Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[r34d1ng]

What was your tinnitus level before and after taking Trobalt?

Same. Trobalt did not provide any lasting reduction, but it definitely lowered my tinnitus, if not completely shut it down, for some hours.

 

[andrewdaniels]

I'm not educated enough, but been reading a lot on here. Many are saying that Gabapentin has helped reduce their tinnitus. I believe someone also said it works on potassium channels? But that it is short lived.

Didn't Trobalt also impact GABA? Could the impact from Trobalt be from GABA itself, and not necessarily from the potassium channels?

I'm trying to keep hope that XEN1011 will work, so I thought I'd ask anyone else to weigh in with their thoughts.

 

[Lucifer]

I'm not educated enough, but been reading a lot on here. Many are saying that Gabapentin has helped reduce their tinnitus. I believe someone also said it works on potassium channels? But that it is short lived.

Didn't Trobalt also impact GABA? Could the impact from Trobalt be from GABA itself, and not necessarily from the potassium channels?

I'm trying to keep hope that XEN1011 will work, so I thought I'd ask anyone else to weigh in with their thoughts.

Maybe but I think tinnitus and hyperacusis/noxacusis reduction was more because of the Kv7 potassium channels, particularly Kv7.2 and Kv7.3. We won't know for sure until XEN1101 or BHV-7000 come out in the market.

 

[Joeseph Stope]

Uh. Wait. WHAT? I have IBS *AND* tinnitus.

The name of the grain is "Teff" -- widely grown in Ethiopia or somewhere... Google it.

The main point as regards tinnitus that I had been trying to make is that -- taking a long view -- ailments, diseases, disabilities kind of come and go. It's like a process.

Just think what the discovery of lenses did for eyesight problems back in Galileo's time. What the simple discovery and development of a wheelchair did for those who had lost their mobility.

The hearing aid and the cochlear implant were big steps forward for people with auditory problems.

But it looks like new disabilities are arriving such as West-Nile Virus, Lyme disease, COVID-19, etc.

So we just have to take it laid back with steady curiosity and some optimism and watch patiently at what the research brings in.

I acknowledge that the clinical trials etc. are time-consuming but who knows, with the objective measures of tinnitus in the pipeline, that may speed up the process.

I hope this helps.

 

[Lucifer]

The name of the grain is "Teff" -- widely grown in Ethiopia or somewhere... Google it.

The main point as regards tinnitus that I had been trying to make is that -- taking a long view -- ailments, diseases, disabilities kind of come and go. It's like a process.

Just think what the discovery of lenses did for eyesight problems back in Galileo's time. What the simple discovery and development of a wheelchair did for those who had lost their mobility.

The hearing aid and the cochlear implant were big steps forward for people with auditory problems.

But it looks like new disabilities are arriving such as West-Nile Virus, Lyme disease, COVID-19, etc.

So we just have to take it laid back with steady curiosity and some optimism and watch patiently at what the research brings in.

I acknowledge that the clinical trials etc. are time-consuming but who knows, with the objective measures of tinnitus in the pipeline, that may speed up the process.

I hope this helps.

Having both XEN1101 and BHV-7000 being each other's competitors, there is more of an incentive on getting these Kv7 potassium channel opener drugs out quickly. I'm hoping these trials could finish by Mid 2024 at the earliest if they recruit patients quickly. Pfizer's Biohaven BHV-7000 still hasn't started its pivotal phase so we have no idea when that trial will start and end but they could be the first one to come out in the market due to the amount of resources they have.

 

[Nick47]

I'm hoping these trials could finish by Mid 2024 at the earliest if they recruit patients quickly. Pfizer's Biohaven BHV-7000 still hasn't started its pivotal phase so we have no idea when that trial will start and end but they could be the first one to come out in the market due to the amount of resources they have.

You're very optimistic. Either that, or I'm pessimistic. I would expect the trials to last 18-24 months, then there is data crunching and then the approval process if all goes well. If I'm right, that means mid 2026 for market launch.

What would help me is seeing evidence that they are effective. I could happily wait knowing that!

 

[StoneInFocus]

You're very optimistic. Either that, or I'm pessimistic. I would expect the trials to last 18-24 months, then there is data crunching and then the approval process if all goes well. If I'm right, that means mid 2026 for market launch.

