Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[Lucifer]

Xenon Pharmaceuticals Announces Conference Call and Webcast to Discuss Second Quarter 2023 Financial Results and Provide Corporate Update

August 10th, 2023 we will find out more about XEN1101 Phase 3 clinical trial. Maybe they announce if they have completed enrollment.

 

[Joeseph Stope]

Xenon Pharmaceuticals Announces Conference Call and Webcast to Discuss Second Quarter 2023 Financial Results and Provide Corporate Update

August 10th, 2023 we will find out more about XEN1101 Phase 3 clinical trial. Maybe they announce if they have completed enrollment.

Well we can relax, their stock price looks pretty solid so no worries there.

 

[Lucifer]

Xenon Pharmaceuticals Reports Second Quarter 2023 Financial Results and Provides Corporate Update

Last patient enrolled in XEN1101 Phase 2 X-NOVA clinical trial in major depressive disorder with topline data expected in late November to mid-December

Continued progress across all XEN1101 Phase 3 epilepsy programs including in X-TOLE2 and X-TOLE3 clinical trials in focal onset seizures and X-ACKT in primary generalized tonic-clonic seizures

 

[haha ear go eeee]

Xenon Pharmaceuticals Reports Second Quarter 2023 Financial Results and Provides Corporate Update

I'm not very knowledgeable when it comes to the phases of clinical trials, what does this mean for the estimated time frame of XEN1101?

 

[Lucifer]

I'm not very knowledgeable when it comes to the phases of clinical trials, what does this mean for the estimated time frame of XEN1101?

X-TOLE2 Phase 3 trial has a study completion of June 2025.

X-TOLE3 Phase 3 trial has a study completion of December 2025.

I believe the study completion date will be earlier depending on how fast they can recruit their patients. Both trials require at least 360 participants each, making it 720 participants in total.

I reckon Biohaven/Pfizer BHV-7000 Phase 2/3 pivotal phase trials will be much quicker due to having more resources but who knows. We won't know until they announce an actual date of starting and completing trials.

What's interesting is that with XEN1101 they are testing once daily 25 mg and 15 mg dosage with an evening meal. So my point is the best time to take it is basically a late meal a few hours or so before bedtime. During sleep is probably when we will expect improvements in tinnitus and hyperacusis/noxacusis if targeting Kv7.2 and Kv7.3 is the cause of these conditions.

 

[InNeedOfHelp]

Here are my findings from the earnings call, I hope this is helpful.

Unfortunately no guidance was given during the call yet, although the topic was addressed several times during the call. They will give guidance on the completion date later this year. What came forward in the Q&A was during COVID-19, in the Phase 2 stage, there was half a year without any screening of patients and afterwards it restarted very slowly. They do not expect such headwinds during Phase 3, and slightly hinting towards a faster Phase 3 than Phase 2. See the below comment from the earnings call (reminder: X-TOLE2 was the Phase 2 trial):

I think we can just remind people what the opt in background is and then kind of the information that we'd require to make that decision. So in terms of the Phase3 epilepsy program, it's probably helpful, maybe just to review a little bit history. So the X-TOLE2 study was first up and running. That was really right at the end of last year, and then that was followed by the exact study a few months later and then a few months after that in terms of X-TOLE3.

So we've been kind of rolling, getting all of these studies up and running. The first jurisdiction for all of the studies has been the US. So we've had US sites up and running, and then over time, we've been bringing other jurisdictions online. And just as a reminder, if we go back to the X-TOLE program, which we're trying to mirror as best we can, especially in the X-TOLE2clinical trial, 60% of the patient enrollment in X-TOLE came from Europe and 40% came from the US.

So I'd say what's the information that we're continuing to generate. Well, we're continuing to get sites up and running in jurisdictions. Some of those come online over time, as everybody is aware, and then we're monitoring so site initiation, we're monitoring the patients that are being screened, what our screen failure rate is, and then what our overall kind of randomization. And it's all that information that we're bringing together that gives us confidence in providing guidance to study completion. And I think we've been really consistent saying that later this year we'll be in a position to give that guidance.

