Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[Athens]

Hey. I'm no expert but it has been scientifically proven that SSRIs cause tinnitus. A poster recently put up six studies confirming that fact. Here is one article. This is out of a University in Oregon and they have multiple studies on this.

Study Suggests Serotonin May Worsen Tinnitus

Zopiclone should not be used for sleep for long periods from my research, but hey, if it works, then keep on it bro.

In my case, lucky me, I was put on Paxil at very high doses when I had my sleep induced psychosis (sound's scary that word psychosis, but thankfully mine was a once off from lack of sleep) but I just developed total insomnia in a period of intense stress (think two babies and a father on ventilators). I tried to be a superhero and keep a vigil but ended up with a complete physical breakdown. I was working full time as well trying to pay the bills. Was just mad.

Anyway, buddy, to keep a long story short, here is a snippet from an article from the ATA written by Neil Bauman, PhD, who has written well over 160 articles on ototoxicity and is considered the world's leading expert on the subject.

View attachment 49693

You can see lucky me and my lovely Paxil (Paroxetine) sitting there in number 3. Apparently it is the SSRI with the most potent affinity for serotonin receptors and yes we have some of these lovely serotonin receptors in our Dorsal Cochlear Nucleus. That is where a lot of tinnitus researchers believe tinnitus emerges from. It is the last point of entry for sound into the brain.

Also, severe disruption in serotonin can also mess up your Potassium channels which aligns with the DCN theory.

It is a tough call regarding benzos. I know they are shit but I need them as my tinnitus is messed up. I was on Clonazepam at 1 mg and managed to taper from 1 mg (20 mg Diazepam equivalent) to 20 mg of Diazepam, and down to 8 mg of Diazepam, however I've nudged up to 12 mg again. I tapered from 20 mg to 8 mg during a period where I had two middle ear surgeries and I reckon I can taper again no problem (fingers crossed), but I am dying to kick the tinnitus provoking Paroxetine but taking it slow as withdrawal from it can be very very severe (worse than benzos even). I'm on 7 mg and tip toeing down and will jump at 1 mg towards end of summer (if I can).

Anyway, sorry for the essay. Hope it helps

It is difficult for me to believe that Xanax and Clonazepam can trigger tinnitus. I know that Clonazepam decreases the electrical activity in the brain and that it helps many people decrease their tinnitus. I think that withdrawing from benzos could certainly trigger tinnitus but not taking them.

I am not surprised that an SSRI might trigger it which is one of the reasons that I have been reluctant to take one along with the potential for it to be too activating and cause insomnia.

My problem with Neil Bauman is that I recall that he has a gazillion drugs on his list of ototoxic medications and includes a drug even if 1% of people taking a drug report various auditory issues.

 

[Chinmoku]

Anyway, buddy, to keep a long story short, here is a snippet from an article from the ATA written by Neil Bauman, PhD, who has written well over 160 articles on ototoxicity and is considered the world's leading expert on the subject.

Sorry to say, I agree with the serotonin-tinnitus link, but Neil Bauman being the world leading authority on ototoxicity is a little stretched. His studies are not in medicine (he has a master's degree in Theology and two PhD degrees, one in forestry and the other in ancient astronomy) and he has diligently compiled anecdotal information and searched databases over the years but I wouldn't say he is the world authority on ototoxicity. He does have ATA support but we all know how sadly flawed the ATA is.

There is this thread on him in Tinnitus Talk.

If one has to look for information on ototoxic drugs I would recommend peer reviewed publications, for example this one from Cianfrone et al (2011).

As an example, Cianfrone et al (2011) argue that Clonazepam is a vestibular risky drug but not a tinnitus/hearing loss risky drug (classification 3). Paroxetine is similarly classified as 3, which is more dubious, given the link between serotonin and tinnitus, so even this paper is not perfect but perhaps we should start from there.

Having said this, as I said elsewhere, there is no world expert on treating tinnitus effectively so Neil Bauman might be helping us, it's just that his list includes practically almost every medication ever seen on Earth, and he is spreading fear and terror to people who might need a medication to survive. I think that's a dangerous path to take, unless the evidence is clear and non-anecdotal.

Edit - Total sympathy for your story, at some point I also had two little babies and a severely ill mother and was holding two jobs to pay the bills, I didn't crash at the time but sometimes I was close. I really hope things get better for you going forward.

 

[Padraigh Griffin]

Sorry to say, I agree with the serotonin-tinnitus link, but Neil Bauman being the world leading authority on ototoxicity is a little stretched. His studies are not in medicine (he has a master's degree in Theology and two PhD degrees, one in forestry and the other in ancient astronomy) and he has diligently compiled anecdotal information and searched databases over the years but I wouldn't say he is the world authority on ototoxicity. He does have ATA support but we all know how sadly flawed the ATA is.