What would help me is seeing evidence that they are effective. I could happily wait knowing that!

I think that estimation is realistic.

What I'm really curious about is the difference between XEN1101 and the already existing Kv7 modulator Gabapentin in terms of effect on tinnitus and noxacusis.

Gabapentin seems to primarily activate the heteromeric KCNQ2/3 and the homomeric KCNQ3 and KCNQ5 channels, while Xenon primarily activates the heteromeric KCNQ2/3 also and the homomeric KCNQ2 channel.

I see a lot of people talking about some sort of 'race' between XEN1101, BHV-7000 and Auricle, like these will completely eliminate tinnitus or hyperacusis. Meanwhile there is no evidence yet that XEN1101 or BHV-7000 works for tinnitus.

Do we have any theories on why XEN1101 would be better for treating tinnitus & hyperacusis than Gabapentin, or Epidiolex for that matter? Or are we just projecting our hopes into these drugs and presenting them as better treatments than they actually are?

I'm not trying to be pessimistic here, I'm just wondering how good of an idea it is to place all of our (mental) chips on a single drug that only becomes available in several years? Again, I'm all open to hearing ideas on why XEN1101 or BHV-7000 will be so much better for tinnitus or hyperacusis than what we have right now, but I'm just not really seeing it at the moment.

 

[andrewdaniels]

I think that estimation is realistic.

What I'm really curious about is the difference between XEN1101 and the already existing Kv7 modulator Gabapentin in terms of effect on tinnitus and noxacusis.

Gabapentin seems to primarily activate the heteromeric KCNQ2/3 and the homomeric KCNQ3 and KCNQ5 channels, while Xenon primarily activates the heteromeric KCNQ2/3 also and the homomeric KCNQ2 channel.

I see a lot of people talking about some sort of 'race' between XEN1101, BHV-7000 and Auricle, like these will completely eliminate tinnitus or hyperacusis. Meanwhile there is no evidence yet that XEN1101 or BHV-7000 works for tinnitus.

Do we have any theories on why XEN1101 would be better for treating tinnitus & hyperacusis than Gabapentin, or Epidiolex for that matter? Or are we just projecting our hopes into these drugs and presenting them as better treatments than they actually are?

I'm not trying to be pessimistic here, I'm just wondering how good of an idea it is to place all of our (mental) chips on a single drug that only becomes available in several years? Again, I'm all open to hearing ideas on why XEN1101 or BHV-7000 will be so much better for tinnitus or hyperacusis than what we have right now, but I'm just not really seeing it at the moment.

I don't think any of these options will completely eliminate tinnitus. If any of them can eliminate it by even 50%, I'll take it.

I don't know enough about pharmaceuticals, but if Gabapentin is a potent activator of the same channels, why would they not bother to use it for seizures as well/bother with creating these drugs? I'm assuming there's something in the mechanism of action of Trobalt vs. Gabapentin that worked for people.

I think both drug companies seem pretty confident in their drug, so much so that Biohaven is trying to expedite/catch up.

Truly, my hopes are on Susan Shore's device, and I suspect that is the first thing that will hit the market (how long it will take us all to get access to it is another matter, as I'm sure there'll be huge waiting lists).

Once these two drugs come out, I will likely wait until a few folks try it and report back before giving it a go. I am hopeful, but like you, don't want to put all my eggs in one basket. Reading threads here about the amount of hope for Autifony, Otomony, etc. seem very similar to the hope for this drug.

Provided they pass the Phase 3 trial, I suspect this drug will likely be end of 2025/early 2026. Maybe they will expedite their trials?

 

[Kam75]

Or are we just projecting our hopes into these drugs and presenting them as better treatments than they actually are?

As we say in French, "hope is life".

We have a damn incurable disease. So every potential treatment gives us hope, even if we're not sure it will work.

It's always better than hearing the perpetual "there's nothing you can do, get used to it" from doctors.

Whenever I'm not feeling well, like now because I'm having sleepless nights again because of my tinnitus, I come to Tinnitus Talk in search of hope.

 

[Kleiner]

I think that estimation is realistic.

