Sound Pharmaceuticals (SPI-5557 & SPI-1005)

[Croaker]

I'm trying to fully grasp in what ways SPI-1005 would be beneficial for noxacusis sufferers and how that would manifest into our everyday lives.

It will essentially eliminate inflammation so that means no more pain unless we re-aggravate it? And what are the implications of that in our day to day life? Does it mean we'd no longer be housebound assuming the drug is effective? And how often would you take it? Presumably right after a noise injury right.

Read the Ebselen description at the top of page 10. The only hard data available is from the mouse study and the Meniere's trials. This forum as usual is getting way ahead of itself and speculating on release schedules before we even know if the drug will help us.

These questions can't be answered until a bunch of people with hyperacusis get their hands on it, either through a trial or off label use.

 

[weab00]

Read the Ebselen description at the top of page 10. The only hard data available is from the mouse study and the Meniere's trials. This forum as usual is getting way ahead of itself and speculating on release schedules before we even know if the drug will help us.

These questions can't be answered until a bunch of people with hyperacusis get their hands on it, either through a trial or off label use.

The optimism seems founded if the science checks out. Of course we will have to wait and see, hopefully sometime in 2021.

 

[tommyd87]

Read the Ebselen description at the top of page 10. The only hard data available is from the mouse study and the Meniere's trials. This forum as usual is getting way ahead of itself and speculating on release schedules before we even know if the drug will help us.

These questions can't be answered until a bunch of people with hyperacusis get their hands on it, either through a trial or off label use.

I think that there would be a lot of benefit if Sound Pharmaceuticals came out and indicated what they are going to do with SPI-1005 going forward. I know that they are pretty busy with testing it for multiple indications and particularly for COVID-19 at the moment but it would be nice to know what they are going to do when it comes to trialling this for its many other indications like hearing loss and also cystic fibrosis.

 

[Born To Slay]

Read the Ebselen description at the top of page 10. The only hard data available is from the mouse study and the Meniere's trials. This forum as usual is getting way ahead of itself and speculating on release schedules before we even know if the drug will help us.

These questions can't be answered until a bunch of people with hyperacusis get their hands on it, either through a trial or off label use.

Considering the fact that no other drug has shown in a trial to reduce tinnitus for any reason (correct me if I'm wrong), people on this forum have the right to be excited. Especially considering the fact that this drug should also definitely be available in the next six months.

There are researchers that believe inflammation has a large role in pain hyperacusis, so a drug that reduces cochlear inflammation could be a game changer for them.

Pessimism doesn't equal realism.

 

[Born To Slay]

The optimism seems founded if the science checks out. Of course we will have to wait and see, hopefully sometime in 2021.

Never lose your optimism buddy, so many different treatments are coming out soon and they all work in a variety different ways. If your problem is cochlear inflammation, it'll be fixed. If it's hair cells, fixed. Synapses, fixed. Potassium channels, treated. Being optimistic is the realistic approach right now.

 

[wwtsai]

Apologize for the backtracking but looking over the press release for their Phase 2b Meniere's trial, they only cover the primary outcome results for safety, PTA, and word recognition. Has there been any mention elsewhere about what the results were for TFI and loudness as those were also primary outcomes?

 

[Rb86]

Never lose your optimism buddy, so many different treatments are coming out soon and they all work in a variety different ways. If your problem is cochlear inflammation, it'll be fixed. If it's hair cells, fixed. Synapses, fixed. Potassium channels, treated. Being optimistic is the realistic approach right now.

I appreciate your positivity. I don't know the subgroups of tinnitus damage too well.

Which company is looking to treat cochlear inflammation and synapses?

 

[Born To Slay]

I appreciate your positivity. I don't know the subgroups of tinnitus damage too well.

Which company is looking to treat cochlear inflammation and synapses?

Inflammation is covered by Sound Pharmaceuticals with their SPI-1005, this one may be becoming very soon because it can also be used for Covid.

There's a few working on synapses, the two I follow most closely are Otonomy with OTO-413 and Hough Ear Institute with their regeneration pill.

