Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[InNeedOfHelp]

@Nick47, a different Kv7.2 modulator currently being trialed in China is Pynegabine HN37. It already completed Phase 1 and is moving to Phase 2. It is based on Retigabine.

HN37, trial number: CTR20201676 and CTR20222616. Hope your mandarin is sufficient

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 program of the symposium is online on their website.

As expected, tinnitus is on the menu. Prof. Thanos Tzounopoulos will speak on tinnitus and Kv7.2 channels.

 

[Josh59]

Are there any potassium channel modulating drugs available today? If not, will XEN1101 be a great advance for medicine?

It remains to be seen whether these drugs can treat other pathologies, such as tinnitus.

I'd like to know why potassium channels are important in relieving tinnitus symptoms? What are the major differences, for example, with Dr. Shore's research?

 

[Nick47]

Are there any potassium channel modulating drugs available today? If not, will XEN1101 be a great advance for medicine?

Gabapentin was discovered very recently (2018 onwards) to open potassium channels Kv7.2/3 & Kv7.5.

Before this it was thought to be a calcium channel blocker. Pregabalin is similar but does not open potassium channels. I wonder if this is why it's rarely reported to reduce tinnitus compared to Gabapentin which certainly is effective for some. I wrote yesterday about this in the Treatments section under Gabapentin. I felt slightly weird on it, but nothing too bad.

Of course I then thought about the wider community and what they would make of that. Retigabine was no silver bullet and seemed to be hit and miss. Maybe potassium channel openers will work better for tinnitus due to acoustic trauma/nerve damage?

Anyway Biohaven, with their aggressive policy, seems to get to market first, as long as efficacy and safety for epilepsy is demonstrated.

 

[InNeedOfHelp]

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CB03-154 in Healthy Participants

There are two trials ongoing for CB03 which is an equivalent to Trobalt, modulating Kv7.2/7.3 channels.

This space of research seems to have become very crowded and for a reason.

Zhimeng Biopharma Announces Dosing of First Subject of Its Novel Antiepileptic Drug Candidate CB03 in First-in-Human Phase I Clinical Trial

 

[Nick47]

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CB03-154 in Healthy Participants

There are two trials ongoing for CB03 which is an equivalent to Trobalt, modulating Kv7.2/7.3 channels.

This space of research seems to have become very crowded and for a reason.

Zhimeng Biopharma Announces Dosing of First Subject of Its Novel Antiepileptic Drug Candidate CB03 in First-in-Human Phase I Clinical Trial

Good find. It seems Phase 1 was completed in March this year.

 

[Lucifer]

Unmyelinated type II afferent neurons report cochlear damage

This was posted earlier in the thread about a 2015 case study where Trobalt helps with noxacusis.

Do you believe that, if XEN1101 can calm the type II fibers' response to hair cell damage, people will experience a permanent improvement in their noxacusis or get rid of it completely?

Do you believe that noxacusis sufferers will have to take XEN1101 permanently or maybe take it for a few months to calm down the type II fibers to experience improvements in noxacusis or it going away?

 

[Josh59]

Unmyelinated type II afferent neurons report cochlear damage

This was posted earlier in the thread about a 2015 case study where Trobalt helps with noxacusis.

Do you believe that, if XEN1101 can calm the type II fibers' response to hair cell damage, people will experience a permanent improvement in their noxacusis or get rid of it completely?

Do you believe that noxacusis sufferers will have to take XEN1101 permanently or maybe take it for a few months to calm down the type II fibers to experience improvements in noxacusis or it going away?

That's a good paper! Is this study similar to that of researcher Megan Beers Wood? @Nick47, wasn't Megan Beers Wood proposing molecules to treat migraines?

I may be getting my hopes up, but it really looks like these researchers and clinicians are on the right track, particularly with a future drug similar to Retigabine.

In terms of timeline, when could XEN1101 be released? In 5-10 years?

 

[Lucifer]

That's a good paper! Is this study similar to that of researcher Megan Beers Wood? @Nick47, wasn't Megan Beers Wood proposing molecules to treat migraines?

I may be getting my hopes up, but it really looks like these researchers and clinicians are on the right track, particularly with a future drug similar to Retigabine.

In terms of timeline, when could XEN1101 be released? In 5-10 years?

