Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[AnthonyMcDonald]

It looks like XEN1101 doesn't have Retigabine's side effects because of how specific and potent it is. So I would say the chances are if XEN1101 works for tinnitus, then it may also resolve visual snow syndrome.

This is a very dangerous assumption. There just isn't enough data or research (especially on people with tinnitus or who already have visual snow) to assume.

Yes, the fact that it's significantly safer than Retigabine is true. However, we won't know for certain until people try it out. The mechanisms of visual snow are unknown. Yes, the side effects results from the clinical trials are not bad at all, but in any case people should be wary. The subjects in the XEN1101 trial did not have tinnitus, as far as I can tell. However, I would assume some might have had it to some degree, due to it being such a common condition.

The dosages of Retigabine were massive. Some were taking up to 900 mg a day, which is ginormous compared to the 10-20 mg of XEN1101. It also hit many potassium channels. My theory as to why some people didn't see as much effect as others is the exact potassium channels being modified for everyone in such a broad drug was very different; some had their KCNQ2/KCNQ3 affected more than others.

People have to be careful with a drug like this, especially if they show signs of visual snow, even mild. We are wired differently than people with epilepsy.

 

[Nick47]

Probably best fits here, although general potassium channel stuff:

Activation of metabotropic (P2Y) purinergic receptors by ATP increases type II afferent excitability by the closure of KCNQ-type potassium channels. Thus a noise-induced hyperexcitability of type II fibers, due to the closure of KCNQ channels, may underlie the increased sensitivity or intolerance to sounds that are normally not perceived as loud, which is a hallmark of hyperacusis. Alternatively, this mechanism may also be involved in hyperacusis with pain (noxacusis).

What's the buzz? The neuroscience and the treatment of tinnitus

 

[Guywithapug]

Xenon Pharmaceuticals Outlines Key Milestone Opportunities for 2023

XEN1101 Phase 3 Epilepsy Program Ongoing in Focal Onset Seizures and Recently Initiated in Primary Generalized Tonic Clonic Seizures

Strong financial position expected to fully support XEN1101 Phase 3 program development and cash runway into 2026

 

[HopeForSilence]

When can we expect clinical results/data from the XEN1101 Phase 3 Epilepsy Program?

At ClinicalTrials.gov they estimate the study completion date in October 2025.

 

[Nick47]

I have read through the threads on potassium channel activators. I accept the theory as good.

However, if the companies thought they would likely be effective tinnitus treatments and, given the size of the market potential, then why are they not in trials for tinnitus?

The scientists will be well read on their actions and also familiar with tinnitus as a market. Even if they were to fail in tinnitus trials, it would not stop successful epilepsy trials taking the product to market.

 

[Gb3]

I have read through the threads on potassium channel activators. I accept the theory as good.

However, if the companies thought they would likely be effective tinnitus treatments and, given the size of the market potential, then why are they not in trials for tinnitus?

The scientists will be well read on their actions and also familiar with tinnitus as a market. Even if they were to fail in tinnitus trials, it would not stop successful epilepsy trials taking the product to market.

This has been talked about endlessly. One of the reasons is because TFI is really the only way to measure the effect of the drug. The pharmaceutical companies need some concrete objective testing measure for results to be able to say the drug works.

 

[HopeForSilence]

The scientists will be well read on their actions and also familiar with tinnitus as a market. Even if they were to fail in tinnitus trials, it would not stop successful epilepsy trials taking the product to market.

Tinnitus is hard to measure. In addition, trials cost a lot of money. I think that these are the main reasons why they are not focussed on tinnitus.

They also stated that these medications (XEN1101) might be potentially helpful for other neurological diseases.

I guess they are aware of the following point: Once they have FDA approval for the targeted market/disease, off-label use and further FDA confirmations/trials for other diseases will be much easier, since they have a stable cash flow from that working treatment.

 

[Josh59]

Have I understood correctly that the clinical trial will end around 2025?

Let's say it's successful and FDA approves XEN1101, would it become available when?

Has anyone asked Xenon Pharmaceuticals if it can in theory reduce tinnitus?

