been playing on my mind @100Hz for a while now is your post from another thread, which I will repeat again here as I still haven't had anyone else's thoughts on this:

"Likewise, measured ex vivo, synaptic excitation is weak and could activate type II afferents only if all of the presynaptic OHCs were maximally stimulated. Alternatively, ATP potently activates type II afferents and serves as a major contributor to the damage-induced response."

I'm curious to further understand how the ATP "leak" theory fits in with this maximal stimulation theory. Does maximal stimulation mean that every single OHC needs to be exposed to some kind of threshold of sound, or do some OHCs need to be stimulated to their maximum "capacity"? The quote clearly says "only if all the presynpatic OHCs", so I presume it's the former. I wonder why then every single OHC would need to be maximally stimulated and not, say, some or most of them. I also wonder how this fits into your theory above that, "for the unlucky few it eventually snaps, and something irreversible happens". Is maximal stimulation of all presynaptic OHCs a precursor (a box that needs to be ticked, shall we say) in order for the sensitisation to occur through whatever molecular/cellular process happens next (say OHC ablation, although it would appear this is not always necessary), or is it the maximal stimulation the end point in itself because this upregulates the receptors for the first time?

If sensitisation of the fibres is permanent, why do some people seem to partially recover from hyperacusis but maintain a particular sensitivity to certain frequencies? Surely once a nerve fibre is sensitised from ATP, it doesn't discriminate between ATP from different OHCs which correspond to difference frequencies. It will simply respond to ATP wherever it comes from. In other words, sensitisation of the pain fibres (or upregulation of the pain receptors) only occurs when ATP, from whatever cell, leaks onto the type II fibres. In many of those who partially recover, that only continues to happen when those sufferers are exposed to higher frequencies - so why is it then that OHCs responsible for transmiting high frequencies seem to continue to leak ATP for a longer period of time, post-trauma, than lower frequencies? I wonder if it has anything to do with that old formula from school that explained that higher frequencies require more energy. ATP is of course the fuel for cells, so perhaps some OHCs require more ATP (and therefore more ATP leaks) to translate information at higher frequencies.

It's late at night and I'm kind of vomiting some layman thoughts on paper here, but I welcome any enlightenment/open discussion on these points.

 

Just to tag on to your second paragraph - my hyperacusis has improved significantly over the best part of the year - to the extent that the sensitivity I had to artificial audio, in particular, has now started to subside significantly in the past few months - I wouldn't say it's completely gone but this was my most troublesome issue - my ears would react like crazy and feel 'raw', and my reactive tinnitus and facial/trigeminal nerve symptoms would spike loads. But for a long time, a good 6 + months, these particular frequencies would be very problematic for me even while most everyday noises were manageable. So I feel pretty much almostback to how I was before this miserable setback started but it's interesting that over time even the sensitivity to certain frequencies has improved as I assumed I would be stuck with it forever. But that's only been a relatively recent development. I wonder what that could possibly suggest about what's going on here and the mechanisms of it all.

 

This is a good conversation, and I'm also curious what people's thoughts are with regards to the mid ear problems that come with hyperacusis. Things like TTTS/fluttering, trigeminal nerve pain, etc. It is unclear to me why cochlear damage would have such a profound effect on the middle ear as well, but clearly it does. I'm wondering if these symptoms are reversible in addition to the sensitized type IIs.

 

@weab00 - Yeh it is just speculation at the end of the day, using what little research we have to back it up. I wonder what's the point in doing it sometimes as well, and how reliable the research is that it's all based on. Just wait for the drugs to see what they do would be the easier option, but all we / I really have at the moment is time to put everything we've got into trying to ascertain if it could be possible to dig our way out of this hole one day one day, and I do think we can be of use to the research effort as we are the ones who have these bizarre symptoms and are able to back up the theories with them. Those 2 bits of research I focus on seem to have the most credible weight behind them (unlike some others which are easy to blow to pieces as you know), and I think that the direction Paul Fuchs is pushing in is very positive. I really look forward to future research from John Hopkins about the ATP-nociceptor relationship.

All I'll say is that 6 months ago I had no hope for noxacusis. None, it didn't seem to fit in anywhere in terms of upcoming treatments. Now I do have some hope though. I believe the middle ear AND cochlea damage research applies to us with acoustic shock induced noxacusis. And if FX-322 does fix it all then that would be the best outcome (which we are all hoping for). And if it doesn't quite do the job then I now think that SPI-1005 and XEN etc. will be catch-alls for what's left behind. I know I appear negative about FX-322 in my posts sometimes, but don't take it that way as I'm not trying to be as I think it will do lots for us. It's just that in case it doesn't quite do everything, at least all other bases seem to be covered by other drugs.

