Sound Pharmaceuticals (SPI-5557 & SPI-1005)

[Zugzug]

Ebselen is not strictly an "anti-inflammatory drug" and, even in that capacity, it is not anti-inflammatory in the way anti-inflammatory drugs usually are (i.e. primarily affect chemotaxis and migration of neutrophils and vascular permeability). Actually, Ebselen may have some direct effects on vascular permeability, too, but it is more akin to the effects of a drug like Amlodipine (more on this in a bit).

In terms of why it's so confusing as to what Ebselen does, it's because it's an extremely odd drug with a lot of varied targets. Even the chemical structure of it is extremely unique:

The Weirdness of Ebselen

Interestingly, Jonathan Kil from Sound Pharmaceuticals actually commented on this blog post:

"The Daichii ebselen stroke trials were probably the most advanced clinically, but were limited due to the sample size, the nature of that disease, and the approval of tPA in 1997. In addition, I thought you maybe interested in our ongoing clinical trials in sensorineural hearing loss and tinnitus with SPI-1005. We have completed a Phase 1 and Phase 2 in acute noise induced hearing loss which were highly successful. We are currently enrolling a Phase 1/2 in Meniere's disease (hearing loss, tinnitus and vertigo) and preparing to enroll two ototoxicity studies involving chemotherapy or antibiotic receiving patients. In several different models of acute neurotologic injury, we and others have shown that ebselen is highly otoprotective through its action as a GPx1 mimic and inducer. This later effect is somewhat dependent upon Nrf2 activation. My feeling is that ebselen will find a home in diseases where decreases in GPx activity result in the establishment of acute injury and the progression to chronic disease and/or in specific organs where GPx is the dominant catalytic antioxidant enzyme such as the inner ear, retina, lung and some areas of the forebrain."​

What he seems to be saying is that he believes Ebselen has a mechanism of action in a variety of acute injuries and also in areas where Glutathione Peroxidase is involved in chronic inflammation: inner ear, retina, lung and parts of the brain.

They are testing it on chronic conditions of the brain, for instance (bipolar disorder, Alzheimer's, as a preventative for Parkinson's, which has been tested in primates, and could maybe help prevent or slow down progression) and plan to test it acutely for COVID-19 lung disease (it may help the long haulers, too, we don't know).

In rodent studies, it seemed to show effects on both tinnitus and (I assume loudness) hyperacusis.

So, what are some of the known targets of this drug?

-- Glutathione peroxidase inducer (this helps with oxidative stress and neuroinflammation) as Jonathan Kil mentioned above

-- It is also shows effects as a cytokine modulator:

Ebselen--an in vivo immune response modifier

Of note, TNF-Alpha was a key cytokine in the Dr. Bao studies.

-- In rodents at least, it's a voltage-gated calcium channel blocker (this would have vascular effects)

-- In rodents, it affects some potassium channels as well (this was an acute rodent study as well) but the only study in people (it was a diabetic vascular study in patients that did not have neuropathy or retinopathy), showed it did not have an effect. This at least shows that, in chronic diabetes, it does not have a restorative vascular effect (which is very specific and not in the scope of what Sound Pharmaceuticals is trying to do).

-- It affects the NMDA receptor and dampens Glutamate hyperexcitabilty effects through multiple mechanisms (redox effects? lipoperoxidase effects?)

-- It also may have anti-depressive effects similar (but reportedly safer) than lithium due to inhibitory effects on inositol monophosphatase:

A safe lithium mimetic for bipolar disorder

-- It also may affect acetylcholinesterase activity (like Huperzine A being studied in China for age-related hearing loss related tinnitus):

Pre-treatment with ebselen and vitamin E modulate acetylcholinesterase activity: interaction with demyelinating agents

If all of this seems confusing, it is because it is. I have never personally seen a drug with so many different targets.

It's one reason this drug has so much potential but also perhaps why it should only be tried as a last resort for people who are at the complete end of their rope until we get more safety data (even if so far, it looks good).