Furthermore some info was given on new team members with experience of commercializing drugs:

Finally, also driven by feedback from FDA, we're in the process of expanding the exact Phase3 clinical trial to include patients as young as twelve years of age. Before I pass the call to Chris Kenney, I'd like to extend a warm welcome to Dr.

Jillian Cannon and Mr. Justin Gover, the two newest appointments to our Board of directors that were announced yesterday. Briefly, Jillian brings a vast knowledge of commercializing novel medicines and leading successful neuroscience franchises at large pharmaceutical companies.

She's been involved in the commercial efforts of some of the most important epilepsy and depression drugs over the past decade, and many of you will be familiar with Justin. As the founding CEO of GW Pharma, Justin and his team led the development and commercial launch of Epidiolex and the eventual sale of GW to Jazz Pharmaceuticals in 2021 for $7.2 billion.

Justin has a deep understanding of what it takes to build companies like Xenon, and he's passionate about the Epilepsy space. We are looking forward to leveraging the experience of both Jillian and Justin as we continue our efforts on the late stage clinical development of XEN1101 prepare for commercialization and progress towards achieving our strategic objective of building a leading, fully integrated neurology Company.

On the MDD trial (depression) Phase 2, the following guidance was given: the enrollment is complete, so now they are in the process of dosing the last patients. Data readout is expected in November-December. They enrolled more patients then expected (160). After data readout, the way forward will be made clear for MDD. It is more or less clear that a Phase 3 is required here - epilepsy would be the first launch of XEN1101:

I'm looking forward to co-hosting a webinar in mid September alongside key opinion leaders in the major depressive disorder space. We intend to focus our discussion on the potential for the Kv7 mechanism to treat MDD and outline the importance of the rationale and trial design of our Phase2 X-NOVA study. Importantly, these top line data will help guide our future plans for XEN1101 in MDD.

You will recall that our initial decision to examine XEN1101 in MDD was based on encouraging published clinical results with Ezogabine, as well as promising preclinical data with XEN1101. We were further interested in gathering additional data given that depression is a common comorbidity within the epilepsy patient population. With patient enrollment now complete, the last few patients are expected to be randomized in the very near-term, which will then be followed by a six week treatment period, a four week follow up visit, and then database log and data analysis. Given these steps, we're looking forward to a top line data readout for X-NOVA in late November to mid December of this year.

 

[andrewdaniels]

Any thoughts on if XEN1101 will work for those of us who have had tinnitus for a while? I'm at 2.5 years, I'm guessing 4.5 years by the time this medication is out... Wondering if it's one of those "use it in the acute phase" drugs. I read through Trobalt reviews and it seemed to help regardless of when tinnitus started, albeit more positive/elimination responses from those that were in acute phase.

 

[Gb3]

Any thoughts on if XEN1101 will work for those of us who have had tinnitus for a while? I'm at 2.5 years, I'm guessing 4.5 years by the time this medication is out... Wondering if it's one of those "use it in the acute phase" drugs. I read through Trobalt reviews and it seemed to help regardless of when tinnitus started, albeit more positive/elimination responses from those that were in acute phase.

It will probably only work for acute tinnitus.

 

[silenceismusic]

It will probably only work for acute tinnitus.

Based on what?

 

[andrewdaniels]

It will probably only work for acute tinnitus.

I am praying and hopeful this isn't the case. I hope it will follow in the footsteps of Trobalt and provide even temporary relief for chronic tinnitus folks.

 

[r34d1ng]

Based on what?

Based on nothing because I tried Trobalt back in the day when I was already several years into my tinnitus and it worked like a charm.

 

[Lucifer]

Based on nothing because I tried Trobalt back in the day when I was already several years into my tinnitus and it worked like a charm.

What was your tinnitus level before and after taking Trobalt?