This is encouraging! Let's stay optimistic.

 

[InNeedOfHelp]

Have I understood correctly that the clinical trial will end around 2025?

Let's say it's successful and FDA approves XEN1101, would it become available when?

Has anyone asked Xenon Pharmaceuticals if it can in theory reduce tinnitus?

This is encouraging! Let's stay optimistic.

Xenon Pharmaceuticals is estimating the trial to last 2 years, just like Phase 2, with an estimated ending of late 2024/early 2025. They stated this during their Q4 call in 2022. They are now expecting more swift patient recruitment because there is no COVID-19 delay and the results of Phase 2 were significant which should encourage doctors to enroll their patients. The 2 years is a conservative estimate.

The end date on ClinicalTrials.gov never seems to be very accurate based on the trials I've followed in the last year.

 

[Nick47]

Has anyone asked Xenon Pharmaceuticals if it can in theory reduce tinnitus?

@Josh59, this is the most important question for me. We are going off 'our' theory and not indication. We really need to see some evidence or intent to treat tinnitus here. I cannot emotionally invest in this until then.

 

[InNeedOfHelp]

In last week's investor call, questions were asked on the Phase 3 timeline.

Unidentified Analyst:

Hi, this is James on for Paul. Thanks for taking our question. Just as it relates to the recruitment challenges, some others are facing in the focal epilepsy space, as you mentioned, you previously guided for trial completion around two and a half years from initiation based on the Phase 2b, which will put data around mid-2025. I guess is that still how you're thinking about it? Can you speak to the possibility of data coming sooner, if possible? Thanks.

Ian Mortimer, CEO of Xenon Pharmaceuticals:

Thanks James. So, we haven't -- as I mentioned in the prepared remarks, we haven't given formal guidance on when we expect topline data for Phase 3 and specifically for the X-TOLE2 clinical trial.

The data point that you're referring to is we often talk about the X-TOLE study, the Phase 2b study that took approximately two and a half years from initiation to topline data. When we compare and contrast that to the X-TOLE2 study, the X-TOLE study was a little bit smaller, 325 subjects. As Chris mentioned in his remarks, the Phase 3 studies are 360 and it's a 12-week double-blind period in Phase 3 versus an eight-week double-blind period in Phase 2. Other than that, the protocols are very similar.

As we've talked to many of you about we're going to a lot of the same investigators, same sites that have experience with the drug from the Phase 2 program. And we're prioritizing those investigators and sites in the X-TOLE2 clinical trial.

And so when we put all that together, as I mentioned earlier, I think we feel confident in the Phase 3 program and executing on the Phase 3 program. But we really need to get a couple of quarters of enrollment under our belt before we'd be in a position where we can provide more specific guidance on timeline to topline data.

 

[InNeedOfHelp]

XEN496 program has been killed mid Phase 3 and they are shifting the focus to only XEN1101. This was reported in the Q1 financial call of Xenon Pharmaceuticals yesterday.

 

[KoolKat]

XEN496 program has been killed mid Phase 3 and they are shifting the focus to only XEN1101. This was reported in the Q1 financial call of Xenon Pharmaceuticals yesterday.

Is that good or bad? What does it mean?

 

[Nick47]

XEN496 program has been killed mid Phase 3 and they are shifting the focus to only XEN1101. This was reported in the Q1 financial call of Xenon Pharmaceuticals yesterday.

I'm losing track here so I may need correcting, buddy.

XEN496 Is a reformulated version of Retigabine that was in Phase 3 trials for pediatric focal epilepsy? They have withdrawn it in Phase 3?

XEN1011 Is a potassium channel opener for epilepsy in adults? It's in Phase 2b? Or Phase 3?

Also, isn't QRA-244 a more potent potassium channel opener than both of the above?

 

[InNeedOfHelp]

I'm losing track here so I may need correcting, buddy.

XEN496 Is a reformulated version of Retigabine that was in Phase 3 trials for pediatric focal epilepsy? They have withdrawn it in Phase 3?

XEN1011 Is a potassium channel opener for epilepsy in adults? It's in Phase 2b? Or Phase 3?

