Sound Pharmaceuticals (SPI-5557 & SPI-1005)

Damage-sensing Nerve Cells in Inner Ear Send Messages to Brain

This is an article actually about ATP leakage from the ear. Essentially this article also predates most of regenerative hearing medicine development and research, however I have a feeling that this tends to suggest that the repairing of hair cells could contribute to assisting with the treatment of this.

There tends to also be a fair likelihood according to the report that treating the ear will probably assist with understanding much more about whether treating the ear will assist and/or whether you might need additional medication outside of the hair cell and synapse medicines.

Thus with successful medicines I think that this will take us a long way towards knowing more about hyperacusis.

 

I'm on the same page as you in that case. One of the things that bugs me as well is the sensitized Type IIs and what would be their potential response to a normalized cochlea where loud noise was concerned. I actually think I've been there. My first recovery was SO good, I even got to another gig, a loud gig, something I never thought I'd ever do again. It raised my symptoms slightly but I got over it in a few days. But then some months later got bitten really hard again as I thought I was fixed and pushed it too hard. My point is that it was inconceivable that I could recover that well for the first 18 months but then like magic it happened. I'm currently at month 14 now on the same timeline so I'm interested in what happens in Feb 21. I will be forever cautious no matter what now though. But could it be those sensitized Type IIs coming back to haunt us?

 

...maybe what all noxacusis sufferers are really waiting for is the channel blockers. (Probably combined with an anti inflammatory of course).

 

Are they investigating channel blockers?

 

Vistagen also has a non-addictive GABA drug for neuropathic pain in the pipeline called AV-101 that looks quite promising. Basically Lyrica with way fewer side effects. It's being fast-tracked.

 

At the end of the day, we KNOW the channel blockers can work for many people, based on Trobalt. So, it is nice to know that XEN-1101 is very likely to work for us. But, I still wouldn't count out SPI-1005 or the regenerative drugs. At the very least, if one of them doesn't work, by process of elimination it will shed light on what the heck is going on.

 

I think there is a good chance regenerative medicine will be hugely helpful but that we'll wind up using SPI-1005 and XEN-496 in the short term.

 

Don’t forget XEN-496.

 

XEN-496 is literally just trobalt. I have bad visual snow so I can’t risk taking that stuff, but good luck to the brave souls who do try it. Although I’m barely clinging to life as it is so perhaps I’ll be forced to.

 

I still believe that to stop pain hyperacusis you need to fix the fundamental issues in the ear such as OHCs, IHCs and synapses. I don’t think it is inflammation that’s causing the problem but it would be good to find out anyways.

 

XEN-496 and XEN-1101 seem to be quite similar as you're probably aware, and RL-81 also seems to be much the same thing. A big difference I can see is that RL-81 is being developed with tinnitus in mind whereas the Xenon drugs are for epilepsy.

"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. Type II afferents may be the cochlea’s nociceptors, prompting avoidance of further damage to the irreparable inner ear."

"KCNQ activators would be expected to silence type II afferents among other targets."​

I see quotes like the above here and there in various papers, and I'm quite surprised by the lack of excitement about it for noxacusis because it seems to be suggesting the answer (or a huge part of it) right there. (I'm never sure whether to refer to these as blockers or openers/activators either. From what I read the aim is to 'open' the channels so is the term 'blocker' used as in blocking the thing that's activating the P2Y receptors that causes the closure of the channel, glutamate?)

I think the focus is now homing in on the relationship between cochlea ATP and sensitized type II afferents. Setbacks happen I do believe, down to this relationship, but it's not as simple as it seems and could be down to a couple of fundamentally different contributing factors. I've been thinking more about how ATP is a natural thing that is required for normal hearing in the cochlea anyway so it's not purely ATP presence that is causing any significant damage, it seems more likely that it's the amount of ATP or the broken regulation of ATP / excess / leaking ATP that's causing the problem (particularly when it comes to actual sensitization, I think there must be some kind of overload). But I really think the most crucial part of the problem is the sensitized type II afferents. From what I've read, everybody is susceptible to noise induced excess ATP from time to time, but it's the sensitized type II afferents that seem to be the crucial difference between what makes loud noise loud but tolerable, enjoyable even, to normal ears vs. loud and painful to damaged ears. Several things I've read recently also seem to suggest that OHC death is not necessarily a certainty with additional ATP build up which could explain why the type II's can seemingly become sensitized, bringing with it the joys of noxacusis, while retaining very good hearing.

@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." I'd be interested to know if they necessarily do die or could possibly sensitize the type II while remaining intact.

@FGG has really helped with this and I finally think I get where she is coming from. To give you a scenario, say you had FX-322 and SPI-1005, and fixed all your hair cells and ATP returned to a normal level in the cochlea, and there was no other leakage. Normal noise is now back to normal, but my worry would still be that once you started to experience the kind of levels that were simply loud but not painful to normal people who would shrug off any excess ATP, we would once again be at the mercy of our sensitized type II afferents and their nociceptor response to it. We wouldn't get away it because that crucial part is still broken and would respond differently than un-sensitized type II's.

I can see FX-322 being good for hopefully lessening the amount of excess ATP leakage by support cells, and I can see SPI-1005 being good for clearing up inflammation, so basically it's a win anyway because the typical 'recovery' timeline would be reduced from years / months down to however long it took for these meds to work, and FX-322's part of the fix would be permanent and SPI-1005 part of the fix would be presumably either ongoing or as needed. I still think we'd be susceptible to setbacks though if not careful with noise due to the sensitized type II's, which is where Xenon or RL-81 would need to fit in.

