Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

I mean, when it comes down to it, tinnitus is screwed up nerves in the DCN or somewhere in that area. In my opinion, this will be a huge help especially to people who can modulate their tinnitus with neck movement / head presses.

"Tinnitus mice present reduced KCNQ2/3 channel activity and increased spontaneous firing rates in DCN fusiform cells"

Pathogenic plasticity of Kv7.2/3 channel activity is essential for the induction of tinnitus

"pathogenic plasticity of Kv7 (KCNQ) potassium channel establishes DCN hyperactivity and triggers the development of tinnitus"

Noise-induced plasticity of KCNQ2/3 and HCN channels underlies vulnerability and resilience to tinnitus

Stimulating the DCN fusiform cells is what Susan Shore was researching as well. Both of these things apparently have a very good track record of reducing tinnitus. It's no coincidence.

 

AUT00063 targeted specifically KCNQ3 channels in the DCN and it failed in phase 3. I mean it had clinically insignificant effect on tinnitus. One would think there would be at least some improvement. But no.

Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus

 

You are correct, but you've linked the wrong study. The one you've linked was a pre-clinical study done in mice. This is the study that reports the result of the clinical trials, which you were referring to. The study actually failed in phase 2, not phase 3, which only strengthens your point.

I agree with you: the failure of AUT00063 is definitely not a good sign. What I'm not sure I agree with is the idea that this spells doom for XEN1101 and RL-81. Here's why:

1. I'm not sure that targeting only KCNQ3 and not KCNQ2 is enough for a therapeutic effect in humans. I really don't know enough to affirm or deny this. If you know more, I'm happy to retract this.
2. Even if the drugs work on the same Kv channels, it is possible that the chemical makeup of them might lead to different results. For instance, here's a paper by Thanos on how fluorines impact potency and Kv channel selectivity.
3. Although the trial showed that the administered dose of AUT00063 was likely enough to reach the brain, they could not determine if it was enough to produce a therapeutic effect. A more potent drug could yield superior results.
4. AUT00063 was given to chronic sufferers in humans, but was administered acutely in mice. This means it's possible that there is a limited therapeutic window after which the drug is no longer effective. This is something that Thanos is well aware of, and it's basically one of the big open questions regarding RL-81. Obviously we would all prefer that the therapeutic window was indefinite, but even helping recent-onset patients would be a huge breakthrough.

 

I get how this would be unsatisfactory results, yet I agree with @addot.

Why then did retigabine show more significant effects than AUT00063? It's unusual.

 

Thanos is using a Fluorine, Xenon is using a Methyl group as well as a ton of other sterically groups. Pretty different groups but the base molecule is the same as retigabine. All about withdrawing/promoting electron density on the other side of the ring. The fluorine is a simple way to reduce reactivity and pull density to one side. Those amines are going to activate the ring too much (bad generally). Fluorine chemistry isn't fabulous, and it looks like Xenon is going more the sterical approach (which imo is better based on my own experience, sterically forcing certain shapes/rxns wins over activating groups). Would cause differences in say Kv7.1/7.2 binding.

 

Yes because there's less reactivity and more binding so overall the effects one would expect and reactivity at the nitrogen bridging the aromatics isn't going to occur as much.

It's still toxic ultimately, it will still react ultimately, the hope is that the amount is trivial when within therapeutic doses as opposed to retigabine.

Reading what Xenon and Thanos are publishing is sufficient.

 

All valid points. I am just trying to keep expectations guarded, seeing as people here cling and hype every new drug that's coming through the pipeline. Like oh, it's gonna work for 90% of sufferers, oh it's going to be the one to cure us, etc.

How can we know anything when even the leading researchers are not even close to being sure?

And another thing is, as @AnthonyMcDonald pointed out, that those folks here who tried Retigabine had mild to moderate tinnitus and nobody with severe tinnitus tried it, which doesn't help to prove its effectiveness.

It's well known that milder cases respond easier to lots of different types of drugs.

And finally if they find a drug that only helps early onset, most of us here are doomed.

 

A couple of possibilities:

1) Retigabine binded to both Kv7.2 and 7.3 channels instead of only one of them.

2) (and this is the one I find most likely) There was no control. I'm not saying these people were lying. It's just that the placebo effect is insidious and very deceptive. If it wasn't, we wouldn't need so many safeguards against it during clinical trials. You might argue that, for many people, the reduction in tinnitus volume was too big to be ascribed to placebo, and that's a good point. But how many people had this effect? For how long? How many people improved only slightly? I'm not sure we have a clear picture unless someone is willing to comb through literally hundred of pages of the retigabine thread (and others) and catalog every report. Even then that data set would be too unreliable. Just to illustrate how unreliable, consider this:

Now, search for "7/10" or "8/10" on that retigabine thread. You're bound to find at least someone claiming that retigabine took their tinnitus down to a 2 or a 3. Here's one of them. Would you classify 7/10 as severe? I would; you might not. Regardless, are their tinnitus really a 7/10? Did it really go down to a 2? Okay, maybe that specific person was extraordinarily precise with their tinnitus estimation. Can you guarantee the same for other people who posted similar results? Etc. etc.

