Xenon Pharmaceuticals at RBC Capital Markets: Strategic Insights on Ezetucalmer

On Wednesday, 21 May 2025, Xenon Pharmaceuticals (NASDAQ:XENE) presented at the RBC Capital Markets Global Healthcare Conference 2025, providing a strategic overview of its ongoing developments. The focus was on Ezetucalmer, a promising drug for epilepsy and major depressive disorder (MDD). While the company reported delays in trial enrollments, it expressed confidence in its long-term potential and market opportunity.

Key Takeaways

• Xenon is advancing Phase 3 trials for Ezetucalmer in epilepsy and MDD, with data expected in early 2026.
• A slight delay in enrollment for the XTOL-2 trial was noted, but completion is anticipated soon.
• Ezetucalmer offers a significant market opportunity, with one million potential candidates in the U.S.
• Long-term data shows a one in three chance of seizure freedom for patients over 12 months.
• Xenon is also developing additional pipeline candidates, including XEN110 and XEN1101.

Epilepsy Program (Ezetucalmer - XTOL Trials)

The XTOL-2 and XTOL-3 trials are pivotal Phase 3 studies mirroring the successful Phase 2 XTOL study. Despite a slight delay in enrollment for XTOL-2, Xenon anticipates data readout by early 2026. The trials are designed with a high power (>99%) to meet primary endpoints. Long-term data revealed a significant potential for seizure freedom, with a consistent safety profile observed over 700 patient-years of exposure.

MDD Program

Xenon’s Phase 3 program for Ezetucalmer in MDD includes Exnova 2 and 3 trials, with plans to extend into bipolar depression. An investigator-sponsored study indicated promising results, although statistical significance was not achieved. The adverse event profile remained consistent with previous studies, showing no significant issues like weight gain or sexual dysfunction.

Market Opportunity and Commercial Strategy

Xenon estimates that approximately one million U.S. patients with focal onset seizures could benefit from Ezetucalmer. Positioned as a second or third-line treatment, Ezetucalmer offers advantages such as no titration, early onset of efficacy, and potential mood benefits over competitors like XCOPRI.

Pipeline Updates

Beyond Ezetucalmer, Xenon is developing other promising candidates. XEN110 is currently in Phase 1 clinical trials, and XEN1101, a NAV1.7 drug, is expected to enter clinical development soon. The Nav 1.1 program also shows promising preclinical data, with upcoming investor webinars planned to discuss these advancements.

Readers are invited to refer to the full transcript for a detailed exploration of Xenon’s strategic developments and future plans.

Full transcript - RBC Capital Markets Global Healthcare Conference 2025:

Operator: to

Brian, Analyst, RBC: have next presenting company, Xenon Pharmaceuticals, represented by their President and CEO, Ian Mortimer. Ian, thanks so much for, for being here and joining us.

Operator: Yeah. Thanks for having me. It’s always great to be at

Brian, Analyst, RBC: the RBC Conference. Appreciate it. Great. So, maybe we can kind of jump right in and and talk about the, sort of calendaring pivotal in epilepsy. And can we maybe start with sort of the latest on the conduct of the XTOL-two and three Phase three studies?

I guess how you’re feeling about the overall trial operationally? And then I know you mentioned on your recent earnings call some metrics that give you high confidence that you’re enrolling a population that should respond similarly to what you saw in the XTOL Phase II study. So can you talk a little bit about maybe the conduct, the types of patients that you’re seeing, how you’re feeling about just the ongoing studies overall.

Operator: Yeah. Happy to. And, maybe even before I get into some of the details on the question, I’ll just take a little bit of a step back. I won’t give an overall corporate overview because I know we’ll go into lots of parts of the business over the next twenty five minutes. But, you know, specifically for rosette to calendar, obviously, our excitement is really to bring a novel mechanism forward in epilepsy.

You know, there are no potassium channel modulators that are available to help and treat these patients. We know still about fifty percent of these patients are having breakthrough seizures, and there’s a need for new medicines. And if we look at our phase two data, which you’re referring to, because I think it’s really important to put that into context, the phase two data that we had for Ezetacalter were incredibly robust. Yeah. Very, very strong, right?

On a placebo adjusted basis, this is the best efficacy ever seen, at least based on our review of the literature in focal onset seizures, really in a population that was the most, refractory or challenging to treat. And then we have all these other attributes of the drug from the novel mechanism to the no titration. We see early onset of activity, and we potentially also have this benefit in mood. So I think just the overall profile of the zeta counter is really interesting.

Brian, Analyst, RBC: And that’s what we hear from docs as well. Yeah. Yeah.