Also, isn't QRA-244 a more potent potassium channel opener than both of the above?

I cannot comment on potency. All we hear from the companies is that their product is best in class. Everyone claims the same.

There are two XEN1101 Phase 3s running. They will likely finish earlier then expected. Xenon Pharmaceuticals will likely comment on an estimated timeline in Q3. There are also two Phase 2s running for MDD (major depression). They made no comment on if these trials can become pivotal as there is a ton of safety data on all of these studies.

XEN496 was mildly optimized Trobalt in pediatric doses. XEN1101 is the de-risked Trobalt which we should keep an eye for. There are four companies running Kv7.2 clinical trials at the moment, some with FDA Breakthrough Designation.

 

[StoneInFocus]

Is that good or bad? What does it mean?

It means they are throwing all their eggs in one basket. Whether that's good or bad, depends on your view of Retigabine. Retigabine/XEN496 opens potassium channels Kv2 to 5. XEN1101 only opens channels Kv7.2/3. Retigabine came with a lot more side effects. These two channels are believed to be involved with tinnitus and hyperacusis symptoms. We don't know yet whether the tinnitus and hyperacusis alleviating properties of Retigabine were only due to its effect on the Kv7.2/7.3 channels, or that other channels were involved as well.

Our business substantially depends upon the successful development of XEN1101. If we are unable to obtain regulatory approval for, and
successfully commercialize, XEN1101, our business may be materially harmed.

(Source)

The positive aspect is that Xenon Pharmaceuticals is now going to focus on XEN1101, which might lead to it being released sooner (I don't know for sure if this will really have much of an influence). The negative aspect is that we will have one less drug to choose from as tinnitus sufferers.

From quickly reading the report, it is not really clear why Xenon Pharmaceuticals has chosen to drop Retigabine. Maybe I am interpreting it wrong, but "For all patients currently on XEN496, Xenon intends to work with study investigators to offer an option for continued access to XEN496 through a transition period" reads like they stopped the study before its completion. Maybe they believe XEN1101 will make XEN496 obsolete? Maybe the market for XEN496 is too small and they are afraid they won't turn a profit. Maybe someone got hurt in the trials and they are trying to cover it up? Who knows.

 

[Nick47]

We don't know yet whether the tinnitus and hyperacusis alleviating properties of Retigabine were only due to its effect on the Kv7.2/7.3 channels, or that other channels were involved as well.

This has ALWAYS been at the back of my mind. I've read literature that Kv7.1 is also expressed in the inner ear. Whether that has relevance, I say this with the general thought that many medications have unknown mechanisms of action. In other words, we know that Retigabine worked on a broad range of potassium channels, however, it may have worked on other channels or neurons that we didn't know about. It's a big leap of faith for me to invest hope and expectation. I will never be persuaded that a treatment not in a clinical trial for tinnitus, but in late stage clinical trial for epilepsy holds great promise. The Retigabine thread seemed a bit messy with the same couple of members who had big benefits posting over and over again, with lots of members asking questions in excitement. It was a bit hard to follow and (unless I missed it) needed putting into a table for data analysis.

Also, given that thousands have been involved in clinical trials (Xenon Pharmaceuticals, Biohaven, and others?) with these potassium channel modulators for epilepsy, we have no anecdotal evidence. Some of these clinical trial participants must have tinnitus.

Am I negative or just being reasonable in expectation?

 

[InNeedOfHelp]

It means they are throwing all their eggs in one basket. Whether that's good or bad, depends on your view of Retigabine. Retigabine/XEN496 opens potassium channels Kv2 to 5. XEN1101 only opens channels Kv7.2/3. Retigabine came with a lot more side effects. These two channels are believed to be involved with tinnitus and hyperacusis symptoms. We don't know yet whether the tinnitus and hyperacusis alleviating properties of Retigabine were only due to its effect on the Kv7.2/7.3 channels, or that other channels were involved as well.

(Source)

The positive aspect is that Xenon Pharmaceuticals is now going to focus on XEN1101, which might lead to it being released sooner (I don't know for sure if this will really have much of an influence). The negative aspect is that we will have one less drug to choose from as tinnitus sufferers.

