Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

Yes, quite contradictory. There's nothing from chronic cases or human studies. A lot of us are perhaps making excuses as to why these compounds are not being trialled for tinnitus (lack of objective measures, easier to get to market for epilepsy etc) but I'm not so sure.

For Major Depressive Disorder (MDD) the same can be said, yet it's in trial for that.

We are again grasping at breadcrumbs?

Until some of us can get in a Phase 1 safety trial or for MDD for instance, and report back positive results, it holds little comfort.

 

@Mithrandir later on came back and said this under the Retigabine thread. Even when it comes to hyperacusis, Retigabine had inconsistent results. The wait for these drugs to come out and then the possibility of them not working is scary...

 

I believe the Kv7.4 dysfunction related to progressive hearing loss in the high frequencies is speculated to be related to the resulting OHC dysfunction.

However, I was unaware that Kv7.4 also regulates neuronal excitability in the auditory pathway (beyond the cochlea), which is why tinnitus and hyperacusis could be directly implicated as well.

People have also reported pain hyperacusis relief from Flomax, a smooth muscle relaxant. So smooth muscles are probably indicated in some forms of hyperacusis. L-type calcium channels also contract smooth muscle, Retigabine blocked that channel as well.

What I'm getting at is, Retigabine worked on multiple receptors possibly implicated with tinnitus and hyperacusis, which is probably why it was so relatively effective.

Whether XEN1101 will work as well as Retigabine on tinnitus and hyperacusis depends of course on the patient. For some people XEN1101 will be sufficient to treat tinnitus/hyperacusis, for others maybe not. But if I gave 100 random tinnitus or hyperacusis patients XEN1101 and 100 random patients Retigabine, the mean symptom reduction of the latter group will probably be greater than that of the former, although the amount of reported side effects probably as well.

 

I tried Flomax with no good results.

After reading your post and going through all I have read in Retigabine threads, I believe we are chasing stars with these potassium channel openers. We already had a prequel with Trobalt and the results were not as satisfactory as one would hope. I also don't think the results will vary too much between Retigabine and XEN1101 either.

One thing I like about BHV-7000 is that, they posted a slide that showed patients who took 50 mg had increased brainwaves in all bands, I'm eyeing especially the alpha waves, maybe this would help with thalamocortical dysrhythmia problems; I have no idea how it would affect tinnitus, it is just a speculation on my part.

I'd say at this point we need more invasive methods like DBS or better yet Neuralink if we are truly looking to eliminate this condition, along with visual snow syndrome. Neuralink at this stage is unfortunately vaporware. We'd be waiting for a looong time.

 

@Mithrandir had TTTS. Trobalt would probably work relatively less effectively for tinnitus and hyperacusis sufferers where a spastic muscle is a major contributor to the symptoms.

Why do you think the fact that "Retigabine had inconsistent results" has more to do with the drug itself or Kv7 openers in general rather than with the diversity of tinnitus and hyperacusis patients?

I am sorry but all of this seems just unfounded speculation on your part.

 

Is it possible that XEN1101 could cause tolerance and subsequent withdrawal in a way does the opposite of its intended effect? Many of the drugs on here that people love (e.g., Klonopin, Mirtazapine) are wonderful until you become tolerant and the subsequent withdrawal process begins and makes you worse off.

I don't know anything about antiepileptics though, and this might genuinely be a stupid concern. I hope it is.

 

Nah. You are right.

The effects vary from person to person.

→ Here is Juan Carlos's experience with Retigabine on his tinnitus and hyperacusis. His TTTS also improved while on Retigabine.

Then there were users like @snow86 and @Christian78, who benefitted from taking Retigabine, but the benefits either stopped or lessened over time, or rather became inconsistent from one day to another. Scary.

What I'm scared of the most is that we are waiting for these drugs to come out, right, and it happens to not work on everybody. Suppose it doesn't work on me or you. What is going to be our next move then? What else is there for us to wait for? Should we at that point call it quits and accept the pain and suffering and move on?

Since tinnitus is a very individual beast, I assume brain implants are our only chance at a real "cure" so to say.