End of 2024/Early 2025 but may be earlier depending on how fast they can recruit patients. They haven't mentioned whether they have reached the max number of patients for the trial or whether they might have compassionate use.

 

[Lucifer]

Just reading the Trobalt User Experiences thread, it seems @Albertus and @Mithrandir experienced improvements in their hyperacusis/noxacusis or got rid of it but I have no idea if the effects were permanent.

Maybe the idea of calming the type II fibers permanently or to the point where they can stay calm for a while to allow for improvements to noxacusis is possible.

 

[haha ear go eeee]

Just reading the Trobalt User Experiences thread, it seems @Albertus and @Mithrandir experienced improvements in their hyperacusis/noxacusis or got rid of it but I have no idea if the effects were permanent.

Maybe the idea of calming the type II fibers permanently or to the point where they can stay calm for a while to allow for improvements to noxacusis is possible.

Is anyone able to get in contact with them to follow up?

Has anyone had their hyperacusis or noxacusis worsen from it?

 

[Lucifer]

Is anyone able to get in contact with them to follow up?

Has anyone had their hyperacusis or noxacusis worsen from it?

They were last online/posting in 2017. Maybe @Markku could get in touch with them.

There were a few users who reported to have started to get hyperacusis from taking Trobalt but as soon as they stopped taking it, it went away.

So I'm a bit surprised by that but I'm hoping when XEN1101 comes out, I'll be one of the people who experience an improvement in noxacusis or get rid of it permanently. I believe if we can calm the type II fibers permanently or to the point they can stay calm for a while, noxacusis/hyperacusis sufferers will start to notice an improvement and won't have to take XEN1101 long term.

 

[Lucifer]

A Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE2)

It seems the estimated study completion date has been changed from October 2025 which was stated earlier in the thread to June 2025.

Still possible it can finish earlier. I think it takes 7-8 months for each patient. I'm hoping we can get this down to mid-end of 2024 if possible.

In the current Phase 3 trial they are testing 25 mg & 15 mg dosing per day.

When will it be the best time to take it, morning or just before sleeping?

 

[Nick47]

It seems the estimated study completion date has been changed from October 2025 which was stated earlier in the thread to June 2025.

Still possible it can finish earlier. I think it takes 7-8 months for each patient. I'm hoping we can get this down to mid-end of 2024 if possible.

It will be end of 2025 before the readout and then however long for approval and manufacture/distribution. Looking at 3 years really. I don't know if Biohaven will be quicker.

Have you tried Gabapentin?

 

[Lucifer]

It will be end of 2025 before the readout and then however long for approval and manufacture/distribution. Looking at 3 years really. I don't know if Biohaven will be quicker.

Have you tried Gabapentin?

I haven't tried Gabapentin.

I think it took 2 years with the previous Phase 2b trial due to COVID-19. Didn't someone mention previously in this thread that the Phase 3 trial might finish quicker due to no more restrictions when it comes with COVID-19?

Hopefully they soon announce that they have reached the max participants for the Phase 3 trial.

What's the likelihood of it passing the Phase 3 trial?

 

[InNeedOfHelp]

It will be end of 2025 before the readout and then however long for approval and manufacture/distribution. Looking at 3 years really. I don't know if Biohaven will be quicker.

Have you tried Gabapentin?

I think we will know more or less the ending date at the 10th of August Q2 quarterly figures call. The date on the trial page is just a placeholder and has no meaning.

I'm expecting earlier than that (Q4 2024) for epilepsy. The Major Depression Disorder Phase 2 trial is currently finishing up. There is no guidance for that one yet on the way forward. I have a tiny bit of hope that they will not do a Phase 3 but claim pivotal due to the fact they are running two Phase 2 trials at the same time for MDD alone.

At the end, there is a ton of safety data available and their readouts are fast. Unfortunately, there is no FDA Fast Track or Breakthrough Designation for XEN1101 (only for XEN496 which was cancelled).

 

[Nick47]

What's the likelihood of it passing the Phase 3 trial?

I have not followed the trials in any detail as they are not for tinnitus. Obviously they have been successful enough to get to Phase 3 for Major Depressive Disorder, Epilepsy or whatever.

I'm just staggered that no one has been part of or knows/hears of someone with tinnitus that's been in any of these trials. Maybe I shouldn't be. I think Biohaven have compassionate use for pain!

Unfortunately, there is no FDA Fast Track or Breakthrough Designation for XEN1101 (only for XEN496 which was cancelled).