 

[silenceismusic]

Based on nothing because I tried Trobalt back in the day when I was already several years into my tinnitus and it worked like a charm.

I was going through those old Trobalt diaries just today and while it didn't work for everyone, I haven't seen anything with such consistent positive results in anything else. Almost everything else is pretty much a mix of hopium, copium and habituation lol, and every strange supplement and treatment has some success on some rare individuals. But this thing just knocked tinnitus down on the most desperate "hardened" tinnitus folk, it was awesome to read.

I mean this is how medical treatments are often found, and that is as an accidental or unpredicted side effect of an original intended purpose. To this date the only two FDA approved hair loss medications came about like that, and we still don't even fully understand how they work. It's just "hey whoa look at that, a bunch of new hair on all these people. Can we profit off this?". And profit they do, big time. Now it's "Hey listen to that? Hear that? Silence. Can we profit?" And profit they will. They will have my money for sure.

 

[andrewdaniels]

I was going through those old Trobalt diaries just today and while it didn't work for everyone, I haven't seen anything with such consistent positive results in anything else. Almost everything else is pretty much a mix of hopium, copium and habituation lol, and every strange supplement and treatment has some success on some rare individuals. But this thing just knocked tinnitus down on the most desperate "hardened" tinnitus folk, it was awesome to read.

I mean this is how medical treatments are often found, and that is as an accidental or unpredicted side effect of an original intended purpose. To this date the only two FDA approved hair loss medications came about like that, and we still don't even fully understand how they work. It's just "hey whoa look at that, a bunch of new hair on all these people. Can we profit off this?". And profit they do, big time. Now it's "Hey listen to that? Hear that? Silence. Can we profit?" And profit they will. They will have my money for sure.

I also spent a lot of time in that thread. And it was nice to see how it helped many folks. The ones that didn't (or reduced slightly), I wonder if it would have been different had they stayed on the drug longer.

 

[Joeseph Stope]

I was going through those old Trobalt diaries just today and while it didn't work for everyone, I haven't seen anything with such consistent positive results in anything else. Almost everything else is pretty much a mix of hopium, copium and habituation lol, and every strange supplement and treatment has some success on some rare individuals. But this thing just knocked tinnitus down on the most desperate "hardened" tinnitus folk, it was awesome to read.

I mean this is how medical treatments are often found, and that is as an accidental or unpredicted side effect of an original intended purpose. To this date the only two FDA approved hair loss medications came about like that, and we still don't even fully understand how they work. It's just "hey whoa look at that, a bunch of new hair on all these people. Can we profit off this?". And profit they do, big time. Now it's "Hey listen to that? Hear that? Silence. Can we profit?" And profit they will. They will have my money for sure.

For your amusement, I believe that this is how Viagra was discovered too (sorry, ladies)! It was originally intended to improve circulation for matters of the heart -- but had this unforeseen side effect.

Who knows? If it hadn't passed muster with trials and marketing as a heart drug, it might have faced all sorts of delays from whoever if it had been introduced as an assistance for penile erectile dysfunction.

 

[lolkas]

Based on nothing because I tried Trobalt back in the day when I was already several years into my tinnitus and it worked like a charm.

Well, we know that Trobalt was hit & miss because of it not being all that potent. But for some folks it was potent enough.

I hope that efficacy of XEN1101 and/or BHV-7000 will be enough to help even more people.

I tend to agree with the comments about some drugs having positive effects on conditions other than they were initially made to treat. If Trobalt wouldn't have such horrendous side effects, many of us could be on it as we speak. Imagine how much $ that would be for Trobalt developers?

 

[InNeedOfHelp]

For people with noxacusis, I'd follow the trial of VX-548 of Vertex Pharmaceuticals which might be of interest.