There is this thread on him in Tinnitus Talk.

If one has to look for information on ototoxic drugs I would recommend peer reviewed publications, for example this one from Cianfrone et al (2011).

As an example, Cianfrone et al (2011) argue that Clonazepam is a vestibular risky drug but not a tinnitus/hearing loss risky drug (classification 3). Paroxetine is similarly classified as 3, which is more dubious, given the link between serotonin and tinnitus, so even this paper is not perfect but perhaps we should start from there.

Having said this, as I said elsewhere, there is no world expert on treating tinnitus effectively so Neil Bauman might be helping us, it's just that his list includes practically almost every medication ever seen on Earth, and he is spreading fear and terror to people who might need a medication to survive. I think that's a dangerous path to take, unless the evidence is clear and non-anecdotal.

Edit - Total sympathy for your story, at some point I also had two little babies and a severely ill mother and was holding two jobs to pay the bills, I didn't crash at the time but sometimes I was close. I really hope things get better for you going forward.

Thanks buddy for the best wishes, plus the excellent information. I will follow up the research you have linked. But I know for a fact Paroxetine caused my tinnitus and MEM. I was put on 80 mg by a useless psychiatrist. If I had my mind about me at the time I would have realised that was a big, big mistake. Paying for it now. I've always read your posts and think we both have struggled recently. I hope things are picking up for you a bit. Now let science give us a helping hand, hopefully. Be ironic if a drug cured me after a drug causing it! Hopefully XEN1101 will help us both + many others.

Thanks again for the great information.

 

[StoneInFocus]

Another thing to be optimistic about is that it might be possible that Xenon Pharmaceuticals would start a compassionate use program if the results of Mt. Sinai results are good. Their site reads:

"At this time, Xenon does not currently have an expanded access program that makes our investigational drugs available to patients other than by participating in one of our clinical trials. Clinical trials are controlled studies in humans designed to establish if an investigational drug is safe and effective. Xenon believes clinical trials are the most appropriate way to efficiently collect all data necessary to seek regulatory approvals. At this time, Xenon does not have sufficient information about the potential risks and benefits of our investigational drugs to ensure that patient access outside the regulated clinical trial process does not delay nor compromise our clinical trials and, ultimately, broad availability to the entire patient community... Xenon may revise this policy at any time. For any additional questions, please contact us at clinicaltrials@xenon-pharma.com."​

 

[Padraigh Griffin]

Transient Delivery of a KCNQ2/3-Specific Channel Activator 1 Week After Noise Trauma Mitigates Noise-Induced Tinnitus

This is the article that I'd like to get access to. Has anyone got a link to the full version?

 

[annV]

Transient Delivery of a KCNQ2/3-Specific Channel Activator 1 Week After Noise Trauma Mitigates Noise-Induced Tinnitus

This is the article that I'd like to get access to. Has anyone got a link to the full version?

Here you go!

 

[Nobody19]

Here you go!

I know what to read this evening, thanks!

 

[Padraigh Griffin]

Here you go!

Excellent. Thank you. Just skimmed it and will give it a full read soon. It finishes with the statement that a drug is needed in this area but never mentions that one exists in the form of XEN-1101 which is just as selective as Prof. Tzounopoulos' compound and slightly more potent. Why don't they acknowledge the fact that the compound they have in pre-clinical stage is already practically in Phase 3, or am I missing something here??

Why this question wasn't asked in the Tinnitus Talk Podcast interview is completely beyond my comprehension.

 

[Padraigh Griffin]

Stifel 2022 CNS Days

Watched this. It might be of interest to those following this drug. The 20 mg dose level is well tolerated and a couple of interesting point regarding FDA and Phase 2. The Phase 2 was a huge success and also a very large trial with excellent data. The interview also goes into some minute detail on the depression trial. The data from previous Ezogabine trials showed good results. They are very confident in this drug for depression as well.

Also mentioned a number of other CNS indications that the drug could possibly treat but no mention yet of the tinnitus word.

 

[Toby1972]

The big thing for the Tinnitus Talk members is that many of us would qualify for this depression trial. It would be amazing if some of our members could get on the trial.

....

Anyone that can find info on trial locations when published, please share.

Only 60 participants.

XEN1101 for Major Depressive Disorder

Tinnitus Talk members will unlikely be there due to the only two locations.

 

[Padraigh Griffin]

Only 60 participants.

