Xenon Pharmaceuticals' XEN1101 — Kv7 Potassium Channel Modulator

[Nick47]

I tried to get in on the XEN1101 MDD trial as well. Same response. Never mentioned tinnitus, just leaned on MDD co-diagnosis.

I would say to others reading this: keep trying if you live in New York or Texas.

 

[ErikaS]

I would say to others reading this: keep trying if you live in New York or Texas.

The girl in New York was hoping I would do it. If I was promised the drug AND told I could keep taking it following the trial if it worked for my depression (and mostly tinnitus), I would consider it. But I just can't do the travel and find living accommodations for 2 months if it were to end up being a placebo.

 

[lolkas]

I just emailed the clinical trial contact for the New York location asking if I had to reside near there for treatment or if I could come there, do the enrollment process and get medication directions, and go home. Will see.

I live in NYC. Could I try to enroll in the trial?

 

[ErikaS]

I live in NYC. Could I try to enroll in the trial?

If you are at all experiencing depression and are not on any other antidepressant medications or are willing to do a washout of your current med, then yes, you can try to enroll. Obviously avoid talking about the tinnitus over the depression, but I even said how I am unable to take any antidepressant due to the sensitivity of my tinnitus to antidepressant drugs, and that wasn't frowned upon at all.

 

[Nick47]

I live in NYC. Could I try to enroll in the trial?

As @ErikaS said, apply. It's also very well reimbursed to the tune of $1,300!

 

[lolkas]

As @ErikaS said, apply. It's also very well reimbursed to the tune of $1,300!

Can you or @ErikaS share a link for the trial's contact information, please? I cannot find it on the web. Ty!

 

[annV]

Can you or @ErikaS share a link for the trial's contact information, please? I cannot find it on the web. Ty!

Under "Contacts and Locations" here:

XEN1101 for Major Depressive Disorder

 

[Nick47]

Can you or @ErikaS share a link for the trial's contact information, please? I cannot find it on the web. Ty!

I would not mention that you have tinnitus.

 

[yeezysqueezy]

I looked into the MDD study ages ago and it requires an MRI, which eliminates the possibility for many/most of us

 

[Justwaitinchilin]

I looked into the MDD study ages ago and it requires an MRI, which eliminates the possibility for many/most of us

Why does an MRI eliminate most of us? Many of us could plug up and sit an MRI. I have. I would again if had the chance to try a med that could help. The sponsors told me no due to travel distance to Houston for XEN1101. I could sit a few MRIs if a med could help this.

 

[yeezysqueezy]

Why does an MRI eliminate most of us? Many of us could plug up and sit an MRI. I have. I would again if had the chance to try a med that could help. The sponsors told me no due to travel distance to Houston for XEN1101. I could sit a few MRIs if a med could help this.

MRIs are tremendously loud. They peak at 130-140+ dB. For those of us with significant hyperacusis/noxacusis, it's out of the question. For people with just tinnitus, it's a risk vs. reward decision. Can't usually wear earmuffs on top of earplugs for brain MRIs and your ears are as close to the magnets as they can get.

 

[ThomasF]

MRIs are tremendously loud. They peak at 130-140+ dB. For those of us with significant hyperacusis/noxacusis, it's out of the question. For people with just tinnitus, it's a risk vs. reward decision. Can't usually wear earmuffs on top of earplugs for brain MRIs and your ears are as close to the magnets as they can get.

Might be a bit off topic but there are apparently MRI machines that are closer to 70-80 dB. Any hearing protection should make that tolerable.

Just one example:

The Sound of Silence: GE's Silent Scan Dials Down MRI Noise to a Whisper | GE News

 

[yeezysqueezy]

Might be a bit off topic but there are apparently MRI machines that are closer to 70-80 dB. Any hearing protection should make that tolerable.

Just one example:

The Sound of Silence: GE's Silent Scan Dials Down MRI Noise to a Whisper | GE News

Yeah I tried to get Canon Pianissimo done last fall and it is quieter hardware but still hits 110+ dB. Turned out a lot of these places don't use the SOFTWARE needed to quiet it down to those levels. And even if they had the software, it's often not possible for the resolution and sequences the doctor needs. Hopefully the tech continues to improve.

The thing that sucks about these clinical trials is you don't get to pick your MRI machine.

 

[InNeedOfHelp]

The abstracts for the 2nd Kv7.2 Channels Symposium are online:

2nd Kv7 Channels Symposium: Programme

Seems like Dr. Thanos Tzounopoulos didn't submit any abstract.

 

[chinup]

Might be a bit off topic but there are apparently MRI machines that are closer to 70-80 dB. Any hearing protection should make that tolerable.

Just one example:

The Sound of Silence: GE's Silent Scan Dials Down MRI Noise to a Whisper | GE News

I had an MRI a couple months back using this machine. I've had severe hyperacusis and noxacusis since 2019 but have slowly recovered to a degree that fluctuates between 80-90%.