That's a shame about the Fast Track status. How long do successful medications take to be approved? Am I right in thinking that they are still enrolling for Phase 3 in Epilepsy?

 

[Lucifer]

Unfortunately, there is no FDA Fast Track or Breakthrough Designation for XEN1101 (only for XEN496 which was cancelled).

They should do whatever they can to speed up the trials so it comes out to the market quicker. I'm hoping FDA Fast Track or Breakthrough Designation happens for XEN1101.

I've given up on regeneration hearing medicines for now, so hopefully XEN1101 solves tinnitus and hyperacusis/noxacusis.

I know XEN1101 is only targeting Kv7.2 and Kv7.3 potassium channels and what we believe are the reasons for tinnitus and hyperacusis/noxacusis.

Do you believe any other Kv potassium channels, other than Kv7.2 and Kv7.3, may be related to tinnitus and hyperacusis/noxacusis?

Do we expect XEN1101 to work better on those who are sensitive to meds or shouldn't that make much of a difference on the effect that it may have on reducing tinnitus and hyperacusis/noxacusis?

 

[InNeedOfHelp]

I have not followed the trials in any detail as they are not for tinnitus. Obviously they have been successful enough to get to Phase 3 for Major Depressive Disorder, Epilepsy or whatever.

I'm just staggered that no one has been part of or knows/hears of someone with tinnitus that's been in any of these trials. Maybe I shouldn't be. I think Biohaven have compassionate use for pain!

That's a shame about the Fast Track status. How long do successful medications take to be approved? Am I right in thinking that they are still enrolling for Phase 3 in Epilepsy?

I'm actually very sure of this progressing through Phase 3 if no severe adverse events are found. At least 4 companies worked on New Drug Application for upgraded Trobalt. The indications are neuropatic pain, epilepsy, MDD and ALS.

Besides that there are a ton of other indications related to hyperexcitability. These medicines will become a blockbuster for sure and will launch a new wave of pharmaceuticals targeting very specific sodium/potassium channels without touching non-relevant channels

Yes, they are still recruiting and likely they will still do so for the coming 1-1.5 years. Again, I think the actual timelines will be presented during the earnings call on 10th of August. During every Q&A, after the preceding earnings calls, the investors were asking for timelines, and they stated they need a couple of quarters of enrollment to give guidance for the future. The race is on and the first one to reach market will control the market - they have every incentive to move as soon as possible.

 

[Lucifer]

I'm actually very sure of this progressing through Phase 3 if no severe adverse events are found. At least 4 companies worked on New Drug Application for upgraded Trobalt. The indications are neuropatic pain, epilepsy, MDD and ALS.

Besides that there are a ton of other indications related to hyperexcitability. These medicines will become a blockbuster for sure and will launch a new wave of pharmaceuticals targeting very specific sodium/potassium channels without touching non-relevant channels

Yes, they are still recruiting and likely they will still do so for the coming 1-1.5 years. Again, I think the actual timelines will be presented during the earnings call on 10th of August. During every Q&A, after the preceding earnings calls, the investors were asking for timelines, and they stated they need a couple of quarters of enrollment to give guidance for the future. The race is on and the first one to reach market will control the market - they have every incentive to move as soon as possible.

I think it's a good thing that there is Biohaven as well so there is more of an incentive to come out as soon as possible. I still think XEN1101 will come out before Biohaven due to XEN1101 being in Phase 3.

To hear that XEN1101 is more potent at lower dosing compared to Trobalt sounds promising for improvements in tinnitus and hyperacusis/noxacusis due to some users experiencing improvements with Trobalt even though it's not as potent as XEN1101.

 

[Utdmad89]

I'd be careful pinning your hopes on this. Visual snow isn't something you want.

 

[haha ear go eeee]

I'd be careful pinning your hopes on this. Visual snow isn't something you want.

We have no idea that it'll cause visual snow though. I thought the idea was that Trobalt caused it because it acted on numerous channels. There's been no mention that XEN1101 has visual snow as a side effect. I'm also wondering if opening specifically the Kv7.5 channel causes it, as Gabapentin opens the Kv7.2/7.3 and Kv7.5 and has caused visual snow.

Also I'd gladly trade loudness hyperacusis, noxacusis, and tinnitus for visual snow lol.