Operator: Yeah. No. It’s been really consistent and good feedback from the medical community. So now if we kinda get into your question on the phase three. So, you know, if we go back a couple of years ago post the phase two b XTOL study where the result was really good, you know, the XTOL study was about the same size as the phase three study, and really one of the mantras coming out of phase two was let’s be consistent in phase three.

So we’re running two phase three clinical trials. Very purposely, we’re calling them XTOL two and XTOL three because, again, we really want that consistency with phase two. So if you look at the inclusion exclusion criteria in phase three, it’s exactly the same. And the studies are approximately the same size. So both XTOL XTOL two and XTOL three, I’m just going to focus on XTOL two because that’s our first data readout, but they’re carbon copies of each other.

Inclusion inclusion criteria is the same. Sample size is the same. Dose is the same. So in phase three, we’ve got, we’ve got three arms to these studies, placebo in two active doses, fifteen milligrams and twenty five milligrams. And just to give you a bit of an idea, if we take those phase two data, and we think about it in phase three, just because the, you know, the robustness of the phase two data, at the high dose we have more than 99% power at that primary endpoint, which is the MPC.

That’s the regulatory endpoint, in The US. So now let’s think about conduct. So when we think about XTOL two, to answer your question, we’ve gone to a lot of the same clinical studies that we had success with in XTOL. So a little bit more biased kind of on The U. S.

Sites versus, versus XTOL three, and went back to a lot of the sites that we’ve worked with. And so these these physicians, one, are familiar to us, two, they’re familiar with the molecule, and many of them continue to have patients on open label extension from the phase two program Because we still have over 150 subjects that have been out more than three years of dosing. We have our first patients that have been dosed more than five years now. So we have this huge amount of safety data. What we disclosed on our call, just recently in our Q1 results

So when we think about running a phase three program, there’s a bunch of things that we’re going to measure, you know, during the conduct of the study. We’re going to look at the types of patients that we’re enrolling. So this is the period at the screening and baseline. That’s pre randomization. Then we can track a number of metrics during the double blind period.

And then we can also track the patients that have completed the double blind and are going to open label extension. And what we said on our call is that we’re seeing this really nice consistency in the phase three program as we compare it to phase two. We can think about that in terms of patient demographics, baseline characteristics. We can think about that in terms of the rollover rate, you know, which was close to ninety seven percent in phase two, into open label extension. So, as we look at all of those metrics and we look across the studies that we’re using and the investigators that have experience, you know, we’re very confident in the of the phase three study.

Brian, Analyst, RBC: Got it. You recently reported a slight delay in enrollment in XTOL two. Anything specific underlying that? And I guess how confident are you in a potential early twenty twenty six readout? And in you know, I guess, are there ways you could proactively accelerate enrollment in XTOLS three?

So I know it’s different sites, but so you can kind of get that, done expeditiously as well.

Operator: Yeah. I mean, to to be clear, our real focus, because it’s the critical path to filing the FDA, is Equitable two. Right? So we’ve had the opportunity to have more than one regulatory interaction from an end of phase two meeting and subsequent to that, to really be clear with FDA that the filing package at the time of NDA is going be our phase 2b study, XTOL plus XTOL two. Obviously, we can use a lot of the safety data from XTOL three as well.

But you’re right, we’ve had a slight delay enrollment and a slight delay to top line data. We do feel confident that we’re getting close to the completion of enrollment, and we’ve said that enrollment will complete in the phase three program in the next few months, and data in early twenty twenty six. In terms of trying to accelerate things, I think the most important thing is a well run study, quality, conduct, all of the things that are critically important, for the success at the end of the day, which we talked about a lot, you know, kind of in the first question in terms of the conduct that we’re very comfortable with. You know, we have spoken with investors a number of times over the years that these epilepsy studies do take some time, and you do see some variability in those screening rates. You do see a little bit of variability even in the screen and baseline failure rate.

Remember, every patient that’s screened doesn’t get randomized. Those patients have to have the appropriate number of seizures during their baseline period, and they have to meet a number of other criteria. We are seeing a little bit of a higher screen failure rate in phase three versus the phase two program, so that means we have to screen a few more patients to get to the end, but we are confident that we’re getting close to the end of the study.

Brian, Analyst, RBC: Good. Sounds like you’re in the home stretch. And then kind of speaking of the, you know, the focus being on XTOL two because it’s a, you know, critical path for for regulatory. I guess, can you talk about some of your most recent regulatory interactions? Have you met with FDA since some of the changes in in leadership?

And what’s your sense as to I I guess, how have your interactions been? Any any corroboration from kinda new leadership that the phase two plus the XTOL two study, can definitely be supportive of approval, or is that something that’s still gonna be, I guess, finalized once you get once you turn over the data card?

Operator: Yeah. Overall, we have not seen a change in our interaction with FDA. Right. You know, I’ll caveat that with it’s early days. Right?