I want to add too, for anyone trying this on their own. More is not always better in terms of efficacy. In fact, the 400 mg group did much better than the 600 mg group in this study:

Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial

FX-322 just broke my heart, but I'm already in love again. I have to give myself time and resist the urge to get into a new hearing drug relationship too soon off the rebound.

 

[weab00]

FX-322 just broke my heart, but I'm already in love again. I have to give myself time and resist the urge to get into a new hearing drug relationship too soon off the rebound.

Ebselen is probably the only clinical stage drug I'm still keeping my eyes on.

 

[Mentos]

Ebselen is probably the only clinical stage drug I'm still keeping my eyes on.

I would add OTO-413 to the list.

 

[Zugzug]

Ebselen is probably the only clinical stage drug I'm still keeping my eyes on.

I would add OTO-413 to the list.

There's a number of promising drugs in the pipeline. I think the issue is timeline. Within 20 years, there will probably be quite a few major QoL improvers.

 

[spacehunter]

FX-322 was great as it had the promise to cure the problem at (one of) its roots and also because it was being developed rapidly.

After the disaster with FX-322, we should lower our expectations.

SPI-1005 will at most alleviate our problems, but not cure them. The beauty of SPI-1005, on the other hand, is that one can immediately try it out...

 

[weab00]

There's a number of promising drugs in the pipeline. I think the issue is timeline. Within 20 years, there will probably be quite a few major QoL improvers.

I don't disagree, but I'm not going to invest my emotional health in a drug that won't be available for another one to two decades.

 

[Emgee]

There's a number of promising drugs in the pipeline. I think the issue is timeline. Within 20 years, there will probably be quite a few major QoL improvers.

I got maybe two years in me. Maybe. For me, it's either some improvement via Ebselen or game over.

 

[DebInAustralia]

Do we know when Phase 3 will be completed?

 

[Mentos]

Do we know when Phase 3 will be completed?

I think Phase 3 has not even started, it's premature to say about completion date.

 

[spacehunter]

Do we know when Phase 3 will be completed?

As far as I know it has not even started yet. According to this website it will probably be completed in April 2023...

 

[Jrblovsky]

I got maybe two years in me. Maybe. For me, it's either some improvement via Ebselen or game over.

As a guy who actually attempted to commit suicide and failed, I would not recommend it. I suffer as bad as anyone here and it's not worth it. Figure out a way to deal with it.

 

[GlennS]

FX-322 just broke my heart, but I'm already in love again. I have to give myself time and resist the urge to get into a new hearing drug relationship too soon off the rebound.

 

[Gee82]

Update on clinical trial dates for COVID-19:

Start May 2021, end June 2022.

Source:
https://clinicaltrials.gov/ct2/show/NCT04483973

Just another piece of bad news.

 

[tarmaced]

Sorry all, another refugee from the FX-322 thread here...

Having worked that thread for over year and jumping ship to skim read the last few pages here... It seems that this drug has had good results and is even oral!

In my mind this is even better than an injection because... No injection.

I recall a concern with FX-322 was EHF / penetration. Do we have indication that this drug acts across all frequencies?

 

[FGG]

I recall a concern with FX-322 was EHF / penetration. Do we have indication that this drug acts across all frequencies?

I think it should act on all frequencies. The drug gets really good systemic penetrance. Crosses both the BBB and Blood/Cochlear barrier well. I don't think everyone will likely get the same benefit from it since I think it will depend on a lot of individual inflammatory factors. That's just my suspicion. Would be great if it did work for everyone.

I think it holds great promise in preventing spikes and new/further damage for pretty much everyone, though.

 

[tarmaced]

I think it holds great promise in preventing spikes and new/further damage for pretty much everyone, though.

I have devoured so many of your posts that it feels like conversing with a celebrity!