What I'm really curious about is the difference between XEN1101 and the already existing Kv7 modulator Gabapentin in terms of effect on tinnitus and noxacusis.

Gabapentin seems to primarily activate the heteromeric KCNQ2/3 and the homomeric KCNQ3 and KCNQ5 channels, while Xenon primarily activates the heteromeric KCNQ2/3 also and the homomeric KCNQ2 channel.

I see a lot of people talking about some sort of 'race' between XEN1101, BHV-7000 and Auricle, like these will completely eliminate tinnitus or hyperacusis. Meanwhile there is no evidence yet that XEN1101 or BHV-7000 works for tinnitus.

Do we have any theories on why XEN1101 would be better for treating tinnitus & hyperacusis than Gabapentin, or Epidiolex for that matter? Or are we just projecting our hopes into these drugs and presenting them as better treatments than they actually are?

I'm not trying to be pessimistic here, I'm just wondering how good of an idea it is to place all of our (mental) chips on a single drug that only becomes available in several years? Again, I'm all open to hearing ideas on why XEN1101 or BHV-7000 will be so much better for tinnitus or hyperacusis than what we have right now, but I'm just not really seeing it at the moment.

In my case, Gabapentin is incredibly weaker in terms of efficacy on tinnitus than Retigabine (Trobalt), although I think they make a good combo.

The real question is can XEN1101/BHV-7000 activate the channels responsible for tinnitus. If they do the same as Retigabine, they will indeed be very interesting tools.

 

[Nick47]

how good of an idea it is to place all of our (mental) chips on a single drug that only becomes available in several years? Again, I'm all open to hearing ideas on why XEN1101 or BHV-7000 will be so much better for tinnitus or hyperacusis than what we have right now, but I'm just not really seeing it at the moment.

It's educated guesswork on current findings really. I just wish they would run a small (20-30) participant trial to see if it has efficacy. They are obviously safe enough to progress to late stage human trials, why not run a small parallel trial on tinnitus patients? I have not seen any anecdotal evidence from an epilepsy patient with tinnitus either.

I'm not critical of the logic that they may be beneficial, I would just like some idea of indication.

 

[Utdmad89]

It's educated guesswork on current findings really. I just wish they would run a small (20-30) participant trial to see if it has efficacy. They are obviously safe enough to progress to late stage human trials, why not run a small parallel trial on tinnitus patients? I have not seen any anecdotal evidence from an epilepsy patient with tinnitus either.

I'm not critical of the logic that they may be beneficial, I would just like some idea of indication.

Do they have any idea that this could work for tinnitus sufferers? As in are they even informed if they are looking for a tinnitus treatment?

 

[DeanD]

It does seem strange that, with 750 million tinnitus sufferers, a test hasn't been carried out for tinnitus - surely if it shows any efficacy it could be an even bigger cash cow.

Seems odd.

Do they even know or are they even aware?

Are there any negatives in terms of their business goals to test this on tinnitus (other than PR on their brand if it makes a bunch of tinnitus sufferers even worse)?

 

[Lucifer]

Do they have any idea that this could work for tinnitus sufferers? As in are they even informed if they are looking for a tinnitus treatment?

They most likely know about tinnitus reduction happening from patients taking Trobalt in the past. Whether they want to test it on tinnitus patients is up to them. Obviously with the number of people suffering from tinnitus in recent times it's a no brainer that they should test XEN1101 and BHV-7000 on tinnitus patients. Imagine the potential market they could unlock if it does end up working for tinnitus like Trobalt.

It's educated guesswork on current findings really. I just wish they would run a small (20-30) participant trial to see if it has efficacy. They are obviously safe enough to progress to late stage human trials, why not run a small parallel trial on tinnitus patients? I have not seen any anecdotal evidence from an epilepsy patient with tinnitus either.

I'm not critical of the logic that they may be beneficial, I would just like some idea of indication.

Just because these drugs might be similar to Trobalt, who knows if these drugs have the same efficacy as Trobalt when it comes to reducing tinnitus and hyperacusis/noxacusis. Biohaven have plenty of resources to have a small trial to test for tinnitus and, if it does end up working, patients don't have to beg their doctors to prescribe it off-label.

Do you know if they are delaying the pivotal phase for BHV-7000 because they are waiting for the full EEG Phase 1 results to come out first?