 

I don’t understand the nuts and bolts of what sensitization really means for the type II fibers but maybe it’s self-correcting once the OHCs are restored.

 

I really do hope that restoring the OHCs will self-correct itself and stop pain hyperacusis.

 

I just hope any of these upcoming treatments put an end to reactive tinnitus. I'd do a lot to take a shower without spiking, or listen to music without my tinnitus competing to be heard.

 

Inflammation isn't causing the problem but it's a byproduct of it, so reducing it should help a lot even if it's just a bandaid until regenerative medicine.

 

Magnesium may partially help with setbacks (every little bit helps):

Magnesium and hearing loss

And it's probably a good idea for most of us to take some (a highly absorbable kind otherwise it's just a laxative).

 

There has been some confusion about SPI-1005 possibly depleting support cells and it occurred to me that maybe some people don't realize Sound Pharmaceuticals has two different drugs for hearing related disorders and are getting them confused.

So, in case this helps anyone, even if that someone is just me, who is having insomnia tonight :

SPI-1005 is ebselen, a drug that can be given orally that has anti-inflammatory, vascular effects (through actions on vascular calcium channels) and effects on glutamate induced neuro-hyperexcitability. It's a glutathione peroxidase inducer as well and has redox effects on receptors like the NMDA receptor.

The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site

SPI-5557 is an intratympanic RNA silencing drug that is very similar to Hough Ear Institute's pre-clinical injection (different from their pill). Hough Ear Institute's injection reportedly transforms support cells into hair cells, thus potentially deleting them (although it's possible it proliferated them first but that wasn't mentioned in the blurb I read) but it looks like that may not be a problem with SPI-5557. At least in rats so far.

 

I didn't think SPI-5557 was even close to being released yet, unlike SPI-1005 which according to Sound Pharmaceuticals' web page is in phase 3 trial status, and very close to being released.

 

I didn't include that but yes they are in different phases too.

 

If you had to guess, when’s the soonest we could see SPI-1005 available for off-label use? I know it’s being fast-tracked because of COVID-19, but like others have said I’m worried it will be for COVID-19 only initially.

 

This isn’t expected to have much to do with the...

...correct? Glutamate seems to do everything so...

 

It's not a potassium ion channel drug if that's what you are asking.

 

No, I just thought that reducing hyper-excitability in the most common neurotransmitter in the cochlea might have something to do with whatever biochemistry that either caused the initial sensitization or is keeping the fibers sensitized.

Edit: Trobalt seemed to only have temporary effects so something must be perpetuating the sensitivity even when you temporarily affect the potassium channels.

I suppose I should reread the mouse study about how it reduced aminoglycoside-induced hyperacusis. Perhaps there is a common mechanism across all types of hyperacusis caused by damage.

 

Trobalt works on the brainstem ion channels. The brainstem receives signals from a damaged cochlea that contribute to hyperexcitability there.

I'm not sure what effects, if any, ebselen would have directly on the brainstem but normalizing the cochlea in some people is bound to reduce the hyperexcitabilty there.

 

It seems I’ve made a fundamental misunderstanding about where the potassium channel drugs do their work. Thank you for the clarification.

So there will have to be a top down approach to desensitizing input from the type II fibers if cochlear regeneration doesn’t do the trick. Perhaps there is some truth to the limbic system/central gain theory, even if it needs to be implemented only after the damage is repaired.

Unless upcoming treatments for neuropathic pain like Vistagen’s drugs can do the trick.

 

Does this therefore mean that in Sound Pharmaceuticals' hair cell treatment support cells can remain untouched and intact? Thus they do not get depleted when you get this treatment?

 

I’d hope that the FDA don't allow it to get used through the fast track for COVID-19 only.

 

I'm not totally sure. Their hair cell treatment (SPI-5557) is still pre-clinical so there isn't much info at this point.

 

Incidentally, Paul Fuchs has spoken about using magnetic nanoparticles for drug delivery to the inner ear in order to avoid systemic effects, so it seems implied that his lab are focusing on developing channel blockers that could be locally delivered although I'm not too sure. I assume they're ultimately aiming to get a drug into clinical trials.

 

Now nanoparticles are something that has been extensively looked into here too to treat a number of issues in the ears. Essentially I have heard how a few ENTs who are actually also involved in treatment development definitely believe that the treatment of the ear is possible but the drug delivery definitely tends to be a barrier. Therefore they have looked at and evaluated multiple possible delivery methods which might work and they think that nanoparticles is definitely one that might work. 6 or 7 years worth of work has gone into this now as well.

Thus it wouldn't be a surprise if medicines were in the near future delivered via nanoparticles, though I think that there might be bigger benefits demonstrated through treatments via intratympanic injection that could mitigate and overcome the need to move away from intratympanic injections to another technique like nanoparticles.

This is especially the case now that Otonomy has started to demonstrate the effectiveness of an intratympanic injection using late release gel medicine to get the medicine deep within the ear. Possibly Frequency Therapeutics will also be able to demonstrate the benefit associated with standard intratympanic injections when utilising multiple doses.

At this point I think that there will be big and hopefully rapid work done on the improvement of drug dosing and drug delivery within the ear if it is necessary. Nanoparticles could conceivably be a beneficial option if they actually allow for a much simpler and more effective single dose to allow the medicine to get in the ear deeper and also more simply.