My point is that thread is a clusterfuck of different patient testimonials. It is more than 250 pages long. It's all over the place as far as effectiveness goes. It's just too hard to draw accurate conclusions from it. What it is, though, is a great instigator for further tests. Hence XEN1101 and RL-81.

 

Where did it show it, on the Tinnitus Talk placebo controlled double blind study?

Mine too. Great for further tests, but no need to get wet dreams over Xenon (or RL that hasn't even done safety trial yet). Also, Dr. Thanos doesn't have the resources for a drug trial, he would need to get a big pharma on board. It's not even on the horizon stage yet, is it? It's him tinkering in his university laboratory with mice and computer modelling.

I'd say give it another 20 years and see where we're at... maybe...

 

I definitely agree that the results posted here are not definite, and there's too much variation and not enough control. But someone claiming to go from a 7-8 to a 1-2 surely can't be placebo, compared to someone saying from a 7 to a 6. Autifony, if potent enough, and correctly hitting the channels, surely would have shown more promise...

Didn't someone talk to a researcher from Autifony, and they straight up admitted that their drug was too broad and didn't hit the receptor well? I don't remember exactly where but I remember seeing it somewhere on an older thread.

In any case it can't hurt to be hopeful, but I agree that it's too early to be jizzing in our pants and yelling about a cure It's just the only thing that comes close to possibly helping a lot.

 

Can someone here please summarise how much of an improvement people with epilepsy have had in their second trial?

Is there an epilepsy drug on the market that at the moment would come close with XEN-1101 in terms of effectiveness and safety?

 

Is there any chance you could be wrong and that you're simply speculating, because man, I understand brother, the truth is the truth, and im not saying your wrong by any means but is there even a shot that this thing could do a total 360 and go well... cause if not

Or maybe Xenon may not work but there's something else that could help us sooner than 20 years... right

Well maybe Autifony did it wrong and these guys or some other team will do it better... right

 

Autifony admitted that their drug wasn't good enough (not potent enough, didn't hit the channels enough, too broad). I talked to the person who talked to the researcher recently. Don't lose hope yet.

 

As for Thanos' progress, he is right. Well, sort of. He's right that Thanos is still in the discovery phase with the drug. It's also true that, right now, Thanos doesn't have the resources for clinical trials; he said so himself on the Tinnitus Talk Podcast. Note though that this is very common. A lot of drugs are born this way, and it doesn't mean Thanos won't get the resources eventually.

The 20-year timeframe is total speculation though. It's not completely baseless: it's born out of skepticism brought on by past failures, as @dan says himself. It is still, at the end, a statement that is impossible to prove or disprove. One thing you gotta understand when reading through these research threads is that everybody brings their own bias to these discussions. Some people are easily impressed and think every little scrap of progress means a cure is just around the bend. Others, partly as a reaction to that, become jaded and cynical. I understand this impulse, as I am skeptical by nature as well, and I think being grounded and keeping expectations in check is generally a good thing. I just think people go a little overboard with it sometimes.

Bottom line is we don't know if it will actually take 20 years for something to come out and help us. Personally, I don't think it'll take that long.

Yes; this is how science moves forward, in a nutshell. Or maybe it's not so much that Autifony did it wrong, just that they're trying stuff that's incredibly complicated, not yet fully understood, and never tried in humans before. Thanos is aware of how AUT00063 played out, as he cited their phase 2 paper in a recent paper he put out. Again, no one knows how this will play out, but he is surely better equipped to deal with it than Autifony was, just by virtue of not being the first to try it.

 

Also keep in mind, COVID-19 set us back 2 years in terms of progress. These times are uncertain, could be another plandemic or some other force majeure...

My wish is to at least experience silence once more before death... I'm in my early forties...

 

Also notice how the Autifony drug didn't directly act on the DCN, but rather on the inferior colliculus, supposedly not the "root cause" of noise induced tinnitus (DCN), as of Thanos' diagram.

(Taken from video)

Sight + Sound Bites: What’s the Buzz?...

 

Are there any epilepsy drugs on the market that act on the DCN, closer to XEN1101 formula?

 

Good stuff. My plan of negativity was to provoke you into trying to prove me wrong and find a reason why we should be optimistic, rather than just saying "...it will work..."

 

This right here. It’s a trend and an ugly one, one of the grave injustices of the government. The fact that these researchers — these pioneers who aspire to cure tinnitus and hyperacusis — all lack the appropriate funding to push forward is just terrible. Many who served in the military are plagued by severe tinnitus and hyperacusis. They gave so much and sacrificed a lot. We wouldn’t have what we have without them. The least the government could do is fork over the money necessary to find a solid treatment or cure, and alleviate the torment. The government has bent over backwards for things like Parkinson’s, Alzheimer’s, depression, schizophrenia, and almost every other brain problem imaginable, yet tinnitus and hyperacusis are relegated to the “just deal with it” category. It shows their huge disconnect with reality, the lack of understanding and lack of empathy for those affected. People are smarter than this, right? Why they choose to be ignorant is puzzling. It’s a choice. Believe me, the funds are available. It’s not like the government is short on money. I worry it’s because those who are truly tormented by tinnitus and hyperacusis — not just suffering, but actual torment — are in such a small group that it’s just not financially profitable to address. Though it’s unspoken, it’s as if they’re simply written-off. They’re just causalities of those darker hues life brings to light. The tragedy is the mismanagement of money. If the government would use it wisely, we might have cures or viable treatments for many ailments that are otherwise hopeless right now.

