Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[Markku]

I saw a post somewhere on the internet stating that Biohaven's community managers or other staff were open to conversations about it, but they were expecting it to come through a big organization like the American Tinnitus Association or something.

What needs to be done is clear, we need to get the ball rolling and ask them with the help of a credible, known organization, if their drugs work for tinnitus or not, if there are any success stories among the trial participants, if we should have any expectations for it, or set up a mini-trial of say ten people, if possible, instead of waiting for UP TO 5 YEARS and have a rude awakening ourselves if it doesn't do the job.

Is this possible, @Nick47?

This was Biohaven's response to us some time back:

 

[antonio77]

I think we would all sign up to take some pills all our lives in exchange for reducing or eliminating tinnitus, even if it is only for a few hours a day. For example, you take it at bedtime, and you can sleep in silence. I agree with that.

 

[dd314]

I think we would all sign up to take some pills all our lives in exchange for reducing or eliminating tinnitus, even if it is only for a few hours a day. For example, you take it at bedtime, and you can sleep in silence. I agree with that.

YMMV, but muscle relaxers have this effect for some people.

 

[BB23]

YMMV, but muscle relaxers have this effect for some people.

So do antiepileptics and benzos. Those side effects, though.

It's a gamble.

 

[BB23]

I'm aware of a person who has had XEN1101 compounded or acquired it somehow. They have only been taking it recently but have had no impact so far, whereas they did respond to Retigabine, although sporadically.

It might be unrelated, but I'm seeing reports on the forums of it not working for visual snow patients, either.

I wonder what exactly it was about Retigabine that made people permanent improvements. It surely can't be its GABA action alone. Otherwise, benzos should also improve people's lives. I remember seeing a chart that showed Retigabine also messed around with chloride on the Keppra topic here on Tinnitus Talk. Maybe it's that? Or maybe, just like you said, a combination of many things, but what exactly is that combo? Why isn't anyone trying to find it out?

 

[Nick47]

wonder what exactly it was about Retigabine that made

It's the combo. A cake mixture. You would not separate the ingredients of a nice cake and say, 'Which one makes it taste nice?'

The tinnitus activity is firing, which causes a network of electrical activity involving many neurotransmitters and pain receptors.

 

[StoneInFocus]

It might be unrelated, but I'm seeing reports on the forums of it not working for visual snow patients, either.

I wonder what exactly it was about Retigabine that made people permanent improvements. It surely can't be its GABA action alone. Otherwise, benzos should also improve people's lives. I remember seeing a chart that showed Retigabine also messed around with chloride on the Keppra topic here on Tinnitus Talk. Maybe it's that? Or maybe, just like you said, a combination of many things, but what exactly is that combo? Why isn't anyone trying to find it out?

I think Retigabine has an edge over XEN1101 because it can also open Kv7.4.

KCNQ4 is known to be also expressed in [OHCs], IHCs, spiral ganglion neurons, and several nuclei along the auditory pathway, for example, cochlear nuclei and inferior colliculus.

The additional opening of Kv7.4 might also have a synergistic effect in combination with the opening of the other Kv7 channels.

I think only mild or very recent cases noticed permanent improvements.

 

[BB23]

I think only mild or very recent cases noticed permanent improvements.

There was at least one significant outlier that can nullify this statement. @preslys was ringing for a while before he got permanent improvements (down to a 0/10).

I still want to be hopeful for XEN1101, but I don't think it is realistic to have a lot of expectations for it anymore. Studies never claimed it did anything for chronic tinnitus, and nobody is pursuing treatment with these kinds of drugs, which is very suggestive of things.

@StoneInFocus, do benzos do anything for your tinnitus? Do you have a take on the KCC2 stuff? I believe that will be the solution we are looking for... I want to hear your opinions if you have any.

 

[dd314]

So do antiepileptics and benzos. Those side effects, though.

It's a gamble.

I don't know if this has been mentioned yet, but XEN1101 is supposed to have side effects comparable to those of most other anticonvulsants. I specifically remember that from one of Xenon Pharmaceuticals' PowerPoint slides after the Phase 2 trials came out. I'd rather not go digging for the source, but they explicitly stated it.