I am an engineer, not a scientist, but digested the 2009 paper on the development of Ebselen. I can't find the 2021 February paper using my sources.

The 2009 paper suggests, like you did, that the primary thrust is prevention, not cure. Has the emphasis on cure increased since that point, or is it wishful thinking on my part?

 

[Kam75]

Sorry if this is a dumb question, but I'm also a refugee from the FX-322 thread here.

What exactly is SPI-1005? According to what I have read, it is a treatment for COVID-19, currently in Phase II or III clinical trials.

How come this drug can help tinnitus?

 

[FGG]

I am an engineer, not a scientist, but digested the 2009 paper on the development of Ebselen. I can't find the 2021 February paper using my sources.

The 2009 paper suggests, like you did, that the primary thrust is prevention, not cure. Has the emphasis on cure increased since that point, or is it wishful thinking on my part?

I think it will be pretty universally effective as a preventative but as far as treating tinnitus, I think it will have some benefit in most people but a dramatic benefit in a certain segment.

You aren't fixing an underlying cause, you are attenuating the after effects.

However, I think people with severe tinnitus might especially benefit in breaking the stress-glutamate and dynorphin release--tinnitus--further stress, perpetuating worse tinnitus cycle. So they could possibly benefit the most.

This is just my take and I would love to hear other opinions.

 

[Tezcatlipoca]

I think it should act on all frequencies. The drug gets really good systemic penetrance. Crosses both the BBB and Blood/Cochlear barrier well. I don't think everyone will likely get the same benefit from it since I think it will depend on a lot of individual inflammatory factors. That's just my suspicion. Would be great if it did work for everyone.

I think it holds great promise in preventing spikes and new/further damage for pretty much everyone, though.

So it should put us at a spikeless baseline? In theory.

 

[Tezcatlipoca]

Update on clinical trial dates for COVID-19:

Start May 2021, end June 2022.

Source:
https://clinicaltrials.gov/ct2/show/NCT04483973

Just another piece of bad news.

Not really, that's always been the timeline.

 

[FGG]

So it should put us at a spikeless baseline? In theory.

It has a lot of effects. That seems to be something the drug could be capable of for sure.

 

[annV]

I can't find the 2021 February paper using my sources.

Here's the full February 2021 paper.

 

[Tezcatlipoca]

It has a lot of effects. That seems to be something the drug could be capable of for sure.

Oh that's awesome, my spikeless baseline is great, I feel completely comfortable with it.

 

[tarmaced]

Oh that's awesome, my spikeless baseline is great, I feel completely comfortable with it.

I am the opposite, I never have spikes, just changes in attitude when it gets too much to bear...

I guess this means that I am in the pool of people it probably won't work for

 

[FGG]

I am the opposite, I never have spikes, just changes in attitude when it gets too much to bear...

I guess this means that I am in the pool of people it probably won't work for

Well, this drug is extremely complex so I'm mostly speculating but if yours is severe enough to be "too much to bear" at times I think you likely have more of a locally inflammatory component than you might otherwise. Just my opinion.

 

[Tezcatlipoca]

I am the opposite, I never have spikes, just changes in attitude when it gets too much to bear...

I guess this means that I am in the pool of people it probably won't work for

Hey who knows really, it could work wonders for you and do nothing for me. Don't knock it till you try it!

 

[Gee82]

Not really, that's always been the timeline.

No, originally the trial was supposed to end in April 2021.

 

[Keith Handy]

Oh that's awesome, my spikeless baseline is great, I feel completely comfortable with it.

You and me both.

Still want "the goop" too, though.

 

[Lucifer]

No, originally the trial was supposed to end in April 2021.

Damn, I thought they were going to start Phase 3 but the ClinicalTrials.gov website states Phase 2.

 

[FGG]

Damn, I thought they were going to start Phase 3 but the ClinicalTrials.gov website states Phase 2.

Phase 3 for Meniere's (ends 2023).
Phase 2 for COVID-19 (ends 2022).