Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[Kleiner]

You're switching the topic to Kv7 channels in general again. You said that theoretically Kv7.2/7.3 was 'enough' to cure tinnitus.

Do you have evidence that Retigabine is a better activator of heteromeric KCNQ2/3 channels than Gabapentin?

Dude, I'm not changing the subject at all.

I don't know what you're trying to say, it's pretty well documented here that Kv7.2 and Kv7.3 are suspected to be the source of some cases of tinnitus, more than any other channel. But other mechanisms are possible of course, that's all my doubt.

Next, Gabapentin is not a Kv7 opener comparable to Retigabine, do you really need an article for that? Sounds a bit like contradiction for fun to be honest.

If you do not agree with my experiments, I strongly encourage you to experiment yourself, I will be happy to compare my results so that we can advance a little more in understanding the mechanisms of tinnitus.

 

[StoneInFocus]

Next, Gabapentin is not a Kv7 opener comparable to Retigabine, do you really need an article for that? Sounds a bit like contradiction for fun to be honest.

When you quoted my post you conveniently left out my citation of the paper that said Gabapentin is a potent heteromeric Kv7.2/Kv7.3 opener.

You say that these channels are majorly implicated in tinnitus. Yet Retigabine works better for tinnitus than Gabapentin. If the tinnitus alleviating mechanism of Retigabine is solely related to its Kv7.2/Kv7.3 modulating properties, as you seem to imply, that would mean that Retigabine is a better activator of Kv7.2/Kv7.3 channels than Gabapentin. So I asked you evidence of that pharmacological difference. That is not unreasonable. I hope you understand what I mean now.

we can advance a little more in understanding the mechanisms of tinnitus.

Lol that is precisely what I'm trying to do here, but it seems like you feel I'm somehow invalidating what you've experienced.

Dude, I'm not changing the subject at all.

I don't know what you're trying to say.

I've asked you the same question three times already, if you still do not understand what I mean than I'm sorry but you just don't have the capability to engage in this discussion.

 

[Kleiner]

When you quoted my post you conveniently left out my citation of the paper that said Gabapentin is a potent heteromeric Kv7.2/Kv7.3 opener.

You say that these channels are majorly implicated in tinnitus. Yet Retigabine works better for tinnitus than Gabapentin. If the tinnitus alleviating mechanism of Retigabine is solely related to its Kv7.2/Kv7.3 modulating properties, as you seem to imply, that would mean that Retigabine is a better activator of Kv7.2/Kv7.3 channels than Gabapentin. So I asked you evidence of that pharmacological difference. That is not unreasonable. I hope you understand what I mean now.

Lol that is precisely what I'm trying to do here, but it seems like you feel I'm somehow invalidating what you've experienced.

I've asked you the same question three times already, if you still do not understand what I mean than I'm sorry but you just don't have the capability to engage in this discussion.

It's especially the desire to converse with you that I miss, you only question dominant theories by raising non-questions, with a quite clumsy scientific rigor to be honest.

You are asking me to prove that Retigabine, which is a Kv7 opener specifically designated for this, in particular Kv7.2 and Kv7.3, is superior to Gabapentin, which is an indirect Kv7 opener whose role remains unclear.

What's the point of proving you an obvious fact?

I remain open to a constructive discussion but I'm done with this one.

Flupirtine interests me because it is a good candidate to compare to Retigabine/XEN1101 etc.

 

[StoneInFocus]

What's the point of proving you an obvious fact?

I don't know about anyone else but to me it is totally not obvious why Retigabine is superior to Gabapentin when the latter is described as a potent Kv7.2/7.3 channel opener unless other potassium channels are involved with tinnitus as well.

I remain open to a constructive discussion but I'm done with this one.

Sure, suit yourself. But don't you ever quote or mention me again.

 

[andrewdaniels]

I don't know about anyone else but to me it is totally not obvious why Retigabine is superior to Gabapentin when the latter is described as a potent Kv7.2/7.3 channel opener unless other potassium channels are involved with tinnitus as well.