@Aaron91 - I posted this for you the other day but I'm not sure you saw it.

@Aaron91 Here's a recent quote that @Diesel found, I believe from John Hopkins. "Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels."

It's a good question though, and I don't know if ALL OHCs need to be maximally stimulated, but the above quote was the first time I'd heard of this and it's kind of been ingrained in my head that it's only a certain number of OHCs that need to be stimulated to sensitize their corresponding type II afferent.

The reason I believe that people get frequency specific sensitivity and setbacks is down to specific OHC damage and the release of ATP from their support cells (or maybe somewhere else) due to the noise at that specific frequency, this is where I definitely think FX-322 will help. Its that physical event of noise stimulating the support cells that causing the excess ATP release which is why we get the pain and possibly setback at that frequency. I agree with you though if there's regular ATP anyway why are the type IIs not permanently stimulated? My guess is that its a massive burst of ATP at that frequency that floods / reaches / touches?? the type II afferent. I really don't know but I think it's where the big questions are heading now. This is as good as provable I believe, because if regular ATP were to stimulate the nociceptors we'd be getting setbacks all the time at whatever frequency, but this doesn't typically happen (maybe in ultra severe cases after setbacks etc?), and as recovery goes on things seem to become more and more defined / refined in terms of how specific frequencies are causing various sensitivities and pains etc., and I sort of imagine that this is due to a very slowly reducing 'ATP baseline'.

@serendipity1996 your current situation sounds really similar to mine. If this were my first time around I'd believe I was recovering right now. I just know though that I'm one moment of complacency away from having to start all over again though.

Me neither (yet!), I was just wondering if it was possible for that as well

 

@weab00 - Have another read of those models, because if you're unsure about the above in particular then they hypothesize on this exact point.

 

I think that the treatment of outer hair cells will provide beneficial outcomes which are also significant. I totally agree that FX-322 won’t do everything. Essentially we know that FX-322 won’t fix all the problems anyhow because it cannot regrow synapses which are missing from good hair cells so this is going to mean that people are still going to have problems even with a very beneficial result from FX-322.

 

This, or RL-81, needs to work. So tired of all the never ending face pain, ear spasms, and migraines. It needs to stop. Hyperacusis and TTTS are literally the worst effing things on the planet.

 

@100Hz I did indeed miss that, so thank you for bringing it to my attention. Thank you also for reminding me that OHCs have their own corresponding type II afferent as it made me re-open up this diagram I saved some time ago and which I've now copied in below.



What I had forgotten was that type II afferents have tributaries, much like a river, to different pools of OHCs.

With this in mind, I come now to the quote from John Hopkins: "Type II nerves will not be activated unless the entire pool of OHCs they are connected to are maximally stimulated by only the most intense sound levels."

When I first read this, I thought it was suggesting that hyperacusis is the product of ALL the type II afferents becoming "sensitised" at the same time (as opposed to some type II afferents becoming sensitised some of the time). I now realise I had read this wrong and what it's really saying is that for a particular type II afferent to become sensitised, its pool of OHCs (however many) must be maximally stimulated. I suppose this maximal stimulation is a prerequisite for ATP leakage, however that occurs. That ATP leakage then upregulates the P2X pain receptors.

This is really making sense to me now. This would also explain why in the year leading up to my own hyperacusis, I would notice the odd occasion where people scraping their plates or putting dishes away would bother me - that particular type II afferent must have been sensitised because its entire pool of OHCs must have been leaking ATP.

What I want to know is: does every single type II afferent have to become sensitised for us to then to experience debilitating hyperacusis, or just some of them? I ask this question because hyperacusis never seems to be a "progressive" condition. What I mean by a progressive is a condition whereby the hyperacusis starts off mildly but gradually and steadily gets noticeably worse over time until the point of complete despair. I think for almost most people, including myself (despite my observation above), we go from complete normality to absolute devastation in an instant. This would suggest to me that either all the type II afferents become sensitised in an instant (and therefore ALL OHCs are maximally stimulated in that instant) or something else is going. But what I also know is that acoustic trauma - and therefore, presumably, maximal OHC stimulation - isn't a prerequisite to developing hyperacusis. I know that many get it after normal headphone use. This would suggest to me that something else IS indeed going on - but where? In the spiral ganglions which connect to the type II afferents? Is something going on in the brain? I know that there is inflammation and other stuff going on in the cochlea from prolonged/acute noise exposure. But it would appear cochlea inflammation can exist without hyperacusis and, when this drug comes out, we will also know whether hyperacusis can exist without cochlea inflammation.