It has 5x Phase 3 trials running at the same time for several pain conditions - the goal is essentially to treat all forms acute and chronic/neuropathic pain. The Phase 3 ends early next year already. VX-548 is the first pharmaceutical pain killer that is non-opioid and non-NSAID (we know their ototoxicity...) since basically the beginning of medicine, and with a mild safety profile this will become a blockbuster in the pain market. There is a reason why they are running so many costly trials at once - the potential is huge.

It works by directly inhibiting the NaV1.8 sodium channel (pain receipt) in the brain. NaV1.8 has nothing to do with tinnitus but everything with feeling pain. Again, as with every drug, we have no idea if this will help noxacusis - but this seems by far the best bet in the short term at this moment.

 

[StoneInFocus]

It works by directly inhibiting the NaV1.8 sodium channel (pain receipt) in the brain.

These upcoming sodium blockers are definitely interesting but where does it say that VX-548 targets the central nervous system?

VX-548 is an oral, selective NaV1.8 inhibitor that is highly selective for NaV1.8 relative to other NaV channels. NaV1.8 is a voltage-gated sodium channel that plays a critical role in pain signaling in the peripheral nervous system.

(Source)

Someone correct me if I'm wrong but it is my understanding that signal transmission in the cochlea is mainly mediated through potassium ions, not sodium ions. I think that in order for VX-548 to work for noxacusis, somewhere in the transmission chain between the outer hair cells and the central nervous system, there has to be cells whose membrane potentials are majorly mediated by NaV1.8 channels. Whether that is the case, is definitely something interesting to find out.

 

[Nick47]

Well, we know that Trobalt was hit & miss because of it not being all that potent. But for some folks it was potent enough.

We don't now why Trobalt helped some and not others. That is actually the problem. Maybe it helped noise induced tinnitus only etc. It had such a broad spectrum of action, we can't be sure what MoA was important. We have some literature on specific potassium channels and tinnitus to go on though. Then there is the question of whether it had some unknown MoA.

All this said, these potassium channel trials are frustrating as hell, as we don't know if we are following a gold mine or a red herring.

 

[Christiaan]

For people with noxacusis, I'd follow the trial of VX-548 of Vertex Pharmaceuticals which might be of interest.

It has 5x Phase 3 trials running at the same time for several pain conditions - the goal is essentially to treat all forms acute and chronic/neuropathic pain. The Phase 3 ends early next year already. VX-548 is the first pharmaceutical pain killer that is non-opioid and non-NSAID (we know their ototoxicity...) since basically the beginning of medicine, and with a mild safety profile this will become a blockbuster in the pain market. There is a reason why they are running so many costly trials at once - the potential is huge.

It works by directly inhibiting the NaV1.8 sodium channel (pain receipt) in the brain. NaV1.8 has nothing to do with tinnitus but everything with feeling pain. Again, as with every drug, we have no idea if this will help noxacusis - but this seems by far the best bet in the short term at this moment.

Hmmm, perhaps this could also help people with tinnitus? Dr. De Ridder believes that (neuropathic) pain and tinnitus share similar pathophysiological mechanisms.

A parahippocampal-sensory Bayesian vicious circle generates pain or tinnitus: a source-localized EEG study (De Ridder et al., 2023)

Pain and tinnitus share common pathophysiological mechanisms, clinical features, and treatment approaches. A source-localized resting-state EEG study was conducted in 150 participants: 50 healthy controls, 50 pain, and 50 tinnitus patients.

Resting-state activity as well as functional and effective connectivity was computed in source space. Pain and tinnitus were characterized by increased theta activity in the pregenual anterior cingulate cortex, extending to the lateral prefrontal cortex and medial anterior temporal lobe. Gamma-band activity was increased in both auditory and somatosensory cortex, irrespective of the pathology, and extended to the dorsal anterior cingulate cortex and parahippocampus.

Functional and effective connectivity were largely similar in pain and tinnitus, except for a parahippocampal-sensory loop that distinguished pain from tinnitus. In tinnitus, the effective connectivity between parahippocampus and auditory cortex is bidirectional, whereas the effective connectivity between parahippocampus and somatosensory cortex is unidirectional. In pain, the parahippocampal-somatosensory cortex is bidirectional, but parahippocampal auditory cortex unidirectional. These modality-specific loops exhibited theta–gamma nesting.