Sure, suit yourself. But don't you ever quote or mention me again.

I'm not an expert, but I am guessing that Gabapentin isn't as potent of an activator compared to Retigabine. If that were the case, I'm not sure why there is currently a race to remake Retigabine (XEN1101/BHV-7000) if Gabapentin has similar efficacy. I remember reading previous stories of epileptic patients who found relief with Retigabine (vs. other drugs, and I'm sure Gabapentin was tried/considered).

Really, we will know once the drug is released... And until then, I am choosing to remain optimistic that it'll help (because optimism is the only thing I can have in this situation).

 

[StoneInFocus]

I'm not an expert, but I am guessing that Gabapentin isn't as potent of an activator compared to Retigabine. If that were the case, I'm not sure why there is currently a race to remake Retigabine (XEN1101/BHV-7000) if Gabapentin has similar efficacy. I remember reading previous stories of epileptic patients who found relief with Retigabine (vs. other drugs, and I'm sure Gabapentin was tried/considered).

Really, we will know once the drug is released... And until then, I am choosing to remain optimistic that it'll help (because optimism is the only thing I can have in this situation).

There are a few things I want to address with your post.

First of all, I don't think XEN1101 or BHV-7000 are some sort of 'remake' of Retigabine, they act on ion channels and GABA receptors differently, therefore you cannot extrapolate the results of the Retigabine User Experiences thread to the effects of these drugs on tinnitus and hyperacusis.

Second of all, a lot of people want to wait out for a drug that will only become available in a few years, claiming it will be the end-all cure for tinnitus and noxacusis, when something similar is already available for us to try. You say that "optimism is the only thing I can have in this situation", then why not try out Gabapentin?

Maybe the way that XEN1101 and BHV-7000 open Kv7.2/7.3 channels is different than how Gabapentin does it. But if people will base their decision on whether or not to try Gabapentin on the basis of a mythical idea of the efficiency of Retigabine, then I think they will make a stupid one.

So far no one has provided an adequate explanation why XEN1101 or BHV-7000 will be better for tinnitus & hyperacusis than Gabapentin.

 

[MFM]

Second of all, a lot of people want to wait out for a drug that will only become available in a few years, claiming it will be the end-all cure for tinnitus and noxacusis, when something similar is already available for us to try.

Why don't you give Gabapentin a try and report back to us?

 

[Joey72]

Has anyone reported their tinnitus getting worse after taking Gabapentin?

 

[StoneInFocus]

Why don't you give Gabapentin a try and report back to us?

I'm currently treated by an anesthetist who also specializes in tinnitus. He prescribed me Clonazepam for one week to see how it goes. Gabapentin is definitely on the table for me (maybe in combination with my remaining Flupirtine pills or CBD isolate) if he allows me to take it, but at the moment I'm at the mercy of his treatment protocol.

If I could pick drugs like I could pick cotton candy from a supermarket, I'd go for Keppra first to be honest, because some people with hyperacusis had good results with it. The results of Gabapentin seem mixed in that regard.

 

[Kleiner]

Of course, there is no evidence that XEN1101 is a superior remake of Retigabine, that's our hope, it's consistent, but it's not proven.

I remind those who speak of the mythical effectiveness of Retigabine that the molecule, without being a miracle cure, has shown effectiveness at some point; there is a thread on Tinnitus Talk about it. I encourage people to go check it out. It remains a safer source about Retigabine than the ideology of a single person who has not tried it.

 

[StoneInFocus]

Of course, there is no evidence that XEN1101 is a superior remake of Retigabine, that's our hope, it's consistent, but it's not proven.

I remind those who speak of the mythical effectiveness of Retigabine that the molecule, without being a miracle cure, has shown effectiveness at some point; there is a thread on Tinnitus Talk about it. I encourage people to go check it out. It remains a safer source about Retigabine than the ideology of a single person who has not tried it.