→ Here in this video, Dr. De Ridder namedrops Neuralink towards the final minutes and says these implants will allow us to read data from the brain and come up with appropriate responses to it. That would be the only way to stop it for good, granted they actually develop the technology for it.

Anyways. I'm taking a break until more news come out. I lost the ability to sleep thanks to Mirtazapine. I can't believe the mess I got myself into anymore...

 

Apart from the tolerance which can develop over time, like a lot of drugs, the random effects of Retigabine must be able to be explained in my opinion.

I noticed huge disparities depending on whether I was fed or not, but also on my physical activities.

I hope XEN1101 will be more reliable in this range.

 

→ Saniona’s CEO: ”Selectivity is the cornerstone of future epilepsy treatments”

Saniona is next in line to develop a Kv7.2 drug. This one is still far out though.

From my understanding, there are now four in trials US/Worldwide, one in China and one starting in the near future.

 

While good to see, it's incredibly frustrating that none of them have direct interest in targeting tinnitus - they must figure there's no money in it.

 

It would be heaps easier to get it approved for epilepsy then just used off-label for tinnitus.

I can’t comprehend how there isn’t more money going into tinnitus research when it’s had a huge surge with COVID-19.

 

I don't know where else to post this but here's another paper that came out this month, that says anterior cingulate cortex plays a big role in tinnitus maintenance.

 

Xenon Pharmaceuticals Announces Topline Results from Phase 2 Proof-of-Concept X-NOVA Clinical Trial of XEN1101 in Major Depressive Disorder (MDD)

Summary of Efficacy Data

• The primary endpoint of the study was a change in the Montgomery-Åsberg Depression Rating Scale, or MADRS, at week 6. The mean reduction was 13.90 in the placebo group, 15.61 in the XEN1101 10 mg group and 16.94 in the XEN1101 20 mg group. A clear dose response and a clinically meaningful, but not statistically significant, 3.04 difference between placebo and the XEN1101 20 mg group (p=0.135) was observed.
• Statistical significance was achieved on the pre-specified endpoint of the Hamilton Depression Rating Scale, or HAM-D17, at week 6 with a mean reduction of 10.18 in the placebo group and 13.26 in the XEN1101 20 mg group (p=0.042).
• Statistical significance was achieved on the key secondary endpoint of a change in the Snaith-Hamilton Pleasure Scale, or SHAPS, measuring anhedonia at week 6 with a reduction of 5.30 in the placebo group and 7.77 in the XEN1101 20 mg group (p=0.046).
• Statistical significance was achieved in MADRS at week 1 with a mean reduction of 4.88 in the placebo group and 7.54 in the XEN1101 20 mg group (p=0.047) demonstrating early onset of efficacy.
• Statistical significance was achieved in reporting of at least minimally improved symptoms of depression as assessed by physicians using the Clinical Global Impression of Improvement (CGI-I) (p=0.004) in the XEN1101 20 mg group compared to placebo.

Summary of Safety and Tolerability Data

• XEN1101 was well tolerated with similar rates of adverse events reported across all treatment arms.
• The most commonly reported treatment-emergent adverse events (TEAEs) in the XEN1101 20 mg group included dizziness (17.9%), somnolence (10.7%), headache (8.9%) and disturbance in attention (8.9%), as compared to the placebo group which reported dizziness (7.3%), somnolence (1.8%), headache (12.7%) and disturbance in attention (0%).
• Rates of discontinuation were similar across all treatment arms and rates of discontinuation due to TEAEs were low with three patients in the XEN1101 20 mg group (5.4%), as compared to two patients in the placebo group (3.6%).
• No serious adverse events (SAEs) were reported in the two XEN1101 treatment groups and there were two patients (3.6%) in the placebo group who experienced a treatment-emergent SAE.
• XEN1101 was not associated with clinically meaningful weight gain or sexual dysfunction.

 

I have discussed the results of a study in the Retigabine thread which might nuance my post above.

 

So, any comment (by anyone) on these results? Doesn't look all that good from some number reading I did?

 

Barely significant on depression.

 

Many people here report spikes with Diclofenac, but apparently it is also a Kv7.2/3 activator.