 

No drugs that are close to XEN1101's formula.

 

@Jerad, I agree with your post in that tinnitus and its surrounding ailments are grossly misunderstood and underplayed; an unfortunate reality we know all too well. But I think we can confidently dismiss the notion that treating tinnitus isn't commercially viable, taking even mild cases into consideration. Its been said before here that even people beginning to experience mild symptoms will seek out care. Most individuals are ill equipped - specifically in the beginning - to mentally combat a constant ailment that they'll immediate read to be "untreatable/incurable".

From Why Is There No Cure for Tinnitus?:

The commercial rewards for a company that could bring an effective pharmacological treatment for tinnitus to market are likely to be considerable. An estimate produced by the United Kingdom hearing charity, RNID (now Action on Hearing Loss) suggested that a novel tinnitus drug could have a product value of $689 million in its first year of launch (Vio and Holme, 2005). This study also estimated that at that time, there were 13 million people in Western Europe and United States actively seeking help for their tinnitus and that 4 million off-label prescriptions for tinnitus were written each year.​

This article is from 2019, and the study was conducted in 2005, so those numbers have likely gone way up. Especially since the onset of COVID-19/vaccine induced tinnitus cases, and the growing number of young people using headphones, as well as the ever expanding cacophony of industry in our everyday lives.

Corporate greed is a powerful motivator. I don't think that's quite the element that's missing behind the equation of why tinnitus is so underfunded. I think it's more a combination of ignorance and that it's an immensely complex condition with many triggers and underlying mechanisms.

I believe it's safe to say that business avarice will eventually be on our side with this endeavor (well... to a certain degree at least lol). The medical establishment just has to prove itself first. It's just an agonizing question of when that'll be.

I hope that'll allay your concern behind the profitable aspect behind treating this garbage.

 

This drug is still 5 years out from being made...

 

XEN1101 is expected to enter phase 3 in the second half of this year. A lot of people online estimate that it will hit the market in 2024 if everything goes well.

Why do you think it will take 5 years?

 

Anthony, can you please explain this photo?

As I understand it, at each level of the auditory network (DCN, inferior colliculus, MGN, auditory cortex) there are different changes? And when the whole network is affected, you would need distinct drugs to repair each and all of them?

 

Because a person I know applied for the clinical trial and that's what they told them. Still 5 years out. Takes 2 years just to approve it.

 

Changes that occur in these various parts of the brain. Could be that most of these changes in areas after the DCN are being affected by the DCN (aka the rest of the network being affected due to the DCN) , or that they could be standalone. No one knows for sure.

These are just various drugs and treatments that are targeted at different areas of the brain/brainstem.

 

Yes. With Deep Brain Stimulation, for example, cases can be individual and seems as if some brain areas can stand alone. They need to map it out for each individual so they know where the hyperactive spots in the network are and then the stimulation can regularize the other affected brain parts as much as possible.

As I saw in the picture you provided, the potassium channels are specially in the DCN and IC, if I'm not mistaken.

 

Retigabine, with its horrendous side effects, took only about 5 months to approve by the FDA. They were also delayed by the DEA but that's another story. No way in hell is it going to take 2 years to approve Xen, even worst case scenario.

Assuming phase 1 took 6 months, phase 2 (not including COVID-19 complications and chaos) took maybe 1.5 years (2 years max), I'd assume that phase 3 will take 2 years at most, maybe less if rushed. After that possibility of compassionate use, maybe 3-5 months for FDA approval (I'm leaning towards less because they are already discussing things with FDA) and a couple more months to prepare production and distribution (I'm sure they are already working on this with how well the trials are going).

So most likely 3 years, maybe 3.5 years *at most* until market release. No way in hell is it going to take 5 years unless something goes horribly wrong or Xenon decides to sit around doing nothing for some reason. I agree, end of 2024 is unrealistic, maybe only for possible compassionate use. It could go either way - maybe they'll be stingy, or maybe they'll be interested in using us as guinea pigs instead of having another long expensive trial. If I was the CEO, I'd like to do the latter before trying any new clinical trials. I'm of course hoping they approve compassionate use to speed things up for us a bit. But knowing how greedy big pharma can be, I don't know.

 

The timelines of phase 3 were shared by Xenon earlier. Phase 3 itself takes 27 weeks starting patient recruiting H2-2022. The total pool is 360 patients which is unfortunately a lot to screen, MRI etc. Xenon is very fast and is pre-aligned with FDA for their NDA. They know exactly what to submit and there is plenty of safety data available across the several studies that they are contacting.

https://investor.xenon-pharma.com/static-files/50a0a75f-704d-4f29-ae32-5269bea0040b

Slide 18

 

Hm. In that case I might even expect less than 3 years. But we'll see I guess.