I used foam earplugs and they didn't allow me to use over-ear protection. It was still quite loud, and I agree that there must have been a software component that wasn't configured properly as there's no way it was 70 dB. Closer to 100 dB. So the heavy foam earplugs mitigated it down to 80 dB or so.

That said, I didn't suffer a major setback. Maybe increased sensitivity for a couple days. Within a week I was definitely back to the 80-90% recovery level. Tinnitus was completely unaffected.

Keep in mind I was desperate for the MRI due to other health conditions. I'd avoided it for half a decade. Fortunately it came back clean.

I'd still say unless you are in a potential life or death situation, avoid all MRIs if you have severe hyperacusis or noxacusis.

 

[InNeedOfHelp]

Xenon Pharmaceuticals has their Q3 update call on the 8th of November. This call will be important for the timelines of XEN1101.

 

[Nick47]

Xenon Pharmaceuticals has their Q3 update call on the 8th of November. This call will be important for the timelines of XEN1101.

I think the current trial completion dates are December 2025. Let's hope these are moved forward.

 

[InNeedOfHelp]

I think the current trial completion dates are December 2025. Let's hope these are moved forward.

The date on ClinicalTrials.gov is a placeholder and not based on facts. They said there is no known estimated completion date. I'm gambling for Q3-Q4/2024.

 

[Nick47]

I'm gambling for Q3-Q4/2024.

I think that's optimistic. Basically forward by a year. I've only seen dates put back, not forward.

 

[dd314]

I looked into the MDD study ages ago and it requires an MRI, which eliminates the possibility for many/most of us

I went down this rabbit hole last year. The Siemens Aera 1.5 T with Quiet Suite (software setting) is genuinely pretty quiet, but you do need double hearing protection. If you have the option, you should ask them to skip a sequence called "Diffusion-weighted image", because it's the loudest sequence. If not, you'll still be fine with double protection. Many people on Tinnitus Talk get MRIs and with double protection are perfectly fine. Just practice inserting foam earplugs and make sure the fit is tight. I used these.

 

[BB23]

The date on ClinicalTrials.gov is a placeholder and not based on facts. They said there is no known estimated completion date. I'm gambling for Q3-Q4/2024.

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

XEN1101 Phase 3 epilepsy program continues to progress with X-TOLE2 and X-TOLE3 in focal onset seizures and X-ACKT in primary generalized tonic-clonic seizures.

Patient enrollment in X-TOLE2 expected to complete in the second half of 2024.

This is going to take a lot longer than our estimates.

 

[ErikaS]

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


This is going to take a lot longer than our estimates.

My goodness, why must it take so long for enrollment I know they want/need a substantial sample size and it's a very complex brain disorder, but it's just crushing how slow the process is. Meanwhile, we are bystanders just wanting to try yet another drug to see if it will help our condition(s).

 

[InNeedOfHelp]

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

This is going to take a lot longer than our estimates.

Why? I just estimated Q3-Q4 2024 and that is exactly what second half year means which they are stating. Right on spot. This is very good news! Within a year from now the trial closes. After that there is the actual trial period and readout of the last patients. This means data readout and preparation of FDA submission are somewhere between end of 2024 and early 2025.

Here are some anecdotes from the investor call:

In X-TOLE, we screened patients over a period of 26 months from the first quarter of 2019 through the first quarter of 2021. And then X-TOLE2, we initiated our first clinical site late last year with our first patient being randomized in Q1 of this year. And we expect patient enrollment to complete in the second half of 2024. So this would be in line or faster than X-TOLE based on our current assumptions and expectations. And as a reminder, X-TOLE2 will recruit more patients than X-TOLE. So overall, we are pleased with the progress our team has made so far this year.

So in terms of XTOLE2, Paul, we've guided today that we think patient enrollment will be completed in the second half of next year. So when the last patient gets screened into the program, there's a two month baseline period. And so we need to count the number of patients or the patients need to count their number -- patients need to count their number of seizures for a baseline number before those patients are randomized. And then it's a three month double blind period, so that's five in total and then there's some follow-up before we can be in a position to unblind data and provide top line results. So it's kind of in that six to eight month range from last patient enrolled to top line data, again, just depending on the timing of follow-up and database lock and data analysis, but in that range. So hopefully, that's helpful.

 

[Nick47]

Why? I just estimated Q3-Q4 2024 and that is exactly what second half year means which they are stating. Right on spot. This is very good news! Within a year from now the trial closes. After that there is the actual trial period and readout of the last patients. This means data readout and preparation of FDA submission are somewhere between end of 2024 and early 2025.

Here are some anecdotes from the investor call:

From reading your extract from the earnings call, it looks like recruitment will be done by end of 2024, then 8 months, so readout around August 2025 as a conservative guess. Then it needs to be successful.

How long does the FDA submission and approval process for a new drug take though?