From quickly reading the report, it is not really clear why Xenon Pharmaceuticals has chosen to drop Retigabine. Maybe I am interpreting it wrong, but "For all patients currently on XEN496, Xenon intends to work with study investigators to offer an option for continued access to XEN496 through a transition period" reads like they stopped the study before its completion. Maybe they believe XEN1101 will make XEN496 obsolete? Maybe the market for XEN496 is too small and they are afraid they won't turn a profit. Maybe someone got hurt in the trials and they are trying to cover it up? Who knows.

No, they are shifting away because they are creating a pediatric version of XEN1101. Also, the age group for XEN1101 has been extended in the trial (12 years and older). Hopefully this increases the target group size and accelerates the enrollment of patients.

 

[lapidus]

This has ALWAYS been at the back of my mind. I've read literature that Kv7.1 is also expressed in the inner ear. Whether that has relevance, I say this with the general thought that many medications have unknown mechanisms of action. In other words, we know that Retigabine worked on a broad range of potassium channels, however, it may have worked on other channels or neurons that we didn't know about.

Then there's also the Kv3.1 which I guess some research must've shown that it's also expressed in the inner ear since Autifony's drug AUT00063, specifically for tinnitus, acted on the Kv3.1. But that turned out to be a dud and they cancelled the drug halfway through Phase 2 due to no effect. I can't remember if Retigabine also acted on the Kv3.1 though.

 

[Nick47]

Are you a betting man, @InNeedOfHelp? How confident, on a scale of 1 to 10, with 10 being certain, are you that these potassium modulators will benefit to some extent at least 50% of us?

 

[Joeseph Stope]

Are you a betting man, @InNeedOfHelp? How confident, on a scale of 1 to 10, with 10 being certain, are you that these potassium modulators will benefit to some extent at least 50% of us?

That's a nice way of putting it.

Let's say that you are a politician --- the one who signs the cheques, and one group of scientists come along with all this data proving that tinnitus is all in the mind... or let's say the brain. Then a second group comes along with all this data telling you that it's all in the ear. Now research money is scarce. You have to make a decision, but you are afraid that dividing the funds would result in just scratching surface of the solution to the problem. Backing one horse might bring tangible results (such as that it's barking up the wrong tree ).

Myself of late, I'm kinda anxious that the research into the TMJ & jaw connection seems to be neglected. But that's just me. Someone who always looks at the outsiders in the race.

 

[InNeedOfHelp]

Are you a betting man, @InNeedOfHelp? How confident, on a scale of 1 to 10, with 10 being certain, are you that these potassium modulators will benefit to some extent at least 50% of us?

You know, I have been dealing with neuropathic pain for some time now in parallel with tinnitus. Neuropathic pain shares a lot of similarities with tinnitus. It is often caused by local nerve damage but, as the pain continues, it gets centralized in the brain. Amitriptyline and Gababentin are the golden standard of treatment. Off-label and 2nd line are drugs such as Carbamazepine and other epileptic drugs. They calm the nerves/CNS down and lower the pain. For some people with tinnitus, these drugs also seem to work due to the way they work on the CNS/hyperexcitability of nerves firing.

I have absolutely no idea how potassium or sodium channels work, so technically I have no clue whether we can benefit. Subjectively, I think we will benefit from anti-epileptics such as XEN1101 for sure, taking previous Trobalt anecdotes together with the mechanisms of action of stopping misfiring of nerves/hyperexcitability.

Either way, XEN1101 will be a heavy drug with significant side effects. This is no Paracetamol/Tylenol. For its users within epilepsy, it outweighs risks/benefits. I'm sure it will be ototoxic like all meds are. There are people that have gotten increases from Trobalt too. But if I had to put my money on something, it would be XEN1101 and less of Dr. Susan Shore's device.

What we really need is the specific gene in people that do not develop tinnitus. As soon as we have that, there is a pharmaceutical target for tinnitus. We are very, very far out of a true pharmaceutical medicine to completely resolve tinnitus. It's not even close to being in sight. None of the people in the SPI-1005/Ebselen trial had their tinnitus resolve either.