Applying a Bayesian brain model of brain functioning, these findings suggest that the phenomenological difference between auditory and somatosensory phantom percepts result from a vicious circle of belief updating in the context of missing sensory information.

This finding may further our understanding of multisensory integration and speaks to a universal treatment for pain and tinnitus—by selectively disrupting parahippocampal-somatosensory and parahippocampal-auditory theta–gamma activity and connectivity.

 

[Lucifer]

For people with noxacusis, I'd follow the trial of VX-548 of Vertex Pharmaceuticals which might be of interest.

It has 5x Phase 3 trials running at the same time for several pain conditions - the goal is essentially to treat all forms acute and chronic/neuropathic pain. The Phase 3 ends early next year already. VX-548 is the first pharmaceutical pain killer that is non-opioid and non-NSAID (we know their ototoxicity...) since basically the beginning of medicine, and with a mild safety profile this will become a blockbuster in the pain market. There is a reason why they are running so many costly trials at once - the potential is huge.

It works by directly inhibiting the NaV1.8 sodium channel (pain receipt) in the brain. NaV1.8 has nothing to do with tinnitus but everything with feeling pain. Again, as with every drug, we have no idea if this will help noxacusis - but this seems by far the best bet in the short term at this moment.

So this is essentially a sodium channel blocker targeting NaV1.8 sodium channel (pain receipt) in the brain. What would be the difference between VX-548 compared to current medication out in the market that targets NaV1.8 sodium channel in terms of potency, safety and efficacy?

 

[andrewdaniels]

We don't now why Trobalt helped some and not others. That is actually the problem. Maybe it helped noise induced tinnitus only etc. It had such a broad spectrum of action, we can't be sure what MoA was important. We have some literature on specific potassium channels and tinnitus to go on though. Then there is the question of whether it had some unknown MoA.

All this said, these potassium channel trials are frustrating as hell, as we don't know if we are following a gold mine or a red herring.

Would you say that Trobalt had an impact on most folks? Looking at the thread, it seemed to be mostly positive to some degree at reducing the tone/volume. Of course, not favorable side effects that impacted many - leading to a stop of the medication/no impact. Here's to hoping those are figured out in this clinical trial and it is successful.

At this point, I'll happily take a pill every day for the rest of my life for even a reduction in volume, and a minute or two of silence.

I'm also hoping this in combination with Dr. Shore's device will give some impact. I will take any relief. I habituated but now it seems like it's come back with a vengeance...

 

[Lucifer]

Would you say that Trobalt had an impact on most folks? Looking at the thread, it seemed to be mostly positive to some degree at reducing the tone/volume. Of course, not favorable side effects that impacted many - leading to a stop of the medication/no impact. Here's to hoping those are figured out in this clinical trial and it is successful.

At this point, I'll happily take a pill every day for the rest of my life for even a reduction in volume, and a minute or two of silence.

I'm also hoping this in combination with Dr. Shore's device will give some impact. I will take any relief. I habituated but now it seems like it's come back with a vengeance...

From the Trobalt User Experiences thread it seems most people's tinnitus was reduced while on it. On the other hand, hyperacusis/noxacusis seems to be a mixed bag. The only person who is still here and who can let us know is @Alue who mentioned that his hyperacusis was basically gone while on Trobalt and when he stopped taking it, his hyperacusis was still at a reduced level.

Hopefully these new reformulated retigabine drugs such as XEN1101 and BHV-7000 are more potent at reducing or getting rid of tinnitus and hyperacusis/noxacusis.

 

[andrewdaniels]

From the Trobalt User Experiences thread it seems most people's tinnitus was reduced while on it. On the other hand, hyperacusis/noxacusis seems to be a mixed bag. The only person who is still here and who can let us know is @Alue who mentioned that his hyperacusis was basically gone while on Trobalt and when he stopped taking it, his hyperacusis was still at a reduced level.