 

[StoneInFocus]

There was at least one significant outlier that can nullify this statement. @preslys was ringing for a while before he got permanent improvements (down to a 0/10).

I still want to be hopeful for XEN1101, but I don't think it is realistic to have a lot of expectations for it anymore. Studies never claimed it did anything for chronic tinnitus, and nobody is pursuing treatment with these kinds of drugs, which is very suggestive of things.

@StoneInFocus, do benzos do anything for your tinnitus? Do you have a take on the KCC2 stuff? I believe that will be the solution we are looking for... I want to hear your opinions if you have any.

Interesting. Do you know how long he had tinnitus and how long he took Retigabine?

Acousia Therapeutics is currently working on Kv7.4 openers. Combined with XEN1101, could it achieve a similar performance as Retigabine?

Benzos don't really improve my tinnitus much I think, but I only have experience with 0.5 mg Clonazepam. I haven't really investigated this KCC2 angle yet.

 

[BB23]

Interesting. Do you know how long he had tinnitus and how long he took Retigabine?

He was ringing for 13 months or so at a 6/10 prior to using Retigabine. If I recall correctly, he used four boxes, so it should have been four months. He took his last dose with some Gabapentin, and his tinnitus went away for good. You can check his post history for details.

@Danny Boy also had his unbearable tinnitus reduced to livable levels. Later on, though, he messed around with a lot of drugs.

Acousia Therapeutics is currently working on Kv7.4 openers. Combined with XEN1101, could it achieve a similar performance as Retigabine?

I can't say. We actually don't know why Retigabine even worked in the first place. Even with the Kv7.4 drug added in, something else could be missing in this cocktail that Retigabine originally had. Maybe its GABA action activated some random subchannel we don't know about. Who knows... However, activating all these potassium channels by adding more drugs will do more harm than good.

The KCC2 aspect started to make more sense to me due to my research on visual snow and neuroinflammation prior to reading Arnaud Norena's paper on it. I mean, benzos work for most visual snow and tinnitus cases by upping the GABA and messing around with chloride as a result, so it would make more sense to make a drug that directly targets the chloride channels without disrupting the overall GABA levels of the brain. That way, you don't mess with sodium or potassium channels; I don't know if you read anything about it, but using sodium channel blockers like Lamotrigine can cause breathing problems, among other things, similar to using Kv7.4 openers causing bladder and heart issues. Touching these channels all at once is dangerous. So, KCC2 should be less harmful for long-term use, or so I hope.

 

[StoneInFocus]

I can't say. We actually don't know why Retigabine even worked in the first place. Even with the Kv7.4 drug added in, something else could be missing in this cocktail that Retigabine originally had. Maybe its GABA action activated some random subchannel we don't know about. Who knows...

What do you mean we don't know why Retigabine worked? Also, Retigabine has a 10-fold higher affinity for Kv7.2/7.3 than GABAa receptors.

However, activating all these potassium channels by adding more drugs will do more harm than good.

Who says that? If I remember correctly, Retigabine's more serious adverse effects had nothing to do with its Kv7 channel opening properties.

I've looked up KCC2 but I haven't seen any explanation why KKC2 agonism is superior to directly modulating the GABA receptors.

 

[BB23]

I've looked up KCC2 but I haven't seen any explanation why KKC2 agonism is superior to directly modulating the GABA receptors.

This may result from different inflammatory responses in these nuclei, since KCC2 downregulation depends on the release of pro-inflammatory mediators (microglial-derived BDNF). To note, the presence of inflammation has been reported in cochlear nucleus after hearing loss

Neuroinflammation is at play in tinnitus. @Nick47 said it was a buzzword in our past conversations. KCC2 being directly involved suggests otherwise. Increase GABA all you want in the inflammatory state where the KCC2 channels are lost; you'd only make things worse since, in this state, it will be excitatory, not inhibitory. This is not a good analogy, but imagine you are watching an old Tom & Jerry cartoon, and there is a hose, and somebody is stepping on it. That is the KCC2 channels being lost. Please turn on the water all you want; it will cause the hose to swell up, and not much water will come out of it, causing issues.

