Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[Jerad]

Prof. Tzounopoulos briefly addressed XEN1101 in his latest paper (see attachment) as another 'promising' potassium channel opener. The idea of a collaboration between Prof. Tzounopoulos and Xenon Pharmaceuticals seems like a total delusion to me.

By the way I am glad to hear from you, your post history had me a bit worried about your safety to be honest. I hope this summer wasn't too bad for you. Take care.

Good to hear from you, too. Been a rough summer for sure. Hoping my tinnitus and noxacusis improve soon. Hope all's well with you, too.

Ya, I don't think a collaboration between Prof. Tzounopoulos and Xenon Pharmaceuticals will ever happen, tbh. I understand what you mean. It would be cool to see and seems logical that the 2 leading groups could benefit and learn from one another if joining forces, but the world doesn't work like that usually. I did see a recent report, however, that Elon Musk is trying to collaborate and join forces with his Neuralink competitor. So who knows...

What I wonder is, does the Department of Defense even know that a very similar drug they've paid Prof. Tzounopoulos to develop is already underway with another company. If they didn't know and found out, would they invest in XEN1101, too?

I don't know. When it comes to solving our medical problems, unfortunately, a lot of our hopes and dreams collide with conjecture or things fantastic, as we're basically on a ship without a paddle, atm, in a sea that's as vast as the cosmos itself. Often, what seems practical or rational won't happen in this world because of egos and money. A lot of this world's current problems could be solved, otherwise.

 

[DoesItStop]

MDD, although I am only depressed due to the tinnitus. But my psychiatrist who caused all of this crap diagnosed me with it, after causing it.

Did you take an antidepressant that caused your tinnitus? I thought your tinnitus was from your ear being too close to a car alarm. I know how it is though, often tough to even pinpoint what pushed our brains into this massive dysfunction.

 

[BrysonKingMe]

Did you take an antidepressant that caused your tinnitus? I thought your tinnitus was from your ear being too close to a car alarm. I know how it is though, often tough to even pinpoint what pushed our brains into this massive dysfunction.

The spike I had from the car alarm was ridiculously mild compared to what it is now. Non reactive, just a little bit louder.

No ADs, not risking it. The day after I took the Clonazepam my tinnitus turned electrical and reactive. Everyone was telling me it was my anxiety, so I stayed on it for 6 months before starting my taper.

I'm sure the noise didn't help, but the back and forth shit started after reinstating.

 

[StoneInFocus]

Good to hear from you, too. Been a rough summer for sure. Hoping my tinnitus and noxacusis improve soon. Hope all's well with you, too.

What I wonder is, does the Department of Defense even know that a very similar drug they've paid Prof. Tzounopoulos to develop is already underway with another company. If they didn't know and found out, would they invest in XEN1101, too?

This is a good point you raise here. Even though XEN1101 and RL-81 operate on the same potassium channels, Xenon Pharmaceuticals doesn't have any concrete plans to investigate their drug's potential for treating tinnitus. What's also important to know is that, according to the Prof. Tzounopoulos, more animal studies are needed to assess the effectiveness of RL-81 in treating tinnitus. According to the Discussion section of his mice study:

"it is crucial that the critical window during which KCNQ potentiation is effective against tinnitus is delineated in a validated animal model. Here, we validated and used an operant animal model of tinnitus, and showed that application of RL-81 even 7 days after noise exposure reduced the percentage of mice that showed tinnitus. Whereas 7 days is the minimum therapeutic window, it is optimistic for future clinical trials.

However, more studies are needed to evaluate the full extent of this therapeutic window.

Moreover, the duration of the therapeutic benefit following transient administration of RL-81, and whether RL-81 can mitigate tinnitus when assessed months after noise trauma remain to be determined.

Finally, given that this potential treatment strategy might be feasible for military personnel exposed to extremely loud sounds, such as blast exposure, assessment of RL-81 in a blast induced animal model of tinnitus could be beneficial. Evaluation of these parameters will be useful for selecting the most appropriate target population for subsequent clinical trials to assess RL-81 as a tinnitus treatment strategy"

So there still remains a lot to be investigated before we know how RL-81 can be used in the treatment of tinnitus, let alone other compounds.

 

[Jerad]

What's also important to know is that, according to the Prof. Tzounopoulos, more animal studies are needed to assess the effectiveness of RL-81 in treating tinnitus. According to the Discussion section of his mice study:

So there still remains a lot to be investigated before we know how RL-81 can be used in the treatment of tinnitus, let alone other compounds.

RL-81 is more potent than its predecessor, Trobalt, right? I know XEN1101 is. Many have theorized that the increased potency of Xenon Pharmaceuticals' drug means it will be exponentially more effective. And it's more selective in the potassium channels it acts on, too, I believe — only the ones that really matter. I think that's one reason it's believed the nasty side effects are eradicated. XEN1101 and RL-81 act on the same potassium channels, right?

Hopefully, both drugs will help tinnitus beyond the acute stage, too. Trobalt did for many, so it stands to reason that these new, improved prospects would, too. It would be nice to see a clinical trial soon for tinnitus with either of these drugs.