If you do end up finding out any patients with tinnitus who were in the trial, let us know. Maybe they had to sign an NDA so they can't say but there may be some tinnitus patients who were in the trials in epilepsy support groups.

It does seem strange that, with 750 million tinnitus sufferers, a test hasn't been carried out for tinnitus - surely if it shows any efficacy it could be an even bigger cash cow.

Seems odd.

Do they even know or are they even aware?

Are there any negatives in terms of their business goals to test this on tinnitus (other than PR on their brand if it makes a bunch of tinnitus sufferers even worse)?

I think the only negative on testing it out on tinnitus is if these reformulated Kv7 potassium opener drugs don't have the same effect of reducing tinnitus as Trobalt did but the likelihood of that happening is very low.

As you stated, if they test it out on tinnitus it could potentially open another market of sufferers. I see a test on tinnitus patients being worth it on that potential.

 

[andrewdaniels]

I do remember reading that one of the companies were aware about the potential to help tinnitus. Part of me wonders if they are not doing a trial due to the subjective nature of tinnitus... It is much easier to measure number of seizures than an objective tinnitus rating. The current objective tinnitus test being crafted in Australia will certainly help in future.

 

[Lucifer]

I do remember reading that one of the companies were aware about the potential to help tinnitus. Part of me wonders if they are not doing a trial due to the subjective nature of tinnitus... It is much easier to measure number of seizures than an objective tinnitus rating. The current objective tinnitus test being crafted in Australia will certainly help in future.

Someone on Tinnitus Talk emailed Biohaven asking if they were going to test BHV-7000 out on tinnitus patients. I think the reply was along the lines of something that they may discuss or consider it with the people who make the decisions at Biohaven.

The tinnitus trial doesn't need to be really long. We know that most people's tinnitus went away with Trobalt within less than 24 hours. So the trial could probably last for a few months. Maybe have tinnitus patients take the drug ranging from a week to a month, then see how long it takes for the tinnitus to come back once stopping BHV-7000 or XEN1101.

 

[StoneInFocus]

As we say in French, "hope is life".

We have a damn incurable disease. So every potential treatment gives us hope, even if we're not sure it will work.

It's always better than hearing the perpetual "there's nothing you can do, get used to it" from doctors.

Whenever I'm not feeling well, like now because I'm having sleepless nights again because of my tinnitus, I come to Tinnitus Talk in search of hope.

The problem is that too many people on here have some unrealistic idea of a one-pill-fixes-all cure for tinnitus, and then consequently they start whining and complaining when a particular drug in the pipeline is taking too long.

I mean I'm all for being hopeful, but right now 80-90 percent of the posts on Research News are a combination of completely overhyping certain drugs in development, and lamenting that it is not magically delivered to their doorstep tomorrow. Very rarely I see actual substantive discussions taking place. It's just a few people actually posting meaningful content, but I feel like a lot of that isn't even read in the first place.

So again I ask, what makes you think that XEN1101 will be better than the anticonvulsants that are already available, or other treatment options for that matter? Still open to hearing good arguments.

In my case, Gabapentin is incredibly weaker in terms of efficacy on tinnitus than Retigabine (Trobalt), although I think they make a good combo.

The real question is can XEN1101/BHV-7000 activate the channels responsible for tinnitus. If they do the same as Retigabine, they will indeed be very interesting tools.

Interesting.

I am particularly interested in the role of Kv7.4 channels in tinnitus, as they are majorly expressed on outer hair cells. It's surprisingly difficult to find information about how XEN1101 compares to Retigabine in that aspect.

As of right now the only thing I could find about the difference between Retigabine and XEN1101 is that the latter is more potent in activating heteromeric Kv7.2/7.3 channels.

 

[Kleiner]

I am particularly interested in the role of Kv7.4 channels in tinnitus, as they are majorly expressed on outer hair cells. It's surprisingly difficult to find information about how XEN1101 compares to Retigabine in that aspect.

As of right now the only thing I could find about the difference between Retigabine and XEN1101 is that the latter is more potent in activating heteromeric Kv7.2/7.3 channels.

That's exactly the point.

I don't have an answer, I just know that according to the dominant theory Kv7.2 and Kv7.3 are "enough".