This condition truly boggles my mind, and I can't wait for science to solve it.

 

My hyperacusis came on gradually. Much like you describe about noting that kitchen sounds bothered you, I had the same problem but with certain people's voices at parties and taking showers in the morning like a year before it got real bad. I never thought much of it in those days. When it did get real bad, it happened rather quickly but I'd still call it gradually.

 

My first bout of hyperacusis also came on fairly gradually - initially, I noticed that cutlery sounded jarring and emptying the dishwasher was unpleasant.

 

So, if I am understanding the description here correctly, it could mean that it might take only 1 OHC being reconnected to the “pool” of Type-2 nerves to begin resolving hyperacusis/noxacusis?

Since the nerve seems to only become over-sensitized from the entire “pool” of OHC dying, then doesn’t it stand to reason that restoring connection to at least one through regeneration, and thereby providing a “signal” would provide notable treatment?

 

I think that would bode well for FX-322 if that were the case.

 

This is a tough question. My understanding is that the sensitisation is the result of ATP "leakage" because ATP is required for upregulation of P2x receptors. One of my long-standing questions with this theory is: what does one mean by ATP leakage? Does it mean an overflow of ATP from the OHCs to surrounding areas, or have the OHCs been structurally compromised and they're actually leaking - the same way a car engine has a leak, for example - ATP?

In which case, I'm not too sure whether it's so much a case of the OHC restoring connection than it is simply restoring the structural integrity of the OHC. If it really is a case of restoring structural integrity of OHCs, that may bode well for potential FX-322 patients as supposedly FX-322 helps not just to regenerate new cells but damaged ones as well. However, @100Hz also mentioned, if I'm not mistaken, that the ATP leakage doesn't always necessarily come from the OHCs - it can come from the supporting cells. This is another reason why I really want to know the answer to this ATP leak theory because it scares me to think that the support cells which FX-322 requires to be effective may be compromised if they are leaking ATP!

 

Yes, the 2015 Johns Hopkins paper states that "...type II afferents are activated when outer hair cells are damaged. This response depends on both ionotropic (P2X) and metabotropic (P2Y) purinergic receptors, binding ATP released from nearby supporting cells in response to hair cell damage."

But I'm not really sure if or how that would have implications for regenerative drugs.

 

We would need to understand which specific support cells are leaking. Not all support cells are progenitor cells. I would think that if there were damaged progenitor support cells that were damaged, FX-322 might not be as effective.

Also, Frequency Therapeutics has shown that during the progenitor cell activation process, the Support/Progenitor cell creates the hair cell and a copy of itself. So, you would essentially get two good cells out of the process. Frequency Therapeutics has also mentioned this in their patents, the concept of the support/progenitor cell making a support cell.

 

In this paper, the only reference I could find to a particular type of supporting cell is under the 'Discussion' heading, mentioning Hensen's cells: "Experimental ablation of OHCs was shown to initiate ATP-dependent calcium waves in nearby Hensen’s cells that further triggers release of ATP through their connexin hemichannels."

To be quite honest, I'm not quite sure exactly what this all means, especially with the references to connexin hemichannels but perhaps those are the support cells which play a role in ATP leakage?

Unmyelinated type II afferent neurons report cochlear damage

 

I know man, it feels like we're all going deeper and deeper into the matrix the more time goes by, and the more information that gets found out. Me I'm just hoping that FX-322, OTO-413, and SPI-1005 are enough to restore my ears back to near squeaky clean meaning excellent hearing, no ringing, no spasming, no pain. Gonna be a long journey but we're about 3-5 years away max from some results.

 

Not to be pedantic, but it's interesting the wording used there is "further trigger" and not "trigger further". This would suggest that it is indeed the Hensen cells that are releasing ATP and not some other cells as well as Hensen cells, unless this is some kind of editorial oversight. However, at the same time, it says the calcium waves in the Hensen cells are ATP-dependent, so to counter what I've just said in the previous sentence, presumably ATP must come first from the OHCs for the Hensen cells to then produce their own? The connexin hemichannels I believe are the gap junctions, which again wikipedia tells me is the cell to cell pathway for electrical currents, small molecules and ions.

A quick Qikipedia search seems to suggest that Hensen cells are responsible for regenerating hair cells in vertebrates, so are progenitor cells the same as Hensen cells or are they something different?