Fingers crossed. I'll take a reduction at this point, I don't even care about a cure. If I have to listen to be able to hear it, that's a win. I feel like, based on previous Trobalt experiences, and all the research out there regarding Kv7.2/7.3 channels, that XEN1101 will likely quiet tinnitus for folks. I also think this will pass Phase 3 and get FDA clearance. And look at competitor Biohaven's BHV-7000, they're confident enough that they're running Phase 2/3 at the same time.

I only hope they figure out the side effects, as those were the scary parts.

 

[Lucifer]

Fingers crossed. I'll take a reduction at this point, I don't even care about a cure. If I have to listen to be able to hear it, that's a win. I feel like, based on previous Trobalt experiences, and all the research out there regarding Kv7.2/7.3 channels, that XEN1101 will likely quiet tinnitus for folks. I also think this will pass Phase 3 and get FDA clearance. And look at competitor Biohaven's BHV-7000, they're confident enough that they're running Phase 2/3 at the same time.

I only hope they figure out the side effects, as those were the scary parts.

I think XEN1101 will definitely pass the Phase 3 trial, and BHV-7000 too unless there were severe side effects with more people in the trial.

I just hope these drugs allow us to get our lives back from suffering from tinnitus and hyperacusis/noxacusis.

 

[andrewdaniels]

I think XEN1101 will definitely pass the Phase 3 trial, and BHV-7000 too unless there were severe side effects with more people in the trial.

I just hope these drugs allow us to get our lives back from suffering from tinnitus and hyperacusis/noxacusis.

Me too! I'm trying to be optimistic, however, I've seen a lot of optimism here over the last ten years... I pray this is the one.

 

[InNeedOfHelp]

So this is essentially a sodium channel blocker targeting NaV1.8 sodium channel (pain receipt) in the brain. What would be the difference between VX-548 compared to current medication out in the market that targets NaV1.8 sodium channel in terms of potency, safety and efficacy?

There are no NaV1.8 blockers on the market at this moment as I am aware.

Hmmm, perhaps this could also help people with tinnitus? Dr. De Ridder believes that (neuropathic) pain and tinnitus share similar pathophysiological mechanisms.

A parahippocampal-sensory Bayesian vicious circle generates pain or tinnitus: a source-localized EEG study (De Ridder et al., 2023)

I'm no scientist but the pain/tinnitus comparison is from hyperexcitability of cells. I don't think VX-548 calms down hyperexcitability - it blocks the 'I feel pain' trigger in the brain.

 

[Christiaan]

I'm no scientist but the pain/tinnitus comparison is from hyperexcitability of cells. I don't think VX-548 calms down hyperexcitability - it blocks the 'I feel pain' trigger in the brain.

I don't mean that it calms down hyperexcitability, but I do hope that pharmacological intervention of VX-548 could at least help with the sensation or awareness of pain for people who have moderate/severe/catastrophic tinnitus. Who knows, maybe VX-548 could help to make us feel indifferent towards it.

 

[Joeseph Stope]

Me too! I'm trying to be optimistic, however, I've seen a lot of optimism here over the last ten years... I pray this is the one.

I guess that's the right attitude. Patient optimism and a small bit of hope.

I have a relative who for years has suffered from IBS (Irritable Bowel Syndrome). Some months back he heard of this form of wild grass grown in Ethiopia that they cultivate and it helps him no end. It doesn't switch his problem off like a light but helps him enormously.

 

[IndyMLVC]

I have a relative who for years has suffered from IBS (Irritable Bowel Syndrome). Some months back he heard of this form of wild grass grown in Ethiopia that they cultivate and it helps him no end. It doesn't switch his problem off like a light but helps him enormously.

Uh. Wait. WHAT? I have IBS *AND* tinnitus.