 

[InNeedOfHelp]

XEN496 has been postponed by a year from November 2022 to November 2023.

As this was a reformulated version of Trobalt, which should according to Xenon Pharmaceuticals not have the retina/eye problems, this is sad news. I could imagine some people including myself taking my chances with this.

 

[Nick47]

XEN496 has been postponed by a year from November 2022 to November 2023.

Where did you find this information?

 

[Ela Stefan]

XEN496 has been postponed by a year from November 2022 to November 2023.

As this was a reformulated version of Trobalt, which should according to Xenon Pharmaceuticals not have the retina/eye problems, this is sad news. I could imagine some people including myself taking my chances with this.

How is XEN496 better than XEN1101 in terms of opening potassium channels and therefore helping tinnitus?

 

[InNeedOfHelp]

How is XEN496 better than XEN1101 in terms of opening potassium channels and therefore helping tinnitus?

Unlikely. But it was supposed to come to market earlier. XEN496 is a copy paste of Trobalt but reformulated. Not improved.

Where did you find this information?

Clinical trial page is modified.

 

[Ela Stefan]

Unlikely. But it was supposed to come to market earlier. XEN496 is a copy paste of Trobalt but reformulated. Not improved.

So XEN1101 is the good one.

 

[Nick47]

XEN496 has been postponed by a year from November 2022 to November 2023.

As this was a reformulated version of Trobalt, which should according to Xenon Pharmaceuticals not have the retina/eye problems, this is sad news. I could imagine some people including myself taking my chances with this.

I'm confused. I thought XEN1011 was the Trobalt reformulation. However, the Xenon Pharmaceuticals website mentions XEN496 as the Trobalt/Retigabine reformulation.

So this is a big fat fcuk!

 

[CRGC]

I'm confused. I thought XEN1011 was the Trobalt reformulation. However, the Xenon Pharmaceuticals website mentions XEN496 as the Trobalt/Retigabine reformulation.

So this is a big fat fcuk!

According to the Xenon website, XEN496 is "is a proprietary pediatric formulation of the active ingredient ezogabine".

I think XEN1101 is the one that could help adult tinnitus sufferers.

 

[Ela Stefan]

According to the Xenon website, XEN496 is "is a proprietary pediatric formulation of the active ingredient ezogabine".

Ezogabine is actually Retigabine.

 

[InNeedOfHelp]

Beyond Retigabine: Design, Synthesis, and Pharmacological Characterization of a Potent and Chemically Stable Neuronal Kv7 Channel Activator with Anticonvulsant Activity

For whoever is knee-deep into Kv7 potassium channel modulators, another one with potential:

Compared to retigabine, compound 60 displayed a higher brain/plasma distribution ratio, a longer elimination half-life, and more potent and effective anticonvulsant effects in an acute seizure model in mice. Collectively, these data highlight compound 60 as a promising lead compound for the development of novel Kv7 activators for the treatment of hyperexcitability diseases

And for RL-81 drug:

Together, these data, while confirming the 10-fold higher potency of RL-81 over retigabine as the Kv7.2/ Kv7.3 activator,12 also revealed that compound 60 was 16 times more potent than retigabine, thus resulting about twice more potent than RL-81.

Unfortunately no mention of XEN1101. Missed opportunity.

 

[Ela Stefan]

For whoever is knee-deep into Kv7 potassium channel modulators, another one with potential:

Compared to retigabine, compound 60 displayed a higher brain/plasma distribution ratio, a longer elimination half-life, and more potent and effective anticonvulsant effects in an acute seizure model in mice. Collectively, these data highlight compound 60 as a promising lead compound for the development of novel Kv7 activators for the treatment of hyperexcitability diseases

Is this compound 60 on the market, or in clinical trials?

 

[Nick47]

For whoever is knee-deep into Kv7 potassium channel modulators, another one with potential:

Compared to retigabine, compound 60 displayed a higher brain/plasma distribution ratio, a longer elimination half-life, and more potent and effective anticonvulsant effects in an acute seizure model in mice. Collectively, these data highlight compound 60 as a promising lead compound for the development of novel Kv7 activators for the treatment of hyperexcitability diseases

Who developed this?

 

[Hottopic29]

So XEN1101 is going into Phase 3 this year? How long is Phase 3? A few years? Meaning maybe another 3 years until it is available in the market?

Google says a Phase 3 clinical trial typically lasts between one and four years and FDA approval happens once Phase 3 has concluded.

 

[Ela Stefan]

So XEN1101 is going into Phase 3 this year? How long is Phase 3? A few years? Meaning maybe another 3 years until it is available in the market?

Google says a Phase 3 clinical trial typically lasts between one and four years and FDA approval happens once Phase 3 has concluded.

It should be under a year. Usually a Phase 3 runs much faster once a drug has had success in the previous ones, when more is already known about the drug, its adverse effects, and so on.

 

[InNeedOfHelp]

It should be under a year.