 

[HootOwl]

Inflammation is covered by Sound Pharmaceuticals with their SPI-1005, this one may be becoming very soon because it can also be used for Covid.

There's a few working on synapses, the two I follow most closely are Otonomy with OTO-413 and Hough Ear Institute with their regeneration pill.

Quick add-on from me:

For inflammation, we also have Otividex (OTO-104) and the Hough Ear Institute Pill. Although I think the Hough Ear Institute Pill is treating cochlear inflammation directly rather than neuro-inflammation like Sound Pharmaceutical's is.

And for synapses you're also looking at PIPE-505 - which also does minor OHC regeneration as well.

 

[weab00]

Quick add-on from me:

For inflammation, we also have Otividex (OTO-104) and the Hough Ear Institute Pill. Although I think the Hough Ear Institute Pill is treating cochlear inflammation directly rather than neuro-inflammation like Sound Pharmaceutical's is.

And for synapses you're also looking at PIPE-505 - which also does minor OHC regeneration as well.

I am most excited by SPI-1005 at present because it seems likely to help with hyperacusis and is coming to market very soon.

 

[xyz]

Quick add-on from me:

For inflammation, we also have Otividex (OTO-104) and the Hough Ear Institute Pill. Although I think the Hough Ear Institute Pill is treating cochlear inflammation directly rather than neuro-inflammation like Sound Pharmaceutical's is.

And for synapses you're also looking at PIPE-505 - which also does minor OHC regeneration as well.

Could it be that apart from the inner ear also the auditory cortex could be inflamed and we need something to calm this down?

 

[tommyd87]

Quick add-on from me:

For inflammation, we also have Otividex (OTO-104) and the Hough Ear Institute Pill. Although I think the Hough Ear Institute Pill is treating cochlear inflammation directly rather than neuro-inflammation like Sound Pharmaceutical's is.

And for synapses you're also looking at PIPE-505 - which also does minor OHC regeneration as well.

Where is the evidence that Hough Ear Institute is treating inflammation, thanks? I thought that they were just treating the synapses?

 

[HootOwl]

Where is the evidence that Hough Ear Institute is treating inflammation, thanks? I thought that they were just treating the synapses?

The main compound of the pill (HPN-07) is a free radical scavenger, and free radicals are heavily implicated in oxidative stress and inflammation.

The synaptic regeneration was I believe a secondary and surprising outcome to the initial study on the compound, which was mostly concerned with its effect on free radical trapping and reducing cochlear and other ototoxic inflammation before hair cells were actually lost.

It has been a while since I looked into their studies though so feel free to correct me.

 

[HootOwl]

Could it be that apart from the inner ear also the auditory cortex could be inflamed and we need something to calm this down?

@FGG could answer that better than I can. Hopefully they'll see this.

 

[HootOwl]

I am most excited by SPI-1005 at present because it seems likely to help with hyperacusis and is coming to market very soon.

It will be a lot of people's go-to drug for their first pass on treating their hearing disorders to be sure. I certainly plan to take it as soon as it comes out, as well as always have some on hand for spikes.

But I wanted to ease the minds of people by showing that the options for treating inflammation that will eventually be available (should everything make it to market) will be even more expansive.

Every little bit helps.

 

[FGG]

@FGG could answer that better than I can. Hopefully they'll see this.

I have nothing to add. I thought you explained it well.

 

[Diesel]

Can someone point me to any detailed results on the prior clinical trials for SPI-1005?

I see on their website, that prior to a COVID-19 treatment, SPI-1005 seemed to be effective in treating Meniere's Disease and Bipolar disorder.

Sound Pharmaceuticals cites a statistically significant reduction in Tinnitus Loudness for Meniere's in their Phase 2b. Does the tinnitus experienced by Meniere's patients translate to those with tinnitus from more common hearing loss?

 

[FGG]

Can someone point me to any detailed results on the prior clinical trials for SPI-1005?

I see on their website, that prior to a COVID-19 treatment, SPI-1005 seemed to be effective in treating Meniere's Disease and Bipolar disorder.