 

Our greatest fear is that the selectivity of XEN1101 doesn't activate a channel necessary for tinnitus suppression.

I'm of course thinking of Kv7.4 which is present in the auditory pathway.

Maybe I'm misinterpreting, but from what I understood from these two papers:

• XEN1101
• Retigabine

XEN1101 has a 4.18 times greater "preference" for Kv7.2/3 compared to Kv7.4.
Retigabine has a “preference” for Kv7.2/3 of 3.25 times over Kv7.4.

XEN1101 is therefore more selective than Retigabine, but not by a factor of two, not a lot if I dare say.

I don't know if this difference makes a proportional or exponential difference. Sorry for poor English, I lack in vocabulary.

So, I would be tempted to conclude that it's possible that XEN1101 continues to open Kv7.4, less, but may be enough to generate efficiency if Kv7.4 is needed.

Pure speculation, I don't know if my deductions are correct, and how to assess this difference.

 

@Kleiner, are you still using and getting relief from the Retigabine?

 

Yes, I use it in "Aspirin mode" for now, but I plan soon to start a 3 x 400 mg/day treatment for 2 months.

 

Two points of concern, not one.

1 - It being TOO specific.
2 - It could induce Visual Snow Syndrome.

Also, I don't think two months will be enough, it has to be taken for longer than that.

What I plan on doing with BHV-7000 (if it doesn't work, I'll try XEN1101 but not before because of its GABA activity), is that if I could induce total silence with it, I'll take it for a lot longer than that before slowly tapering off. Otherwise I don't think the improvements would stick. I hope it will be safe to take long term...

Reading the Trobalt User Experiences thread, one thing did not sit with me well, which is people enumerating their tinnitus levels rather than rating it in decibels. Decibel wise, how loud is you tinnitus before and after taking the pill? Is it possible for you to measure?

 

I responded to you but my message was altered or deleted.

To put it simply, yes, I got an objective reduction with Retigabine, because I simply no longer heard my somatic tinnitus, like 0.

 

What does XEN1101 have to do with GABA?

 

Bıth Retigabine and XEN1101 also have activity on GABA receptors. This is why it is thought Retigabine had nasty side effects.

BHV-7000 either lacks that or has minimal activity on the GABA receptors.

If the issue is solely Kv7.2/3, BHV-7000 should do a better job. If the other channels are involved, then we would need XEN1101.

 

Is there evidence that the GABA activity of Retigabine is a different mechanism from other drugs that act on this neurotransmitter?

 

That is thought by whom?

 

Yeah, I can sense the cynicism in your question. It is thought mostly by the Biohaven crew I guess. There is also this:

I found another paper on Retigabine, it says:

I don't know anymore @StoneInFocus.

I think out of desperation I spent lots of time doing research, but the drugs aren't even out in the market and there are no definite answers out there, and even if we think we found some definitive answers in some study, another study comes out destroying all we know about those previous studies.

At this point we really need to test the drugs for ourselves to know. Then again, I have extensive damage due to the drugs I have been prescribed that gave me this condition, so there is a great chance I might experience paradoxical reactions when these Kv7 drugs come out too.

I just want my old life back.

 

I think it's important to provide sources for your claims. I don't have any ill will towards you.

I was skeptical of what you were saying because Retigabine has about ten times greater affinity for Kv7.2/7.3 than the GABAa receptor. Effects at GABA metabolism occur at twenty times the plasma concentration of Retigabine administrated at the highest dosage. See my post on the Retigabine thread here. The way you phrased your statement was that the adverse effects of Retigabine could be solely attributed to its GABAnergic activities.

I think it's also important to realize that Biohaven is a company that wants to sell their products by the end of the day. A major selling point of BHV-7000 is that it supposedly has less GABAnergic action than XEN1101. This has never been proven though.

It's good that you do research and I want my old life back too. If we want to concoct some 'avant-garde' treatment protocol for tinnitus/hyperacusis ourselves, we need to be precise like a laser, and hold each other accountable too.

 

Here's a peer review on potassium channels. It's only an abstract. I cannot access the full review, but some might.

The potassium channels: Neurobiology and pharmacology of tinnitus

 

I suppose I come to the rescue.