XEN1101 for Major Depressive Disorder

Tinnitus Talk members will unlikely be there due to the only two locations.

That's the Mount Sinai trial. There is soon to be a separate company announced/funded trial in Q2.

 

[Nobody19]

According to a paper from 2015, Retigabine helps with noxacusis. My excitement level for this and Professor Thanos' drug has gone up a notch!

 

[serendipity1996]

According to a paper from 2015, Retigabine helps with noxacusis. My excitement level for this and Professor Thanos' drug has gone up a notch!

We also have anecdotes from people on this site that the old Retigabine (Trobalt) helped their noxacusis.

 

[Nobody19]

We also have anecdotes from people on this site that the old Retigabine (Trobalt) helped their noxacusis.

This is seriously giving me some hope that I might get my life back...

 

[Jerad]

@AlueTrobalt was totally hit and miss for me.
And when I built some tolerance it was pretty much miss all the time.

First time I took 3x300mg for like 3 months, give or take. I do think I developed some tolerance as it didn't lower my tinnitus anymore…

A couple of months later I started again with the same conclusions: lowered my tinnitus for a few months, then stopped because of tolerance and side effects.

For these new potassium channel modulators from Xen Pharmaceuticals and Professor Tzounopoulos, I wonder if the reformulations will help solve some of the other issues reported with Trobalt, like reaching tolerance (mentioned in the above examples).

The users said that they reached tolerance on it eventually and it quit working. I've seen this mentioned by several users when researching Tinnitus Talk.

I hope the reformulated versions, having higher potencies and such, will solve these problems. Or maybe you have to take the drug/cycle it a certain way to avoid reaching tolerance. I dunno. It would be amazing to finally have something that works, but suck to have it quit working after a few months use.

I am confident that these new potassium channel drugs will help those reverse tinnitus in the acute stage — and keep it away permanently. Not sure what the above means for chronic cases, though.

 

[Nobody19]

For these new potassium channel modulators from Xen Pharmaceuticals and Professor Tzounopoulos, I wonder if the reformulations will help solve some of the other issues reported with Trobalt, like reaching tolerance (mentioned in the above examples).

The users said that they reached tolerance on it eventually and it quit working. I've seen this mentioned by several users when researching Tinnitus Talk.

I hope the reformulated versions, having higher potencies and such, will solve these problems. Or maybe you have to take the drug/cycle it a certain way to avoid reaching tolerance. I dunno. It would be amazing to finally have something that works, but suck to have it quit working after a few months use.

I am confident that these new potassium channel drugs will help those reverse tinnitus in the acute stage — and keep it away permanently. Not sure what the above means for chronic cases, though.

If tolerance will be an issue, we'll hear about it from epilepsy and depression patients taking the drug.

 

[Padraigh Griffin]

This is seriously giving me some hope that I might get my life back...

Same here. I have to believe in this one.

If tolerance will be an issue, we'll hear about it from epilepsy and depression patients taking the drug.

Exactly. Hopefully tolerance is not an issue. In theory if it works by modifying potassium channels, then it should not be an issue as if it shows continued efficacy for epilepsy, then it should in theory show the same for tinnitus.

We won't know as the dosing schedule and potency is quite different to Trobalt. There is hope with this drug.

Some of the Trobalt user reports stated no tolerance but rather discontinuance due to side effects. The thread make for harrowing reading in some places, but there is a lot of information that showed it worked for chronic patients.

It really is an unknown and I suppose a long shot, but maybe the best near term 'long shot' we have.

Also, on ClinicalTrials.gov page the depression trial is extended out to 2024. By then it should be launched for epilepsy and I'd imagine no Phase 3 will be needed for depression off-label if the data is positive. They should have accumulated enough safety data for the FDA by then. The depression dose of 20 mg is generally well tolerated vs. placebo. It's the 25 mg dose that shows a significant increase in side effects such as somnolence and dizziness vs. that of placebo.

With regards to acute or chronic tinnitus and tolerance, I don't know about that, but tolerance could be subjective based on the anecdotal Trobalt user reviews. The mechanism of action suggests that tolerance won't be an issue and it hasn't been mentioned as an issue from its primary focus of treating epilepsy.

 

[Jerad]

Same here. I have to believe in this one.

Exactly. Hopefully tolerance is not an issue. In theory if it works by modifying potassium channels, then it should not be an issue as if it shows continued efficacy for epilepsy, then it should in theory show the same for tinnitus.

We won't know as the dosing schedule and potency is quite different to Trobalt. There is hope with this drug.

Some of the Trobalt user reports stated no tolerance but rather discontinuance due to side effects. The thread make for harrowing reading in some places, but there is a lot of information that showed it worked for chronic patients.