And, and so, you know, we aren’t we’re interacting with the FDA on on a semi regular basis, but obviously not all the time. As we get closer to the NDA, there’ll be more interaction, so I expect more interaction through the remainder of 2025 and obviously a lot of interaction as we get into 2026. But overall, at least in our interaction with FDA over the last couple of months, we have not seen a change in terms of, in terms of

Brian, Analyst, RBC: You mentioned the 150 patients you have in the long term extension from the phase two. Can you a little bit more in terms of the most recent looks there at that database, what you’ve seen both on the efficacy side and then with regards to some of the AEs you might be looking for, pigmentation, urinary retention. What what what are you seeing there?

Operator: Yep. Yeah. So I think one of the, real benefits of where we are in our program when I compare it to other programs out there and the amount of data that we’re going to have, not only at the time of NDA Yeah. But at launch, And I would say the profile of the Zet2 calendar and the profile of Xenon in the epilepsy community has been really driven by a lot of this open label extension data. So if we go back and just talk a little bit about the history, so this started as a one year open label study in phase two, and we hadn’t yet unblinded the phase two data when we had a number of physicians were coming up to that twelve month period, and a number of physicians were calling us saying, you know, I believe my patient’s doing really well on open label extension.

Can you, you know, provide drug longer than the twelve months? We hadn’t yet unblinded the data, and we all always know even a study that may not be successful, there may be some individual patients that are having some benefit. But, obviously, once we unblinded the data and saw how robust the signal was that I think that this is a very important medicine for patients. So we took that one year open label. Initially, we extended it to three years and then to five years.

It’s now a seven year open label extension. So of those patients that are doing well on therapy continue to have access to drug. That’s also given us an opportunity to cut the data once a year and be able to provide that to the medical community. So, our last update was a three year update. Even though we have patients that have been on the drug more than five years, every patient had the opportunity to go through three years of dosing, and that’s why I said we have, you know, just over 150 patients that have been on the drug more than three years.

So we did a cut of those data last fall, and we had the opportunity to share that at the largest medical congress in epilepsy, which is AEF, the American Epilepsy Society meeting that takes place in December every year. And what we found on the efficacy side, for those data is for those patients that had gone through three years of dosing, they had a one in three chance of being seizure free for twelve months or more. And I really want to put those data into context, because it’s quite a remarkable outcome. You know, if we look at the baseline characteristics of these patients, the median patient in our phase two program had failed six drugs, they were on three background medications, and they were having 13 and a half seizures per month for twenty eight days. So think about it as seizure every other day.

And now we’re getting one in three of them are going a year with no seizures at all. And that year is critically important because that year generally brings a lot more independence to your life. In many states, you can drive again if you’ve been seizure free for more than twelve months. And then the anecdotal feedback we’re hearing from physicians, these patients are working more, they’re having more social interactions, they’re gaining more independence. And, you know, I think it’s really rewarding, for the work that we do and the patients that we’re helping.

On the safety side of the equation, again, with long term data, we get to really be able to understand the overall safety profile of the data. You’ve heard a couple of comments from us made, you know, over time, which is we see a consistency in the adverse event profile. We know as we push dose higher, that dose does provide more efficacy, but you do see more adverse events in a dose dependent manner. We see the CNS adverse events that are very common with all anti seizure medicines, some level of dizziness, somnolence, and fatigue. And then we see some adverse events, at lower levels as well.

That adverse event profile is consistent whether we look at, in the double blind period or over the open label period. So we really have, a huge amount of understanding on the profile of the drug, and we can really educate the medical community as we get ready for launch. You asked about two specific adverse events, about pigmentation and urinary retention. And for those that don’t know, the reason that Brian’s asking those questions is there was a predecessor molecule before Ezetucalmer called ezogabine. That drug, was the same mechanism.

It’s no longer available commercially, but that drug had a chemistry risk around pigmentation, and it also some of the patients did see urinary retention, and a very small number of patients needed to be hospitalized and needed a catheter. So we haven’t seen any ezogabine like pigmentation in any patient now, and we have over seven hundred patient years of exposure. So we feel very comfortable in making the comment that that what we believed was a chemistry related ezogabine pigmentation risk has been addressed. On urinary, we saw two patients in our double blind, of a denominator of two eleven patients, on active dose, and we’ve seen a couple of patients in open label extension. We haven’t seen any patients come off drug due to any urinary symptoms.

We’ve seen a few dose reductions, but no one’s come off drug. We’ve seen no hospitalizations. We’ve seen no medical intervention at all. And so I think the profile that we’re seeing when we have a much more potent drug that is not renally excreted, and has modestly a better selectivity profile as well, I don’t think we’re seeing the types of urinary events that we’re seeing with ezogabine, with azetacalnor. So, again, you know, I think bottom line here, overall, we feel very comfortable with the adverse event profile.