 

[Lucifer]

I'd be careful pinning your hopes on this. Visual snow isn't something you want.

So far there has been nothing stated whether anyone has experienced visual snow so I'm guessing safety is fine. We know more in the Phase 3 trial about safety.

How do they know that XEN1101 is more potent than Trobalt? Have they done tests to prove it?

We have no idea that it'll cause visual snow though. I thought the idea was that Trobalt caused it because it acted on numerous channels. There's been no mention that XEN1101 has visual snow as a side effect. I'm also wondering if opening specifically the Kv7.5 channel causes it, as Gabapentin opens the Kv7.2/7.3 and Kv7.5 and has caused visual snow.

Also I'd gladly trade loudness hyperacusis, noxacusis, and tinnitus for visual snow lol.

Same lol.

I didn't know Kv7.5 might be the reason for visual snow, that's interesting.

I know XEN1101 are mainly targeting Kv7.2 and Kv7.3 but from a past presentation slides that was posted earlier in the thread it also opens up Kv7.4 and Kv7.5 but definitely not as potent compared to Kv7.2 and Kv7.3.

 

[Matchbox]

We have no idea that it'll cause visual snow though. I thought the idea was that Trobalt caused it because it acted on numerous channels. There's been no mention that XEN1101 has visual snow as a side effect. I'm also wondering if opening specifically the Kv7.5 channel causes it, as Gabapentin opens the Kv7.2/7.3 and Kv7.5 and has caused visual snow.

Also I'd gladly trade loudness hyperacusis, noxacusis, and tinnitus for visual snow lol.

We don't even know what causes visual snow and why the correlation to tinnitus is so high.

 

[Lucifer]

We know that XEN1101 targets mainly Kv7.2 and Kv7.3.

In the past presentation slides there was no mention of Kv7.1. Any idea what Kv7.1 is for?

 

[haha ear go eeee]

We don't even know what causes visual snow and why the correlation to tinnitus is so high.

My guess is those potassium channels. Maybe the act of the two channels closing can sometimes trigger other ones to malfunction? Do we know if anyone is researching potassium channels in visual snow?

 

[Utdmad89]

We have no idea that it'll cause visual snow though. I thought the idea was that Trobalt caused it because it acted on numerous channels. There's been no mention that XEN1101 has visual snow as a side effect. I'm also wondering if opening specifically the Kv7.5 channel causes it, as Gabapentin opens the Kv7.2/7.3 and Kv7.5 and has caused visual snow.

Also I'd gladly trade loudness hyperacusis, noxacusis, and tinnitus for visual snow lol.

Trust me, you don't want visual snow. And I have loudness hyperacusis, noxacusis, tinnitus, and visual snow.

 

[Lucifer]

Editorial: Kv7 Channels: Structure, Physiology, and Pharmacology

This is what it mentions about Kv7.4:

Later, Kv7.4 (KCNQ4) was identified on the basal membrane of the outer hair cells of the inner ear and auditory nerves, with mutations to the channel associated with autosomal dominant deafness (DFNA2; Kubisch et al., 1999; Kharkovets et al., 2000, 2006; Søgaard et al., 2001).

Mutations in Kv7.4 result in an autosomal-dominant, non-syndromic, progressive, high-frequency hearing loss, denoted as DFNA2 (Kubisch et al., 1999).

I don't know what this would mean for hyperacusis/noxacusis sufferers?

So it seems like Kv7.4 relates to hearing loss/deafness. So what would exactly happen when XEN1101 opens up Kv7.4 potassium channels?

Are XEN1101 & BHV-7000 more potent than CBD when it comes Kv7.2 & Kv7.3 potassium channels?

 

[Matchbox]

Trust me, you don't want visual snow. And I have loudness hyperacusis, noxacusis, tinnitus, and visual snow.

I have visual snow. I think you mean severe visual snow that interferes big time with daytime vision? My night vision is like... static mostly lol.

 

[Nick47]

@Matchbox, you seem well versed in pharmacology. What do you think of these potassium channel modulators? I'm not 100% convinced yet. I have doubts due to Retigabine being hit and miss + the broad spectrum of functions it had. Plus, there is the unknown MoA that many medications have.

 

[lolkas]

We don't even know what causes visual snow and why the correlation to tinnitus is so high.

Perhaps chaos in DCN causes visual snow? I have it too and never had prior to getting tinnitus.