In the quarterly earnings call they expected 2 years. They are hoping that because of good results in Phase 2, more doctors will actively pursue patients to join the trial. Because of COVID-19, the number of trial participants decreased drastically.

 

[ARN]

When can we expect XEN1101 to be on the marked for tinnitus? 2024-2025?

 

[InNeedOfHelp]

I wouldn't be surprised if the two trials for MDD will count as a pivotal trial since there is so much safety data surrounding XEN1101 available.

With this number of MDD participants, there are enough candidates to count the two trials as pivotal which puts completion of the final Phase 2 for MDD in January 2024. Wouldn't make sense to launch a Phase 3 after this for completion in 2026-2027. Simply not necessary. Efficacy and safety will be well proven after 150 candidates.

Tomorrow is the quarterly conference call. Maybe some additional information comes available, also for the fact that the Phase 3 for epilepsy didn't kick off while it was supposed to start in H2/2022.

 

[Boone]

I wouldn't be surprised if the two trials for MDD will count as a pivotal trial since there is so much safety data surrounding XEN1101 available.

With this number of MDD participants, there are enough candidates to count the two trials as pivotal which puts completion of the final Phase 2 for MDD in January 2024. Wouldn't make sense to launch a Phase 3 after this for completion in 2026-2027. Simply not necessary. Efficacy and safety will be well proven after 150 candidates.

Tomorrow is the quarterly conference call. Maybe some additional information comes available, also for the fact that the Phase 3 for epilepsy didn't kick off while it was supposed to start in H2/2022.

I heard a rumor from a reliable source that the MDD (Major Depressive Disorder) trials were not showing good efficacy. Hopefully that's not true...

 

[CRGC]

I heard a rumor from a reliable source that the MDD (Major Depressive Disorder) trials were not showing good efficacy. Hopefully that's not true...

That's unfortunate if true. On a more positive note though, the company announced the launch of Phase 3 trials for focal onset seizures. If the results are good, hopefully the drug can still be released for that purpose and then possibly prescribed off-label by some open-minded doctors even if it's not approved for MDD or tinnitus.

Xenon Pharmaceuticals Announces Launch of XEN1101 Phase 3 Program with Initiation of X-TOLE2 Clinical Trial in Patients with Focal Onset Seizures

 

[InNeedOfHelp]

I heard a rumor from a reliable source that the MDD (Major Depressive Disorder) trials were not showing good efficacy. Hopefully that's not true...

The trial is quadruple blinded. I don't believe in any rumors as unblinding is done at the end. We are not even halfway through the trial.

 

[Travis Henry]

The trial is quadruple blinded. I don't believe in any rumors as unblinding is done at the end. We are not even halfway through the trial.

They need to hurry up and release it for something.

 

[Travis Henry]

Well, the positive results from Dr. Susan Shore's device means that XEN1101 does have a pretty good chance at taking people's tinnitus down & hopefully helping hyperacusis/reactive tinnitus.

 

[AfroSnowman]

Well, the positive results from Dr. Susan Shore's device means that XEN1101 does have a pretty good chance at taking people's tinnitus down & hopefully helping hyperacusis/reactive tinnitus.

Sorry I'm ignorant, how are the two linked?

 

[AnthonyMcDonald]

Sorry I'm ignorant, how are the two linked?

It's kind of hard to explain, because there's of a lot of information to describe here.

However, to put it simply, both of these treatments lower hyperactivity in the Dorsal Cochlear Nucleus. Albeit XEN1101 would do this by opening the KCNQ2/KCNQ3 potassium channels (which people with tinnitus have abnormally closed - as per Professor Thanos Tzounopoulos). Potassium channel function is crucial in dampening excitatory signals.

Due to the results of the Susan Shore trial, I am now absolutely certain that XEN1101 will give us a massive improvement, possibly full suppression. Even better due to the problem being solved at the root cause. If we combine both these treatments... Well, that would be fabulous.

 

[Travis Henry]

Anyone got thoughts on interactions between XEN1101 and benzos? I'm to be off Clonazepam by the time XEN1101 comes about, but can XEN1101 help tinnitus that's been worsened by benzos? Is it possible to take XEN1101 at the same time as tapering off benzos?

I'm also interested to know if XEN1101 could cause visual snow or any other serious side effects? I'm hoping they have eliminated a lot of the risk Retigabine had and that XEN1101 is a lasting treatment.

 

[lolkas]

Anyone got thoughts on interactions between XEN1101 and benzos? I'm to be off Clonazepam by the time XEN1101 comes about, but can XEN1101 help tinnitus that's been worsened by benzos? Is it possible to take XEN1101 at the same time as tapering off benzos?

I'm also interested to know if XEN1101 could cause visual snow or any other serious side effects? I'm hoping they have eliminated a lot of the risk Retigabine had and that XEN1101 is a lasting treatment.

It looks like XEN1101 doesn't have Retigabine's side effects because of how specific and potent it is. So I would say the chances are if XEN1101 works for tinnitus, then it may also resolve visual snow syndrome.