It really is an unknown and I suppose a long shot, but maybe the best near term 'long shot' we have.

Also, on ClinicalTrials.gov page the depression trial is extended out to 2024. By then it should be launched for epilepsy and I'd imagine no Phase 3 will be needed for depression off-label if the data is positive. They should have accumulated enough safety data for the FDA by then. The depression dose of 20 mg is generally well tolerated vs. placebo. It's the 25 mg dose that shows a significant increase in side effects such as somnolence and dizziness vs. that of placebo.

With regards to acute or chronic tinnitus and tolerance, I don't know about that, but tolerance could be subjective based on the anecdotal Trobalt user reviews. The mechanism of action suggests that tolerance won't be an issue and it hasn't been mentioned as an issue from its primary focus of treating epilepsy.

I know XEN-1101 won't be exactly like Trobalt, but I was also concerned to find that 2 users reported worsenings of their tinnitus as a result of taking Trobalt, which is the first time I've ever seen that reported. I was confident in the potassium channel drugs because I thought they were one of the few options where tinnitus worsenings were never reported as a result of experimenting with them.

Both me and @Zimichael had worsening, I am still in acute stage and he is in really long chronic so the only thing that is same for me and him is taking 50mg while others started with 100mg and I have read that 50mg are made in different place than others. It is possible that one of the channels which retigabine is affecting makes tinnitus louder and us two are sensitive to that.

There are now more than 1750 posts in this thread. Would it be possible for somebody who has been following it to summarize in two or three sentences where things stand in terms of the drug and the discussion about it. Thanks so much.

Yes, here it is: a few users tried it so far, one had great results, 2 had worsening and other 5-6 had significant improvements, the sideeffects were mostly bearable except for the 2 who got worsening of tinnitus. So far the effect of retigabine is quite random so the discussion is about how and why is it having such an effect but since benryu is not here we laymen can only guess.

Both you and Zimichael had previous bad experiences with medication, so that could be a factor.

So, it looks like a lot of people did experience benefits from Trobalt, but the 2 worsenings are concerning for me personally, as it seems that every single med that I take causes me to have either a spike or permanent worsening. Not sure why I'm so sensitive.

I know that perhaps I'm getting ahead of myself with all this, but I'm feeling pretty desperate as of late due to the suffering of debilitating tinnitus and hyperacusis, and I've been researching the Trobalt thread a lot because of the hope I've been putting in XEN-1101.

 

[Ela Stefan]

Phase 3 trial is planned for New Year 2023. Probably 2024/2025 before market.

So it would be on the market in 2026 then? That is so far away. Feels like a lifetime for someone who suffers from severe tinnitus.

 

[Padraigh Griffin]

So it would be on the market in 2026 then? That is so far away. Feels like a lifetime for someone who suffers from severe tinnitus.

Hi Ela, I expect it to be on the market in 2024, perhaps towards the end of the year. It was a very large Phase 2 so I believe that if Phase 3 meets endpoints it will be fairly straightforward with the FDA.

 

[Padraigh Griffin]

I know XEN-1101 won't be exactly like Trobalt, but I was also concerned to find that 2 users reported worsenings of their tinnitus as a result of taking Trobalt, which is the first time I've ever seen that reported. I was confident in the potassium channel drugs because I thought they were one of the few options where tinnitus worsenings were never reported as a result of experimenting with them.

So, it looks like a lot of people did experience benefits from Trobalt, but the 2 worsenings are concerning for me personally, as it seems that every single med that I take causes me to have either a spike or permanent worsening. Not sure why I'm so sensitive.

I know that perhaps I'm getting ahead of myself with all this, but I'm feeling pretty desperate as of late due to the suffering of debilitating tinnitus and hyperacusis, and I've been researching the Trobalt thread a lot because of the hope I've been putting in XEN-1101.

50 mg of Retigabine would have practically zero effect at that level so I would not be concerned about those reports of 'worsenings'. I am very sensitive to medication too, but 50 mg is 20% of minimal therapeutic starting dose of 300 mg and 5% of the maximum dose.

Sometimes 'worsenings' are in our minds as we all well know. Like today my tinnitus is 5x worse if I am indoors or pay more attention to it. All of us traumatised by severe unpredictable tinnitus will attest to that. Every day is a roller coaster. I go between hope and despair everyday. Like many, many on here.

The 20 mg of XEN-1101 would have a lot more of an effect than 50 mg of Trobalt. By many, many multiples.