I'm just asking questions that you are simply not capable of answering and that pisses you off, deal with it.

I hope XEN1101 will treat or cure tinnitus or hyperacusis just as much as you, but until it becomes available we just have to make due with the drugs that we have.

Let's stop this discussion between you and me because it's not going anywhere.

 

[Kleiner]

I'm just asking questions that you are simply not capable of answering and that pisses you off, deal with it.

I hope XEN1101 will treat or cure tinnitus or hyperacusis just as much as you, but until it becomes available we just have to make due with the drugs that we have.

Let's stop this discussion between you and me because it's not going anywhere.

There's nothing to respond to someone who only contradicts for fun. I agree for the rest.

 

[StoneInFocus]

There's nothing to respond to someone who only contradicts for fun. I agree for the rest.

Mate I don't care about you and I didn't even ask my original question to you in the first place.

I came here with an open mind to find genuine answers to a question, not to argue with someone who doesn't even speak English properly.

You're not even close to interesting or intelligent enough for me to be able to have fun contradicting you.

 

[gameover]

@StoneInFocus, I do not know if you are right or wrong in this discussion, but you are a jerk.

 

[andrewdaniels]

@StoneInFocus, I do not know if you are right or wrong in this discussion, but you are a jerk.

I agree here. He wants some evidence/guarantee that XEN1101 will be effective - no one has it, or will until it's released and people try it. His comments have been antagonistic throughout.

I feel like I'm echoing what @Kleiner said already - Retigabine worked for some folks. Kv7.2/7.3 channels seem to be implicated in tinnitus based on research coming out (again, who really knows if those are the only channels, or if it will even have an impact).

You asked why I haven't tried Gabapentin - maybe I will, but I've read plenty of experiences where it had minimal or no impact, so I'm not in a rush to try it. I won't be in a rush to try XEN1101 either, but I'll for sure be watching. You also seem to say that because they both target KCNQ3 channels, that if one is not effective, then the other won't be. I'm not a chemist, so I don't understand the method of action or potency/differences between the drugs, however, I feel like that is a flawed comparison. It's like saying Citalopram doesn't work for some so why would Escitalopram work.

I am exiting this conversation because it is no longer productive. I'll join back once Phase 3 results are released.

 

[Lucifer]

I agree here. He wants some evidence/guarantee that XEN1101 will be effective - no one has it, or will until it's released and people try it. His comments have been antagonistic throughout.

I feel like I'm echoing what @Kleiner said already - Retigabine worked for some folks. Kv7.2/7.3 channels seem to be implicated in tinnitus based on research coming out (again, who really knows if those are the only channels, or if it will even have an impact).

You asked why I haven't tried Gabapentin - maybe I will, but I've read plenty of experiences where it had minimal or no impact, so I'm not in a rush to try it. I won't be in a rush to try XEN1101 either, but I'll for sure be watching. You also seem to say that because they both target KCNQ3 channels, that if one is not effective, then the other won't be. I'm not a chemist, so I don't understand the method of action or potency/differences between the drugs, however, I feel like that is a flawed comparison. It's like saying Citalopram doesn't work for some so why would Escitalopram work.

I am exiting this conversation because it is no longer productive. I'll join back once Phase 3 results are released.

I agree we have no definite proof on whether BHV-7000 or XEN1101 could help with tinnitus and hyperacusis/noxacusis but there was a presentation slide by Biohaven comparing BHV-7000, XEN1101 and Retigabine which showed that BHV-7000 and XEN1101 were more potent in targeting Kv 7.2 and Kv 7.3 potassium channels compared to Retigabine. That is the only proof we have along with past patients having success with Retigabine for their tinnitus and hyperacusis/noxacusis.

I'm not a fan of the gaslighting that is happening for the people who believe in the potential of these potassium opener drugs such as BHV-7000 and XEN1101. I had to put people like that on ignore as their antagonistic comments have not been good for my mental health.