Sound Pharmaceuticals cites a statistically significant reduction in Tinnitus Loudness for Meniere's in their Phase 2b. Does the tinnitus experienced by Meniere's patients translate to those with tinnitus from more common hearing loss?

I don't think there are more specifics than that but Ebselen has both anti inflammatory and vascular effects, both of which are factors in Meniere's pathology.

As far as more common hearing loss, if you had hair cell damage without as much cochlear neuroinflammation, I'm not sure the drug would help. But if it continues to be proven safe, I think it's good to have additional drugs in the arsenal.

They are currently recruiting for acute noise induced loss where the inflammation would be more universal.

 

[tommyd87]

The main compound of the pill (HPN-07) is a free radical scavenger, and free radicals are heavily implicated in oxidative stress and inflammation.

The synaptic regeneration was I believe a secondary and surprising outcome to the initial study on the compound, which was mostly concerned with its effect on free radical trapping and reducing cochlear and other ototoxic inflammation before hair cells were actually lost.

It has been a while since I looked into their studies though so feel free to correct me.

This is explained exceptionally well and also easily better than how Hough Ear Institute have been explaining it lately lol.

 

[weab00]

I don't think there are more specifics than that but Ebselen has both anti inflammatory and vascular effects, both of which are factors in Meniere's pathology.

As far as more common hearing loss, if you had hair cell damage without as much cochlear neuroinflammation, I'm not sure the drug would help. But if it continues to be proven safe, I think it's good to have additional drugs in the arsenal.

They are currently recruiting for acute noise induced loss where the inflammation would be more universal.

What is making the inner ear chronically inflamed for someone with hyperacusis?

 

[tommyd87]

It will be a lot of people's go-to drug for their first pass on treating their hearing disorders to be sure. I certainly plan to take it as soon as it comes out, as well as always have some on hand for spikes.

But I wanted to ease the minds of people by showing that the options for treating inflammation that will eventually be available (should everything make it to market) will be even more expansive.

Every little bit helps.

I agree. Actually at first people will be trying treatments that come out to market first like SPI-1005 or PIPE-505 but then over time as more medicines make their way onto the market, people will obtain a better understanding of what treatments actually work best for their individual and specific situation.

More medicine means a better chance of getting effective treatments then too.

 

[FGG]

What is making the inner ear chronically inflamed for someone with hyperacusis?

This is my understanding of it so far:

The inflammation from noise starts acutely with the cytokine mediated recruitment of immune cells (just like anywhere else in the body):

Inflammatory and immune responses in the cochlea: potential therapeutic targets for sensorineural hearing loss

This takes awhile to disappear. Usually "longer than 6 months" in mice per the above link, so you can just assume it can take even longer in people.

That kind of immune response should be self limiting as it is elsewhere in the body unless you have an immune/auto immune disorder or have something perpetuating inflammation. In the ear, I imagine things like viruses, TMJ, ototoxins etc could perpetuate inflammation but otherwise inflammation after injury is designed to be self limiting in the body.

With noxacusis, you have sensitization of the pain fibers and this is the big unknown. The hope is that you can put the cochlea in a better environment to recover to normal sensitization over time but it's possible other drugs like channel blockers may be needed (I don't think anyone knows). There is also the question of whether there is continuous ATP leakage from a damaged cochlea or not.

 

[100Hz]

This is my understanding of it so far:

The inflammation from noise starts acutely with the cytokine mediated recruitment of immune cells (just like anywhere else in the body):

Inflammatory and immune responses in the cochlea: potential therapeutic targets for sensorineural hearing loss

This takes awhile to disappear. Usually "longer than 6 months" in mice per the above link, so you can just assume it can take even longer in people.

That kind of immune response should be self limiting as it is elsewhere in the body unless you have an immune/auto immune disorder or have something perpetuating inflammation. In the ear, I imagine things like viruses, TMJ, ototoxins etc could perpetuate inflammation but otherwise inflammation after injury is designed to be self limiting in the body.

With noxacusis, you have sensitization of the pain fibers and this is the big unknown. The hope is that you can put the cochlea in a better environment to recover to normal sensitization over time but it's possible other drugs like channel blockers may be needed (I don't think anyone knows). There is also the question of whether there is continuous ATP leakage from a damaged cochlea or not.

