Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

Study Drug (XEN1101)

There is a dedicated website launched for the MDD trial for those who are interested. 66% chance of getting the real drug, 33% placebo.

 

Once again people from Europe don't exist.

 

Bro trust me, it doesn't matter who gets it first, just as long as it's proven to work. Just imagine if it's established it helps or cures our condition!

After the OTO-313 incident, I just want something to work

 

I've digested every word from Xenon Pharmaceuticals in these last four months. Bottom line is that they are absolutely thrilled with the efficacy in the Kv 7.2 channel. They also believe that efficacy in the Kv 7.3 channel will help depression.

I've also read and re-read many times the Trobalt User Experiences thread, took a screen shot of every post from a user who was on a correct dose for an extended time period (discounted those on low dose or mixing doses, etc,) and my impression was POSITIVE.

The bottom line that keeps coming back to me is that most of those that tried Retigabine at a 900 mg dose for an extended period experienced tinnitus reductions and a large proportion of that cohort experienced drastic reductions from Retigabine. NOTE: side effects as discussed many times were not positive plus not all experienced tinnitus reductions.

Now regarding XEN1101, this is the slide that most people will want to look at. The efficacy of XEN1101 for epilepsy is cumulative and the progress made in the OLE is quite staggering. This is the 'most difficult to treat' patient population ever in any epilepsy trial. Take from it what you will.



It is my hope that with prolonged use of XEN1101 the neuro excitability, including that in the tinnitus regions, will be practically eliminated.

Just another ray of hope, especially today when Dr. Susan Shore has finished her final trial, and Sound Pharmaceuticals are busy recruiting for a short/small Phase 3 with 'fast track' approval in place.

We live in hope.

 

Regarding MRIs: I have low drone buzzing tinnitus that is made worse by droning noise. I went to a party (I know stupid) with custom made earplugs and next day my tinnitus became louder... so I get it from just bone conductive sound waves.

That said: I have had 2 MRIs and never once did they made my tinnitus worse (and one of them was a really old, loud MRI)

But of course - I get it if you're too scared to go ahead with the trial.

 

How you doing P? Hope you're OK.

Xenon's share price is certainly acting bullish right now, and has also broken out of a 12 month high.

 

Honestly been a rough time since April and still is. That is the nature of the beast, isn’t it. Back to Tinnitus Talk after a break. Really hope we get some good news soon.

I always have high hopes for XEN1101. Maybe ‘blind faith’ but maybe not?

Hope you are doing well!

 

Maybe this new XEN1101 study with 160 patients will be completed faster than the current one kicking off in H2 2022, @Padraigh Griffin?

Xenon Pharmaceuticals Reports Second Quarter 2022 Financial Results and Provides Corporate Update

XEN1101 for Epilepsy (Primary Generalized Tonic Clonic Seizures)
Alignment was obtained with the FDA at the EOP2 meeting on key elements of a single Phase 3 clinical trial to pursue an additional epilepsy indication of primary generalized tonic clonic seizures (PGTCS). Following the initiation of X-TOLE2, Xenon plans to initiate a Phase 3 clinical trial, called X-ACKT, to support potential regulatory submissions in PGTCS. This multicenter, randomized, double-blind, placebo-controlled study will evaluate the clinical efficacy, safety, and tolerability of XEN1101 administered as adjunctive treatment in approximately 160 patients with PGTCS. The primary efficacy endpoint is the MPC in monthly PGTCS frequency from baseline through the DBP of XEN1101 compared to placebo. On completion of the DBP in X-ACKT, eligible patients may enter an OLE study for up to three years.

 

No, they will file for Focal Epilepsy first using the Phase 2 plus OLE and the Phase 3 data.

In the Fireside chat the other night, they indicated that Generalised Tonic Clonic Phase 3 may finish at the same time and if it does, they will include it in the NDA.

If it finishes later, they will add it into the NDA.

Hopefully there is a queue out the door for the Phase 3 given the compelling results of the OLE.

I posted on a few epilepsy forums but there was very few responses.

 

Just so I'm clear on this, is the XEN1101 trial being followed optimistically due to its similar chemical action to Trobalt and therefore people hypothesize it will work lowering tinnitus? And then persuading GPs to prescribe it off label for tinnitus?

I ask as I see no interest from the company in testing it for tinnitus. One would think if they thought they had an effective treatment for tinnitus it would be in trials for it yesterday!

 

That is exactly the hope, however, I don’t agree with you as regards Clinical Trials.

First Target equals primary efficacy of Focal Epilepsy and Generalised. This is a $1B plus a year market as per recent forecasts from the company themselves.

Then second target is MDD, which is a massive market.

A company such as Xenon Pharmaceuticals has limited resources and tinnitus is not a priority. Getting XEN1101 to market as an epilepsy treatment is the first strategic move.

However, Trobalt is also being reformulated for tinnitus by Pittsburgh University and there is a significant amount of publications that indicate that the potassium KCNQ 7.2 channel is very involved in Tinnitus.

XEN1101 has shown compelling efficacy in addressing neuroexcitability in this KCNQ 7.2 channel.

Finally, a lot of tinnitus theories are based on ‘hyperexcitability’ in various regions of the brain.

The ‘hope’ is that a drug that is very effective in the CNS on the KCNQ 7.2 channel will calm tinnitus.

 

The reason is probably as it was discussed in the OTO-313 thread: seizures per month is probably much easier to measure as an outcome versus tinnitus improvement.