 

[haha ear go eeee]

Yeah, @StoneInFocus. I know you want to find a medication while we wait for XEN1101 and BHV-7000, we all do. But being rude and antagonistic to people won't get you anywhere.

 

[Kleiner]

@StoneInFocus, you can criticize my intelligence and my English if you want, but apart from proving that you have nothing left to say except personal attacks, it won't change your incoherent speech. And, obviously, your opinion is only shared by you.

To conclude, I would say that this is a bit too simple, but I was reassured when Pr. Tzounopoulos recognized that XEN1101 could potentially act on tinnitus, implying that its properties target the supposed tinnitus-generative channels. He has a good understanding of the differences between the channels, it's the heart of his work, so I think he knows what he's talking about.

But the truth is that we will have the answer by practice before elucidating it by theory.

 

[grate_biff]

my English

Your English is fine Gordon

It would be nice if you entered the information to your profile though. Country, cause of tinnitus, etc.

I think it's nice to at least share that information. That applies to everyone!

As you were, Mr. Freeman!

 

[StoneInFocus]

@StoneInFocus, I do not know if you are right or wrong in this discussion, but you are a jerk.

I am a bit sad that some people think I am somehow being 'antagonistic' just for the fun of it. I simply do not have the energy or time for such things. I can only say that I have the best interests in mind of the people suffering on here. I like to think that my posts provide valuable information to people or provoke insightful discussions, but I have obviously failed in that regard here.

Also, I don't see it as my job to sugarcoat things or provide people their daily dose of hopium. I want to gain a deeper understanding of my condition and search for possible solutions. I think it's a bit strange that on a thread specifically dedicated to discussing research I am attacked for asking critical questions.

I know I can be very blunt sometimes so I encourage people that do not comprehend my posts, feel angered by them or are not going to respond to me intelligently to go to my profile page and ignore me. I will not change my tone.

When I'm going to once again put my health on the line I want to make sure it is absolutely worthwhile to do so. If I have to decide between trying a drug now or waiting several years for one in development I need to completely understand the reality of the situation at hand, no matter how brutal that may be. Sorry if that is distressing to some people.

 

[Nick47]

Based on nothing because I tried Trobalt back in the day when I was already several years into my tinnitus and it worked like a charm.

@r34d1ng, could you tell us a little more about your Trobalt experience? Did you get any side effects and how long did it reduce the tinnitus for?

What caused your tinnitus and do you have hearing loss?

Many thanks.

 

[lolkas]

@r34d1ng, could you tell us a little more about your Trobalt experience? Did you get any side effects and how long did it reduce the tinnitus for?

What caused your tinnitus and do you have hearing loss?

Many thanks.

It would be nice to also know how much of a reduction (subjective of course) he got? I read that people's tinnitus got eliminated while on Trobalt.

 

[r34d1ng]

@r34d1ng, could you tell us a little more about your Trobalt experience? Did you get any side effects and how long did it reduce the tinnitus for?

What caused your tinnitus and do you have hearing loss?

Many thanks.

I don't remember the exact details as it has been 6-7 years. No side effects other than mild to major dizziness for 10-15 minutes here and there. I do remember a major dizziness episode where I briefly passed out; it was definitely scary, but that was it, and I can't really fully blame Trobalt for it because I was exhausted that day.

Effects on my tinnitus (from an acoustic trauma back in 2014; no hearing loss) also varied, from volume being slightly reduced to completely shut off, lasted for from 30-60 minutes to several hours. No lasting effect, though.

 

[Josh59]

I don't remember the exact details as it has been 6-7 years. No side effects other than mild to major dizziness for 10-15 minutes here and there. I do remember a major dizziness episode where I briefly passed out; it was definitely scary, but that was it, and I can't really fully blame Trobalt for it because I was exhausted that day.

Effects on my tinnitus (from an acoustic trauma back in 2014; no hearing loss) also varied, from volume being slightly reduced to completely shut off, lasted for from 30-60 minutes to several hours. No lasting effect, though.