 

[InNeedOfHelp]

From reading your extract from the earnings call, it looks like recruitment will be done by end of 2024, then 8 months, so readout around August 2025 as a conservative guess. Then it needs to be successful.

How long does the FDA submission and approval process for a new drug take though?

Second half 2024 could be anywhere between July and December. Trial completion will be at the end of 2024. Best case scenario would be essentially a December 2024/January 2025 data readout, worst case scenario data readout summer 2025.

XEN1101 does not have FDA Fast Track. I'm still hoping this becomes the case though. Either way, I'm expecting a product approval in the winter of 2025, so roughly 2 years from now. There is really a ton of safety data because of open label extensions and MDD trials. It seems like far away but we finally have two viable tinnitus treatments in hands' reach.

 

[StoneInFocus]

The abstracts for the 2nd Kv7.2 Channels Symposium are online:

2nd Kv7 Channels Symposium: Programme

Seems like Dr. Thanos Tzounopoulos didn't submit any abstract.

Thank you for the link, I quickly scanned through the abstracts.

According to one abstract, "voltage-gated potassium channel subfamily q member 4 (KCNQ4), which is predominantly expressed by hair cells and auditory neurons, regulates the neuronal excitability in the auditory pathway."

I guess it really makes sense why Retigabine as a pan-Kv7 was so relatively effective in treating tinnitus. Maybe Kv7.4 mediated smooth muscle relaxation helped too? It also blocks L-type voltage-gated Ca2+ channels as well.

When looking for hyperacusis biomarkers, Dan Polley, PhD, found that "cortical Parvalbumin GABA Neurons Regulate the Perceptual Volume Knob", and that "activating these target neurons can downshift a mouse's loudness perception by 15 decibels." "This type of cell becomes hypoactive after noise-induced hearing loss." (source).

Retigabine also positively modulated GABAa receptors.

Also, apparently Melatonin is a Kv7.4 channel activator in vitro.

 

[BB23]

Thank you for the link, I quickly scanned through the abstracts.

According to one abstract, "voltage-gated potassium channel subfamily q member 4 (KCNQ4), which is predominantly expressed by hair cells and auditory neurons, regulates the neuronal excitability in the auditory pathway."

I guess it really makes sense why Retigabine as a pan-Kv7 was so relatively effective in treating tinnitus. Maybe Kv7.4 mediated smooth muscle relaxation helped too? It also blocks L-type voltage-gated Ca2+ channels as well.

When looking for hyperacusis biomarkers, Dan Polley, PhD, found that "cortical Parvalbumin GABA Neurons Regulate the Perceptual Volume Knob", and that "activating these target neurons can downshift a mouse's loudness perception by 15 decibels." "This type of cell becomes hypoactive after noise-induced hearing loss." (source).

Retigabine also positively modulated GABAa receptors.

Also, apparently Melatonin is a Kv7.4 channel activator in vitro.

OK, so what you are saying is that XEN1101 might not work as efficiently as Retigabine since it doesn't target Kv7.4 as much, is that it?

 

[StoneInFocus]

OK, so what you are saying is that XEN1101 might not work as efficiently as Retigabine since it doesn't target Kv7.4 as much, is that it?

Are you asking whether I think XEN1101 might not work as efficiently as Retigabine since it doesn't target Kv7.4 as much? Or are you asking what I intended to say?

 

[BB23]

Are you asking whether I think XEN1101 might not work as efficiently as Retigabine since it doesn't target Kv7.4 as much?

Do you think XEN1101 will work as well as Retigabine or not? Especially based on what you posted just now.

I went through the papers myself, it seems like the loss of those channels leads to progressive hearing loss in the high frequencies, but there is no mention of tinnitus as a result.

I believe we might need Kv7.4 for the relaxation of tensor tympani problems, since Kv7.4 is present in smooth muscle. But I have no idea when it comes to tinnitus.

 

[Kleiner]

Do you think XEN1101 will work as well as Retigabine or not? Especially based on what you posted just now.

I went through the papers myself, it seems like the loss of those channels leads to progressive hearing loss in the high frequencies, but there is no mention of tinnitus as a result.

I believe we might need Kv7.4 for the relaxation of tensor tympani problems, since Kv7.4 is present in smooth muscle. But I have no idea when it comes to tinnitus.

This effect on smooth muscles may be the cause of certain side effects of Retigabine. Particularly on urinary retention and cardiac "disorders".

So, if I recall correctly, it's a channel that reformulations avoid.

According to Professor Tzounopoulos, Kv7.2/3 are clearly the induction mechanism of tinnitus, but it's unclear what their role is in the maintenance mechanism, it's quite contradictory.

In my case and some others', Retigabine acts mainly on somatic tinnitus (located in the DCN). Apparently the DCN is a structure where Kv7.2/3 is very expressed, so this leads me to think that it's remains the main target even for chronic patients.

Difficult to make deductions with so little information.