Really interesting. The only thing I'll say with regard to the question of 'is there continuous ATP leakage', I would lean towards it not being continuous, at least not continuous in a permanent sense. Maybe continuous for a period of time after a noise assault. I doubt it can be permanently continuous because the symptoms do calm down when care is taken around noise, also if it was continuous I don't think noise being a trigger would be as obvious a factor in noxacusis as it is.

Given how very specific noise events set setbacks off when seemingly all is going quite well, I assume that means the resuming release of ATP etc that leads to the fresh inflammation. The more burning question to me is where the ATP is coming from with these noise events. I think this is what you were getting at when you posted that stuff about GAP junctions. But if it's coming from somewhere that one of the potential upcoming drugs may be able to fix that's great, but if it's also coming from somewhere else, or only coming from somewhere else (that is not currently in the scope of what could possibly be fixed) then I'm imagining a world when inflammation management or channel blockers, or maybe both, are our best hope until something else comes along specifically for this.

 

[FGG]

Really interesting. The only thing I'll say with regard to the question of 'is there continuous ATP leakage', I would lean towards it not being continuous, at least not continuous in a permanent sense. Maybe continuous for a period of time after a noise assault. I doubt it can be permanently continuous because the symptoms do calm down when care is taken around noise, also if it was continuous I don't think noise being a trigger would be as obvious a factor in noxacusis as it is.

Given how very specific noise events set setbacks off when seemingly all is going quite well, I assume that means the resuming release of ATP etc that leads to the fresh inflammation. The more burning question to me is where the ATP is coming from with these noise events. I think this is what you were getting at when you posted that stuff about GAP junctions. But if it's coming from somewhere that one of the potential upcoming drugs may be able to fix that's great, but if it's also coming from somewhere else, or only coming from somewhere else (that is not currently in the scope of what could possibly be fixed) then I'm imagining a world when inflammation management or channel blockers, or maybe both, are our best hope until something else comes along specifically for this.

I should have said "excess ATP leakage" because ATP release is normal during hearing.

 

[100Hz]

I should have said "excess ATP leakage" because ATP release is normal during hearing.

Yes agree. I'm also talking about the bad, excess, or 'leaking from the wrong place' ATP. (The type or quantity of ATP that begins to initiate pain and inflammation /activate the sensitized nociceptors?)

 

[Born To Slay]

Really interesting. The only thing I'll say with regard to the question of 'is there continuous ATP leakage', I would lean towards it not being continuous, at least not continuous in a permanent sense. Maybe continuous for a period of time after a noise assault. I doubt it can be permanently continuous because the symptoms do calm down when care is taken around noise, also if it was continuous I don't think noise being a trigger would be as obvious a factor in noxacusis as it is.

Given how very specific noise events set setbacks off when seemingly all is going quite well, I assume that means the resuming release of ATP etc that leads to the fresh inflammation. The more burning question to me is where the ATP is coming from with these noise events. I think this is what you were getting at when you posted that stuff about GAP junctions. But if it's coming from somewhere that one of the potential upcoming drugs may be able to fix that's great, but if it's also coming from somewhere else, or only coming from somewhere else (that is not currently in the scope of what could possibly be fixed) then I'm imagining a world when inflammation management or channel blockers, or maybe both, are our best hope until something else comes along specifically for this.

I just want to tell you that I really enjoy reading your well researched and realistic posts. You are one of my favorite people to read from in the Research News section.

 

[FGG]

Yes agree. I'm also talking about the bad, excess, or 'leaking from the wrong place' ATP. (The type or quantity of ATP that begins to initiate pain and inflammation /activate the sensitized nociceptors?)

Right but if you have "excess leakage" even normal hearing can cause excessive ATP, which is why sound would continuously cause setbacks.

 

[100Hz]

Right but if you have "excess leakage" even normal hearing can cause excessive ATP, which is why sound would continuously cause setbacks.