K7.4 is indeed expressed in the hair cells.

In my case I am 95% sure that the tinnitus affected by Trobalt is not located in the hair cells but in the DCN.

It is possible that Kv7.4 is not important in the sense that tinnitus is rarely expressed directly at the hair cells.

But there might be another mechanism that would make Retigabine work and XEN1101 not.

 

[Lucifer]

That's exactly the point.

I don't have an answer, I just know that according to the dominant theory Kv7.2 and Kv7.3 are "enough".

K7.4 is indeed expressed in the hair cells.

In my case I am 95% sure that the tinnitus affected by Trobalt is not located in the hair cells but in the DCN.

It is possible that Kv7.4 is not important in the sense that tinnitus is rarely expressed directly at the hair cells.

But there might be another mechanism that would make Retigabine work and XEN1101 not.

That's a good point about tinnitus rarely being expressed directly at the hair cells in terms of Kv7.4.

We know that some people who suffer from hearing loss don't have tinnitus so the likelihood of Kv7.4 being important for tinnitus is low.

I have a feeling tinnitus and hyperacusis/noxacusis is more likely to do with Kv7.2 and Kv7.3.

Hyperacusis/noxacusis could also be related to Kv7.4 but if the theory is true, I believe once we calm the type II fibers synapses by opening Kv7.2 and Kv7.3 potassium channels, it should stop the stabbing, aching and burning pain that noxacusis sufferers have, and loudness hyperacusis as well.

 

[StoneInFocus]

I don't have an answer, I just know that according to the dominant theory Kv7.2 and Kv7.3 are "enough".

Do you mean the heteromeric or the homomeric potassium channels and according to whom is that the 'dominant' theory?

In my case I am 95% sure that the tinnitus affected by Trobalt is not located in the hair cells but in the DCN.

How would you even know that?

I have a feeling tinnitus and hyperacusis/noxacusis is more likely to do with Kv7.2 and Kv7.3.

Hyperacusis/noxacusis could also be related to Kv7.4 but if the theory is true, I believe once we calm the type II fibers synapses by opening Kv7.2 and Kv7.3 potassium channels, it should stop the stabbing, aching and burning pain that noxacusis sufferers have, and loudness hyperacusis as well.

Curious why you would say that?

As far as I know, no particular potassium channel has been proven to be expressed on type II SGNs. As OHCs connect to type II afferents and their ribbon number and size increases after cochlear trauma, it's really interesting to think about what opening Kv7.4 could do for noxacusis.

We know that some people who suffer from hearing loss don't have tinnitus so the likelihood of Kv7.4 being important for tinnitus is low.

Did you read this in a paper or is that something you made up yourself?

 

[andrewdaniels]

An interesting read if you haven't come across it before:

XEN1101: A Novel Potassium Channel Modulator for the Potential Treatment of Focal Epilepsy in Adults

It seems to imply that XEN1101 will also impact Kv7.4/7.5 as well, albeit not as strong. If Kv7.4 is involved, there is a chance that it could still have some impact.

 

[Kleiner]

How would you even know that?

Let's say I did more than just theorize.

Besides the hundreds of papers on the auditory system, experiments (including Trobalt for example, but not limited to) and random events have enabled me to determine where my tinnitus generation site is.

There remains a small doubt, the inferior colliculus could be involved too. But no other structure is a good candidate for my situation.

 

[StoneInFocus]

Let's say I did more than just theorize.

Besides the hundreds of papers on the auditory system, experiments (including Trobalt for example, but not limited to) and random events have enabled me to determine where my tinnitus generation site is.

There remains a small doubt, the inferior colliculus could be involved too. But no other structure is a good candidate for my situation.

Okay but I'm still curious why you think that opening Kv7.2 and Kv7.3 (I still don't know if you mean heteromeric or homomeric) channels is sufficient to cure tinnitus. I have never read anywhere that "according to the dominant theory Kv7.2 and Kv7.3 are 'enough'" (whatever you mean by that). Maybe it was in your case but who says that holds true for the rest of the people with tinnitus?