We really don't know if it will work for any of us and if so what cohort it might help the most. The fact is though, as you well know, that hyperexcitability is a fairly common theory and that is caused by malfunction in the Potassium channels. Professor Thanos explains it well. Sodium channels are the accelerators and potassium channels are the brakes to keep it simple.

Let's not torture ourselves by going through the Trobalt thread as it was not anywhere near as specific and people were screwing around with doses, etc, but I do believe that there were many other reports of success if Prof. Tzounopoulos is pursuing it as his tinnitus treatment.

XEN-1101 is a derisked drug from a side effect profile, and there is some hope it will help tinnitus. It is our nearest hope in my opinion but remember breakthroughs come all the time. TMS, DBS, brain zapping can be an overnight success.

Take the Stanford depression TMS breakthrough for example:

Experimental depression treatment is nearly 80% effective in controlled study

I am in the same boat as you, Ela and many others here.

I find every day a challenge and a lot of the time I long for a peaceful death, but science keeps my hopes alive.

I truly have faith in XEN-1101 being of help. I really do.

 

[Ela Stefan]

Hi Ela, I expect it to be on the market in 2024, perhaps towards the end of the year. It was a very large Phase 2 so I believe that if Phase 3 meets endpoints it will be fairly straightforward with the FDA.

It would be on the European market in 2024 as well? FDA is for United States, isn't it?

 

[ajc]

It would be on the European market in 2024 as well? FDA is for United States, isn't it?

Only Xenon Pharmaceuticals would know that... It's up to them if they apply to FDA and EMA at the same time. Sometimes a company first applies to FDA and EMA then comes later. Sometimes it's the opposite and a company first applies to EMA.

Below are a couple of lists that demonstrate EMA is not bad at all and if XEN-1101 passes the trials successfully, it will probably be available in EU without a long wait.

 

[Ela Stefan]

Only Xenon Pharmaceuticals would know that... It's up to them if they apply to FDA and EMA at the same time. Sometimes a company first applies to FDA and EMA then comes later. Sometimes it's the opposite and a company first applies to EMA.

Below are a couple of lists that demonstrate EMA is not bad at all and if XEN-1101 passes the trials successfully, it will probably be available in EU without a long wait.

View attachment 49816

View attachment 49817

Thank you! Look at how many drugs got approved in all these recent years, but for tinnitus, still nothing. I hope it will be as you say. I can't get it from the United States because I'm in Europe.

 

[StoneInFocus]

So it would be on the market in 2026 then? That is so far away. Feels like a lifetime for someone who suffers from severe tinnitus.

Our best bet right now is hoping the company starts an early access program, or that we can participate in one of their clinical trials.

I don't know if this has been mentioned elsewhere but their site reads:

"In addition [to the Mount Sinai trial], an investigational new drug (IND) application has been submitted to the FDA to support Xenon's plans for a larger company-sponsored clinical study in MDD with XEN1101, which is expected to be initiated in the first half of 2022."​

Hopefully Xenon Pharmaceuticals will conduct clinical trials in Europe as well. The only problem will be participating in the study without having major depressive disorder, but where there's a will, there's a way.

 

[Gb3]

but for tinnitus, still nothing.

Because nothing works lol.

 

[ajc]

The only problem will be participating in the study without having major depressive disorder, but where there's a will, there's a way.

Are you one of those who think it is fine to lie to get into a clinical trial? Think again. AM-101 Phase 3 and FX-322 Phase 2 were ruined because people lied their way into the trials. It is a serious problem if enough people get to participate in a trial under false pretenses. It can compromise the integrity of the trial in a major way.

 

[Ela Stefan]

Many people suffering from tinnitus have depression as a consequence!

I found this article. It is not exactly on the thread's topic, but I wonder if anyone here can explain more. DCN maladaptation is a major issue in chronic tinnitus sufferers.

So can XEN1101 affect the potassium channels enough so that it will eventually induce DCN changes as well? Those NMDA receptors are pretty important in moderating the tinnitus signal.

Here's the link:

NMDA Receptors Mediate Stimulus-Timing-Dependent Plasticity and Neural Synchrony in the Dorsal Cochlear Nucleus

 

[StoneInFocus]

Are you one of those who think it is fine to lie to get into a clinical trial? Think again. AM-101 Phase 3 and FX-322 Phase 2 were ruined because people lied their way into the trials. It is a serious problem if enough people get to participate in a trial under false pretenses. It can compromise the integrity of the trial in a major way.

Never said that, but if the illness is severe enough, I think lying would be okay if that is the only option to participate. But ideally companies should just be compassionate and allow early access usage.

 

[Joey72]

I don't know how anybody with severe tinnitus could not be severely depressed.

You're a stronger person than me, that's for sure.