TL;DR: KCC2 modulates how GABA works; without KCC2 channels, GABA won't be able to draw chloride out and can't hyperpolarize the neurons.

Also, as you already know, directly modulating GABA with benzos for a while will cause downregulation of receptors and dependence and withdrawals that might end up causing you harm. There is more information on BenzoBuddies.

KCC2 should not cause downregulation and global total destruction like benzos do. It will still be neurotoxic to a degree, though, as with all stuff that crosses the BBB. Further tests are required for us to know.

Who says that? If I remember correctly, Retigabine's more serious adverse effects had nothing to do with its Kv7 channel opening properties.

Like how do you know that? Do you have any studies? Did anyone study the side effects of opening Kv7.2/3 or 4 in the long run? Remember that Gabapentin can also cause visual snow and other horrible stuff; there are support groups for it. These drugs would tell your CNS to slow down and stop firing action potentials globally. Even the healthy neurons will be affected. Who knows if this isn't why visual snow happened with Retigabine use? You don't think this would cause any issues, and you want to open more potassium channels by adding in more drugs? Can you say for certain that opening these channels is safe? Here's my reasoning. Pick an anticonvulsant, any anticonvolsant. You'll see a support group on Facebook, Reddit, or wherever. Long-term use of these drugs will come with side effects or withdrawals. That's why these companies are trying to make more selective drugs, and that's why Retigabine was removed from the market. If you recall, some people here reported having seizures and some other stuff after quitting Retigabine. It's pretty common with pretty much all anticonvulsants out there. I hope it makes some sense.

What do you mean we don't know why Retigabine worked? Also, Retigabine has a 10-fold higher affinity for Kv7.2/7.3 than GABAa receptors.

Since no study exists, we don't know how Retigabine works for chronic tinnitus. We know that Kv7.2/3 drugs can prevent tinnitus after noise exposure and BEFORE IT SETS IN, thanks to Tzounopoulos's research. It probably worked because it slowed down everything in the brain due to its unique mechanisms that nobody knows. If I recall correctly, it also activates some other potassium and calcium channels off-target; you can find out about it on Google. And, of course, I want to remain hopeful. All the stuff I have written above could be conjecture, and XEN1101 might come out the door and work for chronic tinnitus, but all the reports so far suggest it doesn't do much for tinnitus or visual snow.

 

[StoneInFocus]

Increase GABA all you want in the inflammatory state where the KCC2 channels are lost; you'd only make things worse since, in this state, it will be excitatory, not inhibitory.

Sorry, but I don't see the logic here.

TL;DR: KCC2 modulates how GABA works; without KCC2 channels, GABA won't be able to draw chloride out and can't hyperpolarize the neurons.

I think you misunderstand how KCC2 works. The GABA neurotransmitter does not draw chloride ions out of the cell; the KCC2 transporter does. By doing this, the cell is depolarized, not hyperpolarized, which results in increased GABA release at the presynaptic terminal. This GABA then interacts with GABA receptors at the postsynaptic terminal.

KCC2 should not cause downregulation and global total destruction like benzos do. It will still be neurotoxic to a degree, though, as with all stuff that crosses the BBB.

Where is the evidence for this?

Like how do you know that? Do you have any studies?

So, I was actually referring to what Prof. Tzounopoulos said in an interview with Tinnitus Talk Podcast:

People that were taking Retigabine for a year, again it was working for epilepsy, they started developing this blue colouration to their skin and their retina due to some degradation products of Retigabine and also the lack of specificity of Retigabine.

He does not specify which aspect is the biggest contributor to these adverse effects or whether channel Q4 or Q5 is involved. I couldn't find much information about how Retigabine causes discoloration, so maybe this should be taken with a grain of salt.

Remember that Gabapentin can also cause visual snow and other horrible stuff; there are support groups for it. These drugs would tell your CNS to slow down and stop firing action potentials globally. Even the healthy neurons will be affected. Who knows if this isn't why visual snow happened with Retigabine use? You don't think this would cause any issues, and you want to open more potassium channels by adding in more drugs? Can you say for certain that opening these channels is safe? Here's my reasoning. Pick an anticonvulsant, any anticonvolsant. You'll see a support group on Facebook, Reddit, or wherever. Long-term use of these drugs will come with side effects or withdrawals. That's why these companies are trying to make more selective drugs, and that's why Retigabine was removed from the market. If you recall, some people here reported having seizures and some other stuff after quitting Retigabine. It's pretty common with pretty much all anticonvulsants out there. I hope it makes some sense.