 

[Kleiner]

Okay but I'm still curious why you think that opening Kv7.2 and Kv7.3 (I still don't know if you mean heteromeric or homomeric) channels is sufficient to cure tinnitus. I have never read anywhere that "according to the dominant theory Kv7.2 and Kv7.3 are 'enough'" (whatever you mean by that). Maybe it was in your case but who says that holds true for the rest of the people with tinnitus?

Well, in most of the papers I've read about Kv7s and tinnitus, there's rarely any mention of channels other than Kv7.2 and Kv7.3.

If you have papers which explore the application of other channels in tinnitus (and not in hair cells), I'm interested.

For what it's worth, if I recall correctly, Prof. Thanos Tzounopoulos seemed to view XEN1101 as potentially effective medicine for tinnitus, and XEN1101 targeting KV7.2 and Kv7.3 specifically (Retigabine also favors them, but is much less selective). But I still have doubts.

Retigabine is also not effective against all types of tinnitus, my non-somatic tinnitus reacts only slightly, in the range of the placebo in the worst case, hard to say. This situation seems similar to those that preceded me years ago.

All this to say the actual mechanism must be more complex than we can imagine.

 

[Lucifer]

An interesting read if you haven't come across it before:

XEN1101: A Novel Potassium Channel Modulator for the Potential Treatment of Focal Epilepsy in Adults

It seems to imply that XEN1101 will also impact Kv7.4/7.5 as well, albeit not as strong. If Kv7.4 is involved, there is a chance that it could still have some impact.

That seems to be the case. They also mentioned in their presentation slides a while back about which potassium channels they target and by how much.

BHV-7000 only targets Kv7.2 and Kv7.3. Depending on which one comes out first, would it be easy to switch between BHV-7000 and XEN1101 since they are both potassium channel opener drugs or would we need to come off on one of them completely before starting another one?

 

[andrewdaniels]

BHV-7000 only targets Kv7.2 and Kv7.3. Depending on which one comes out first, would it be easy to switch between BHV-7000 and XEN1101 since they are both potassium channel opener drugs or would we need to come off on one of them completely before starting another one?

I don't think anyone will know the answer to that until they're out, and even then, I doubt folks will know! I'm so desperate lately, I'm trying to hold on to hope.

 

[Lucifer]

I don't think anyone will know the answer to that until they're out, and even then, I doubt folks will know! I'm so desperate lately, I'm trying to hold on to hope.

Same, these Kv 7 potassium channel opener drugs seem to be the key in reducing tinnitus and hyperacusis/noxacusis.

Especially since these Kv7 potassium channel opener drugs are more potent compared to Retigabine, there's a better chance it could get rid of tinnitus and hyperacusis/noxacusis permanently.

 

[StoneInFocus]

If you have papers which explore the application of other channels in tinnitus (and not in hair cells), I'm interested.

Certainly, another ion channel which involvement has been investigated in tinnitus is the HCN2 channel.

Tzounopoulos has shown that reduced HCN channel activity in fusiform cells of the DCN is associated with tinnitus resilience after noise exposure. He says that "drugs that increase activity of [heteromeric] KCNQ2/3 channels (which are modulated by Gabapentin!), and/or reduce activity of HCN channels, could thus boost resilience to tinnitus. In the future, targeting both channel types at the same time could provide an effective treatment with minimal side effects."

McNaughton et al. found out that systemically administrated HCN2 blockers reach the auditory nerve and reduce tinnitus perception in guinea pigs.

So if heteromeric Kv7.2/Kv7.3 channels are the main channels implicated in tinnitus as you seem to imply, then why did Retigabine work so much better for you then Gabapentin? Really interesting to think about.

 

[Kleiner]

So if heteromeric Kv7.2/Kv7.3 channels are the main channels implicated in tinnitus as you seem to imply, then why did Retigabine work so much better for you then Gabapentin? Really interesting to think about.

Precisely because Retigabine is a Kv7 opener and Gabapentin is not, at least much less so.

 

[StoneInFocus]

Precisely because Retigabine is a Kv7 opener and Gabapentin is not, at least much less so.

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

Here, we report that gabapentin is a potent activator of the heteromeric KCNQ2/3 voltage-gated potassium channel, the primary molecular correlate of the neuronal M-current, and also homomeric KCNQ3 and KCNQ5 channels.

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