Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

Xenon Pharmaceuticals Announces Positive Outcome of End-of-Phase 2 Meeting with the FDA | Xenon Pharmaceuticals Inc. (xenon-pharma.com)

 

We’re lucky Penicillin was invented when it was as otherwise we might have been up for several hundreds of thousands for treatment by a wonder drug...!

 

To best of anyone's knowledge, has Xenon ever been asked about the drug's potential for tinnitus and whether it's something they'd consider investigating or running a trial for at some point (even if in the distant future)?

If it offers benefit, but needs to be off-label, finding someone to prescribe it and paying for it may make it a very expensive proposition for many of us.

 

How much would it cost if it were to be bought off-label?

 

Afaik we only have a quote of their CEO: https://www.fool.com/earnings/call-...maceuticals-inc-xene-q2-2020-earnings-ca.aspx

We're exploring indications outside of the focal epilepsy indication, which remains our primary indication for this drug, but there's a tremendous amount of literature that's building in the role of the KB72 and/or 3 channel in neuronal hyperexcitability that underlies a number of interesting neurological disorders where hyperexcitability appears to perhaps drive, for example, apoptosis in motor neuron disease in hyperexcitability through this channel, mediating Pain signaling. Hyperexcitability through this channel thought to have potentially a role in anhedonia and major depressive disorder. And we know these channels are also expressed in the ear and the hair cells, in particular, and the potential for treatment using a Kv7.2 modulator for tinnitus is also of interest.​

 

Yes. TDLR: they are interested in the drug's potential for treating tinnitus but, so far, there are no concrete plans for clinical trials.

 

In my experience, which is in the US, if a medication is prescribed off-label, it makes no difference in the price.

 

Agreed, but (and the reason I asked), is off-label unlikely to be covered by insurance whereas an approved treatment has a much better chance? Anyway, getting ahead of myself here already - let's hopefully see it get on the market soon where I'll definitely be in line to try it out!

 

But it does matter regarding insurance or getting it on "blue script" as it's called in my country, i.e. being cheaper.

An antiemetic drug Zofran is basically free in Norway if you have cancer. But if you have nausea because of benzo withdrawal for instance, it's $5.5 a pill.

 

Since XEN1101 targets depression as well, maybe it will not be that hard to get a doctor to prescribe it.

 

Anyone with epilepsy + tinnitus tried this yet?

 

It's in clinical trials, not available yet. Many people tried an earlier version of this drug, with varying results. Keep in mind the new version is supposed to be more potent and have less side effects.

 

They have a trial open now for depression.

 

Which country please?

 

XEN1101 for Major Depressive Disorder

 

If they don't exclude people with tinnitus, just apply to it, yeah...

 

So just a recap, this may resolve tinnitus and if it doesn't, at the very least it helps treat your depression or anxiety that goes along with the tinnitus. Basically Trobalt without all the evil side effects...

If Trobalt right now had no side effects, would that be the number 1 thing to take?

 

It's much more potent than Trobalt and targets the correct potassium channels. I'm sure it will help 90% of people.

 

Are you really that confident? Is this confidence based solely on the good reports of Trobalt?

When is it likely to be available? It would have to be an off label prescription I would think, like someone mentioned previously on here. Also concerns as to whether dependence and needing to up the dose develop.

 

My confidence is based on Thanos's research on these certain potassium channels in tinnitus (listen to / read his interview with Tinnitus Talk), it's really worth a read (potassium channels in humans with tinnitus are disrupted, they are the "breaks" for abnormal neural activity, hence why Xen is so amazing for epilepsy). Not only the results from Retigabine. Retigabine targeted literally all potassium channels, so people responded differently of course. I'm guessing some channels of some people were more affected than others (less effect on the correct ones).

I'm guessing late 2023/early 2024. You will be able to get it prescribed for depression. There cannot be any physical dependable on potassium channel openers, they don't work the same as receptors.

 

I just checked that. Tinnitus isn't explicitly in their exclusion criteria, although they do exclude participants with "any unstable medical condition" (including "clinically significant abnormalities of laboratory tests, physical examination, or ECG") and with "presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data".

So anyone who feels like it might at least give it a shot (though still please don't lie just to get in). Also be aware that they will perform MRIs on you, which could aggravate your tinnitus and hyperacusis.

 

Two questions:

I imagine it is proven that this compound is not ototoxic or neurotoxic?

I also assume it doesn't cause a stroke or damage to any organs, including the eyes?

 

It will absolutely be toxic and cause the same issues of liver/bluing toxicity of organs, but because it's so much more potent and resistant to having that bond break causing issues, it should require much less drug for the effect, hence overall the toxicity is "less". If you needed 10% of the drug compared to Trobalt, then the toxicity is a bit of a nuance.

 

What makes you say that, and where could I learn more about it?

Someone correct me if I'm wrong, but I believe the most up-to-date information we have on safety comes from Xenon's press release reporting the results of the phase 2b trial for epilepsy. There were no reports of pigmentation adverse events. There were mentions of serious adverse events in <5% of patients but no mention of what these side effects were.

 

@Matchbox, @addot:

I believe these are the official adverse effects.

https://www.xenon-pharma.com/wp-con...022_-XTOLE-Topeline_French_Poster_2-21-22.pdf

 

What is the difference between Xenon and Thanos' drug?

I remember Autifony AUT00063 drug (potassium channel) - specifically for tinnitus - failed...

Sure, Retigabine helped some folks with tinnitus, but most had little to no effect.

Clonazepam also helps some people shut down their tinnitus.

How can you say Xenon will help 90% of us? That's quite a leap of faith.

 

From what I can tell, this is still unclear. People have tried to ask Thanos himself about this, to no avail. Some folks here seem convinced that they are exactly the same compound; as far as I know that assumption is baseless.

The difference between AUT00063 and retigabine versus XEN1101 and RL-81 (Thanos' drug) is that the newer drugs are supposed to be both more selective in the potassium channels they target and much more potent. The idea is that this would lead to greater therapeutic effect and fewer side effects, so we can't really make a 1-to-1 comparison with retigabine. Again, that's the idea: whether or not it will actually work remains to be seen.

 

Most had little to no effect from retigabine? I honestly didn't get that impression from reading the main thread and the experience thread. Many people had significant reductions, and some decided to discontinue due to side effects. I haven't seen many truly severe/reactive cases who have tried retigabine (most were 3-4/10, maybe 6/10 at most on a self-imposed scale), but the ones I've seen had very impressive results (and this is retigabine we're talking about).

Xen targets the *exact* channels that are broken/hyperactive according to Thanoses research, unlike retigabine, that is much less potent and targeted dozens of other ones too. I honestly don't think this drug will help too many people who are mild/moderate/stable with purely phantom cochlea tinnitus, but again, we don't know. Some people with fairly mild tinnitus got total silence with retigabine.

I'm fairly confident because Xen is actually backed by science and research (albeit not exactly about Xen, but the exact channels it affects), not a random shot in the dark.

 

What about people who have sensory tinnitus? Due to falls, sensory nerves of the CNS that affect the auditory nerve due to their cross over? Would it help with that kind of brain tinnitus?

 

In the Prof's last paper it is explicitly stated that RL-81 differs from "Xenon Compound A", which is obviously XEN-1101, so that is indeed total nonsense.