Look at the current chronic pain situation. People with a specific gene that blocks NaV1.7 sodium channel cannot feel pain, ever. Now NaV1.7 blocker is the holy grail of pain management and a ton of companies are working on compounds of this. It will help people with noxacusis for sure. But 15 years after identifying the target, only one medicine is in Phase 3. All the others just don't work out.

Fun read:

→ Fifteen years of NaV1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy?

What I'm saying is, even if we finally have the target identified, it will take years of trial and error to get something to market.

Any other drug in the meantime will be patchwork in my opinion. They might help for sure! But it will not be a 100% shutdown.

If you want to read some of the progress of the current Phase 3 trial, I'd suggest you to check the transcript of the latest earnings call of Xenon Pharmaceuticals here:

→ Xenon Pharmaceuticals Inc. (XENE) Q1 2023 Earnings Call Transcript

 

[InNeedOfHelp]

@Nick47, a different Kv7.2 modulator currently being trialed in China is Pynegabine HN37. It already completed Phase 1 and is moving to Phase 2. It is based on Retigabine.

HN37, trial number: CTR20201676 and CTR20222616. Hope your mandarin is sufficient

There is a Kv7 symposium this year in Naples: https://kv7channelssymposium.org/

I suspect tinnitus being mentioned there too as a therapeutic area, but it's in September. I'll keep an eye on this.

 

[Nick47]

@InNeedOfHelp, you're a very valuable member of this community as far as I'm concerned.

As for potassium channel modulators, the theory is good. Retigabine wasn't a magic solution, and the threads seemed largely dominated by the same 2-3 people who claimed great success. For a few it didn't help.

For pain hyperacusis, have you considered a CGRP antagonist, similar to the findings in the Megan Beers Wood animal trials?

 

[CaliGirl]

So @Nick47, XEN1101 may or may not help us? Is there anything we can look forward to in the near future?

 

[Nick47]

Is there anything we can look forward to in the near future?

Dr. Shore's device maybe.

 

[ZFire]

@InNeedOfHelp, you're a very valuable member of this community as far as I'm concerned.

As for potassium channel modulators, the theory is good. Retigabine wasn't a magic solution, and the threads seemed largely dominated by the same 2-3 people who claimed great success. For a few it didn't help.

Regarding potassium channel modulators, I feel like there are still many unanswered questions and hypothetical scenarios to consider. For instance, does anyone know whether this medication would have to be taken permanently in order to achieve lasting relief. What dosage do we need to be on to get the relief anyway? Also, what action does one have to take if they were to experience an acoustic trauma that resulted in a tinnitus worsening while on the drug? Does the dosage have to be increased? I think these are very important questions that need answering. I didn't read this whole thread, so I might be speaking from a place of ignorance.

Seems like there is a lot of uncertainty and ambiguity surrounding these medications. It would be nice if we had objective measurements for tinnitus in this instance.

 

[Nick47]

For instance, does anyone know whether this medication would have to be taken permanently in order to achieve lasting relief.

I would think almost certainly. The most important question is does it work? We don't seem to have anyone that managed to get in a Phase 1 safety trial to give us an indication.

 

[Josh59]

Is this drug (XEN1101) really a novelty compared with other drugs used to treat epilepsy? Is it the first drug to have this specificity with Kv7?

If so, it's a great advance in medicine, for people with epilepsy and perhaps for us in the future with tinnitus and hyperacusis.

 

[StoneInFocus]

Is this drug (XEN1101) really a novelty compared with other drugs used to treat epilepsy? Is it the first drug to have this specificity with Kv7?

The first anticonvulsant with Kv7 modulating properties was Retigabine, which got pulled out of the market due to side effects. As of now, Epidiolex (cannabidiol) is the only FDA approved anticonvulsant which has been shown to activate Kv7.2/7.3 channels in vitro. I am currently taking high doses of CBD isolate, corresponding to the dose regimen of Epidiolex, unfortunately with little effects so far. You can read about my experiments here:

Cannabidiol (CBD) — Epidiolex