Was your tinnitus reactive to the sound environment (everyday sounds)?

If a similar drug came out tomorrow, would you take it again?

Thank you.

 

[r34d1ng]

Was your tinnitus reactive to the sound environment (everyday sounds)?

If a similar drug came out tomorrow, would you take it again?

Thank you.

No, it is not.

Yes, I would definitely take it even if my tinnitus is not really bothersome (but I fucking hate it).

 

[Nick47]

One positive case study:

Can the American Tinnitus Association, Tinnitus Research Initiative and Tinnitus UK collaborate with Xenon Pharmaceuticals and Biohaven to run a trial with XEN1101 and BHV-7000 on tinnitus?

1) The compounds exist.

2) They have passed safety checks. Can we use a small amount of money these organizations have raised to run a placebo-controlled, double-blinded 50 person trial? Retigabine was effective and the science supports Kv7.2/3 channel involvement (Dr. Shore, Prof. Tzounopoulos). Is this really too much to ask? There is also a case study with XEN1101.

The ATA is sitting on $700,000 from Texas Roadhouse. A pilot trial would make a small dent in that. The pharma company could be sponsored and paid to carry out this trial.

It's an absolute no brainer to me.

 

[DeanD]

Can the American Tinnitus Association, Tinnitus Research Initiative and Tinnitus UK collaborate with Xenon Pharmaceuticals and Biohaven to run a trial with XEN1101 and BHV-7000 on tinnitus?

1) The compounds exist.

2) They have passed safety checks. Can we use a small amount of money these organizations have raised to run a placebo-controlled, double-blinded 50 person trial? Retigabine was effective and the science supports Kv7.2/3 channel involvement (Dr. Shore, Prof. Tzounopoulos). Is this really too much to ask? There is also a case study with XEN1101.

The ATA is sitting on $700,000 from Texas Roadhouse. A pilot trial would make a small dent in that. The pharma company could be sponsored and paid to carry out this trial.

It's an absolute no brainer to me.

Does anyone have any contacts here in an attempt to push this forward or gain any traction?

I hate to see so much donated money continued to be ploughed in to supportive services and devices - surely we have enough of these by now - it is time money is spent looking for the cure!

 

[Josh59]

There is a Kv7 symposium this year in Naples: https://kv7channelssymposium.org/

I suspect tinnitus being mentioned there too as a therapeutic area, but it's in September. I'll keep an eye on this.

The 2nd International Kv7 Channels Symposium took place this week in Naples, Italy.

Prof. Thanos Tzounopoulos was there, "Roles and mechanisms of Kv7 channel plasticity in hearing loss and tinnitus".

Has anyone heard from him?

 

[Nick47]

Does anyone have any contacts here in an attempt to push this forward or gain any traction?

I would think the best bet would be for someone in the US to contact the American Tinnitus Association. They could fund the initial pilot trials. So in effect they sponsor it. If it's efficacious, then it's a win for the pharma companies. If not, then it doesn't cost them either.

 

[BTaylor12]

One positive case study:

View attachment 55780

Can the American Tinnitus Association, Tinnitus Research Initiative and Tinnitus UK collaborate with Xenon Pharmaceuticals and Biohaven to run a trial with XEN1101 and BHV-7000 on tinnitus?

1) The compounds exist.

2) They have passed safety checks. Can we use a small amount of money these organizations have raised to run a placebo-controlled, double-blinded 50 person trial? Retigabine was effective and the science supports Kv7.2/3 channel involvement (Dr. Shore, Prof. Tzounopoulos). Is this really too much to ask? There is also a case study with XEN1101.

The ATA is sitting on $700,000 from Texas Roadhouse. A pilot trial would make a small dent in that. The pharma company could be sponsored and paid to carry out this trial.

It's an absolute no brainer to me.

I'm not sure the ATA has a stellar track record of using funds wisely. If they do, I stand corrected...

Maybe contact them with this idea?