I understand your fears, however I think you should see it in perspective.

Visual snow was not the reason Retigabine was discontinued. It is probably a rare side effect. Is there any evidence that visual snow has anything to do with the quantity of ion channels opened? Psychedelics can also cause visual snow.

Also, Lyrica was developed as a more selective version of Gabapentin, yet I've read more horror studies about the former than the latter.

I don't think you can generalize that more drug targets equal more danger and that this danger always outweighs the benefits of the added drug targets. Sometimes, multiple drugs can also nullify each other's negative effects. Polypharmacy is not uncommon. For instance, Dirk de Ridder's modus operandi is to give patients small doses of multiple drugs at once. Sometimes, anticonvulsants are also combined with each other.

Since no study exists, we don't know how Retigabine works for chronic tinnitus. We know that Kv7.2/3 drugs can prevent tinnitus after noise exposure and BEFORE IT SETS IN, thanks to Tzounopoulos's research. It probably worked because it slowed down everything in the brain due to its unique mechanisms that nobody knows. If I recall correctly, it also activates some other potassium and calcium channels off-target; you can find out about it on Google. And, of course, I want to remain hopeful. All the stuff I have written above could be conjecture, and XEN1101 might come out the door and work for chronic tinnitus, but all the reports so far suggest it doesn't do much for tinnitus or visual snow.

In your other comment, you seem to suggest that the mechanism of action by which Retigabine causes tinnitus relief is up for debate:

Even with the Kv7.4 drug added in, something else could be missing in this cocktail that Retigabine originally had. Maybe its GABA action activated some random subchannel we don't know about. Who knows...

As said before, Retigabine's main therapeutic mechanism is Kv7 activation, with a preference for Q2/3. I think it's safe to assume this is why it relieved tinnitus. See the picture:

It probably worked because it slowed down everything in the brain due to its unique mechanisms that nobody knows.

Are you saying nobody knows how Kv7 openers can reduce neuronal excitability?

I don't think it's some big mystery why Retigabine worked for tinnitus. It hyperpolarizes neurons across the auditory system, which results in a net decrease in tinnitus. Also, Kv7.4 is disproportionately expressed in the auditory system. I don't understand why you assume that there is some unique or unknown mechanism behind why retigabine gave tinnitus relief. Why make things complicated?

Peace and take care.

 

[StoneInFocus]

Xenon Pharmaceuticals dropped some new posters at the 15th European Epilepsy Congress, about the "Ongoing, Long‑Term, Open‑Label Extension of a Phase 2b Study (X‑TOLE)." So far, there have been no concerning long-term side effects.

They did not publish anything about X-TOLE2 or X-TOLE3.

In August, they said they expect to "deliver X-TOLE2 topline data in the second half of 2025, in support of our expected NDA submission."

There is also this paper published in April, which I might upload tomorrow if anyone is interested:

→ A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy

 

[Nick47]

I was reading the Flupirtine thread where you, @StoneInFocus, were mentioned as a case study. I saw that 3 out of 4 people showed improvement with it. My concerns are that XEN1011 and BHV-7000 might be too selective. Flupirtine acts on Kv7.2, 7.3, and 7.4 channels.

Kv7.4 might also be important—or even more important.

 

[StoneInFocus]

I was reading the Flupirtine thread where you, @StoneInFocus, were mentioned as a case study. I saw that 3 out of 4 people showed improvement with it.

Wait, I was mentioned in a case study? I don't see anything in the thread.

My concerns are that XEN1011 and BHV-7000 might be too selective. Flupirtine acts on Kv7.2, 7.3, and 7.4 channels.

Kv7.4 might also be important—or even more important.

Those concerns are valid. Fortunately, Acousia Therapeutics is developing a Kv7.4 channel opener; however, it still has a long way to go.