 

Thanks for the detailed reply. Is this reformulated version being specifically done with the aim of having a tinnitus treatment available at the end of it?

 

Xenon Pharmaceuticals have also mentioned tinnitus specifically in press releases and their hope that it will help for tinnitus.

 

Well listen to this...

Reviving Retigabine for Tinnitus — Thanos Tzounopoulos, PhD

 

Yes I saw that, but I took it as a pacifying type throwaway comment.

 

I will have a listen. From what I gather there is frustration as there have been no updates in the last 2 years.

 

Yep. Thanos has done some amazing research but the lack of any movement towards any trials is frustrating.

 

A long time ago, Thanos said human clinical trials could begin in a year or so. Wonder why there’s the long delay.

 

As some others on here, I have tried every means known to me to contact Prof. Tzounopoulos and his team, but he will not answer a very specific question, which I feel is in our interests.

As a world leader in tinnitus research, particularly as regards the reformulation of Trobalt, and the effect of the Kv7.2 channels on tinnitus, what are his thoughts on a drug such as XEN1101 being an effective treatment for tinnitus?

Some feel it is irrelevant what he thinks, but as for me, I really would like his opinion on this.

In fact, the whole logical side of me can see a potential for a collaboration here. A small team full of tinnitus specific researchers allied with a large corporation with $800M in cash, that do not want to focus on tinnitus at present.

It's as easy as this. Department of Defense, Pittsburgh Hearing Research Center and Xenon Pharmaceuticals run a proof of concept trial with XEN1101 as the lead candidate. This could be a small Phase 1 trial with 20-40 participants and be run by Pittsburgh, funded by DoD, with Xenon Pharmaceuticals the commercial partner. It this not just logical?

If results are positive, then a larger Phase 2 could be run, and also we could have off label prescribing until the data from this Phase 2 are in. In the meantime, Pittsburgh could still continue work on RL-81 if needed.

As for clinical trials, Prof. Tzounopoulos is STILL pre clinical. He would need to do 3 trials to get a treatment to market. This takes an average of 9 years, from IND to NDA and commercialisation. He would also need to partner with a larger corporation just like Frequency Therapeutics was a spin off from Langer Labs at MIT.

I don't know what age the Professor is but at a guess he is maybe late 40s and perhaps early 50s. The chances of him bringing a treatment out during his career at this pace are unlikely.

I guess a lot of 'academics' just like research. That is their game.

More research papers are useful, but I don't think any amount of typed words is ever going to reduce our tinnitus.

What we need is action.

 

I wonder if Xenon Pharmaceuticals knows about the hype of their anti-epileptic drug in the tinnitus world.

And as for Prof. Tzounopoulos' drug, if they would announce a clinical trial today, it will take them at least 7 years to get to market. I see no point in waiting for it unless he will offer compassionate use. But even compassionate use is only offered once efficacy is proven after Phase 2. Sad to say but we can forget about RL-81 unless a miracle happens.

In 7 years we will have more electric cochlea/brain stimulation options which are the ideal treatments. Nothing fun on staying on anti-epileptic drugs long term. Brain plasticity/retraining the brain is what needs to happen.

 

What cheers me is the knowledge that the research field is alive and flourishing. When I see all these different approaches:

• Trying to tackle tinnitus by means of sound.
• Or sound in combo with electrical stimulation.
• Examining the possibility that tinnitus has more to do with inflammation.
• Fine tuning and tweaking Trobalt which is known to have worked but the side effects were too heavy.
• Working on the brain side of things á la Elon Musk.

No harm in cheering on your own particular horse in the race and I hope you win, but dead-certs have gone pear-shaped even in the recent past so you gotta factor in disappointment too.

 

I wonder, does the DoD even know XEN1101 is a similar drug to RL-81? How “in the know” are these groups? Maybe someone ought to contact the DoD or Prof. Tzounopoulos, or both, with your idea. I dunno if Prof. Tzounopoulos would like the idea, though, since it basically skips over his drug. It’d be awesome, though, to see the collaboration and the clinical trial happen for tinnitus. I would love to see Xenon Pharmaceuticals do compassionate use, too. If a drug exists that can truly help those with no alternatives (people like us), then a company should almost be morally obligated to step in. Wishful thinking perhaps, but helping people should come before money and unnecessary red tape. There are ways to do compassionate use properly without high liabilities. Some people are literally dying here from tinnitus and hyperacusis.

 

Why are the hopes so high on the XEN1101 for tinnitus? A lot of research is saying tinnitus is mostly due to NMDA and the glutamate being on high, causing overexcitability to the nerves. How do you tackle this? XEN1101 looks like just a small part of the picture...

 

Depends on what research you read.

 

Yes but what I said is a fact. Maybe XEN1101 will provide partial relief then...

 

I’m outta here for another bit. Will continue to update this thread with news from Xenon Pharmaceuticals when it comes out.

 

Load up on Magnesium.

 

Small molecule modulation of the large-conductance calcium-activated potassium channel suppresses salicylate-induced tinnitus in mice

@Padraigh Griffin, you are the 'expert' on XEN1101. I'm having trouble comparing this new study published yesterday with XEN1101.

These are sodium channel potassium blockers. I didn't find anything related to Kv 7.2 in the article, but this concerned me:

But, to conclude:

 

Just adds more evidence that CNS hyperexcitability and deficiencies in the ion channels are a MAJOR cause of tinnitus.

Good find.