I'm trying to understand what you're saying so bear with me, no doubt your science is way ahead of mine but I think I get it. When you say 'continuously cause setbacks', can you expand what you mean. Do you mean setbacks happening continuously upon hearing any random general noise, over and over, regardless of timeline? Because that's not really what happens. That may happen after a setback has just occurred and while in a very fragile state, but after some time (usually weeks, maybe months) the tolerance to noise does increase really slowly and to give an example, you may be able to finally sit and watch TV, drive without earplugs, handle walking down the street for a while etc. But then when you think everything's going well someone will sneeze a bit close to you and it all of a sudden it punches you straight in the ear and does something really significant to cause yet another setback. If you had excessive leakage throughout that whole recovery period, the pattern of recovery itself may suggest the leakage reduced over time maybe (or if it wasn't excess leakage then maybe it was ATP from the previous setback that dissipated over time)? And then the sudden blast of noise that once again was too much for whatever component of the inner ear to handle (say dead OHC support cells for example) triggered a fresh burst of ATP that breached the pain threshold. (I still believe this is frequency specific ATP release, however that may happen.).

As I'm writing I think I understand what you're saying. A continuous leak of ATP in addition to normal hearing ATP. So basically an increased ATP baseline? I'd question this then, if the Type II's were permanently sensitized (as I suppose they are) and there is that much ATP around, there must still be a threshold for an actual setback event to happen, and more importantly that baseline surely decreases over time as tolerance to noise grows. It makes me think about these charts I made several months ago to describe what I felt was happening over time.

I just want to tell you that I really enjoy reading your well researched and realistic posts. You are one of my favorite people to read from in the Research News section.

Thanks so much, I enjoy reading your posts as well. It's an amazing community and I've learnt so much from the members here.

 

[FGG]

I'm trying to understand what you're saying so bear with me, no doubt your science is way ahead of mine but I think I get it. When you say 'continuously cause setbacks', can you expand what you mean. Do you mean setbacks happening continuously upon hearing any random general noise, over and over, regardless of timeline? Because that's not really what happens. That may happen after a setback has just occurred and while in a very fragile state, but after some time (usually weeks, maybe months) the tolerance to noise does increase really slowly and to give an example, you may be able to finally sit and watch TV, drive without earplugs, handle walking down the street for a while etc. But then when you think everything's going well someone will sneeze a bit close to you and it all of a sudden it punches you straight in the ear and does something really significant to cause yet another setback. If you had excessive leakage throughout that whole recovery period, the pattern of recovery itself may suggest the leakage reduced over time maybe (or if it wasn't excess leakage then maybe it was ATP from the previous setback that dissipated over time)? And then the sudden blast of noise that once again was too much for whatever component of the inner ear to handle (say dead OHC support cells for example) triggered a fresh burst of ATP that breached the pain threshold. (I still believe this is frequency specific ATP release, however that may happen.).

As I'm writing I think I understand what you're saying. A continuous leak of ATP in addition to normal hearing ATP. So basically an increased ATP baseline? I'd question this then, if the Type II's were permanently sensitized (as I suppose they are) and there is that much ATP around, there must still be a threshold for an actual setback event to happen, and more importantly that baseline surely decreases over time as tolerance to noise grows. It makes me think about these charts I made several months ago to describe what I felt was happening over time.

I mean the latter. ATP is normally released with normal hearing. The louder the sound the more energy is needed, so more ATP.

Excess ATP from OHC +/- gap junction leakage causes sensitization of the nociceptive nerve fibers with the initial injury. These fibers are now more sensitive to ATP. With quiet sounds, there is less ATP.

The question to me seems to be whether reducing ATP leakage to the normal physiologic amount will over time reduce the sensitization or whether the neurons themselves need pharmacologic intervention (e.g., Ion channel drugs).

Edit: I should add that I firmly believe there is at least some (if not great) potential to normalize the sensitivity with a more normalized cochlear environment (e.g.. less gap junction leakage with less inflammation) in a lot of people because plenty of people do improve over time and don't seem "stuck" in as high level of sensitivity.

 

[Croaker]

Does all this ATP speculation provide an explanation for how setbacks work?