Brian, Analyst, RBC: Great. Let’s talk a little bit about the market opportunity in epilepsy. There’s obviously a lot of polypharmacy in the space, but still there’s many patients who aren’t getting good seizure control. Based on the efficacy and safety profile you’re seeing, based on your conversations and feedback from KOLs, what’s your latest thinking on where zucalnair might slant into the treatment paradigm? And are there any learnings you can take from some of the recent branded launches?

I know there are different profiles and different mechanisms, but launches like XCOPRI, which have gone reasonably well. What what can you take away from that, that might shape your commercial strategy?

Operator: Yeah. I mean, if we start at the highest level and just look at epidemiology, there’s about three million Americans that have epilepsy, sixty percent have focal onset seizures, so call it just under two million patients. And we think about fifty percent of them, thirty to fifty percent of them are not getting good seizure control. So, we think those are good candidates for, as you mentioned, polypharmacy and having access to a branded agent. When we add in some of the adolescent and pediatric patients that have focal seizures as well, call it in rough terms about a million patients in The U.

S, I think is probably the addressable market for a drug like a set to counter. The medical practice and commercial, payer environment are really well aligned here. If you’re a newly diagnosed patient, you’re going to get a monotherapy and you’re going to get a generic drug. You’ll get a drug like levetiracetam, Keppra, maybe a drug like lamotrigine or locosamide. We’re seeing more locosamide usage now that VIMPAT went off patent a couple of years ago.

So those are kind of the drugs that are you’re going to have really high scripts. And for patients that are doing well, on a generic drug and a monotherapy, that’s good. That’s great. We know a lot about those molecules. As we have patients that are having breakthrough seizures, or they’re having tolerability issues, we’re starting to introduce polypharmacy, so call this at either a second or kind of third line, that’s where we’re going see the introduction of a branded medicine.

And I think that’s the opportunity for Ezetucalner. If we think about, the profile of Ezetucalner versus some of the other launches, there’s been some very successful drugs in epilepsy and focal onset seizures. You know, Keppra comes to mind Lamictal, Vimpat those have all been multi blockbusters. And as you mentioned, the most recent branded drug is XCOPRI or Sunobemade is the generic name. They’re guided to they’ll do about 400 to $450,000,000 in sales this year.

SK Life Sciences believes that’s going to be a billion dollar drug by the end of the decade. And I think we would agree with you. I think that launch has been fine. You know, it was challenging in the early days of launch during the pandemic, but I think over the last couple of years, the growth in that has been good, and I think that’s an important medicine to be available, for physicians and their patients. I do think is that two calendar has some real benefits over XCOPRI.

You know, XCOPRE has to be titrated over twelve to sixteen weeks. You are not on a therapeutic dose on day one. There are a number of DDIs associated with that molecule as well. So not only are you increasing the drug over time, but you may have to adjust other drugs that are being used in polypharmacy. And what we know with the Zetu calendar is there is no titration.

You’re on your therapeutic dose on day one. We see early onset to efficacy. Remember in the phase two program, we were statistically significant at week one, which is something that we’re going to measure in phase three as well, and we potentially have mood benefit also. So, when we just look at the attributes of Ezetucalendar, whether we compare it to XCOPRI or a number of the other drugs that have been used either currently or in the past, I think the profile of ezetucalendar really shows up very well. Okay.

Brian, Analyst, RBC: Great. And then maybe shifting gears to major depressive disorder. You guys recently revealed some new data from investigator sponsored study, the Mount Sinai study of a Zyd Calder in that indication. Obviously, small, you know, single site investigator study, but you did see some there were some treatment effects observed there. So can you talk a little bit about just, you know, how those data impact, how you’re seeing the likelihood of success of your studies, if there’s anything any new learnings there that would impact your overall either study design or kind of how you think about positioning of the drug?

Then just remind us, I know you alluded to this a little bit on your earnings call, but maybe a little bit more detail on how the tolerability profile, in the Mount Sinai study compared to what you saw in ex Nova. Because that’s one of the biggest questions that we get is, you know, just how the CNS side effects line up relative to other treatments for for MDD. I think everyone’s very convinced about potential benefit risk equation in in epilepsy, but maybe less sure given that there’s more options in MDD. But maybe you can

Operator: walk us through the Sinai Yeah, all good questions. So, you know, we’ve had an interest in this mechanism in depression for a few years now, and it’s really some of the pioneering work that the collaborators at Mount Sinai did both preclinically and trying to understand the mechanistic rationale. They also did some of the early work on ezogabine in major depressive disorder as well. So I always put more weight on a company sponsored study than an IST, and I think that’s probably a consistent view. So just as a reminder, about eighteen months ago, we had our phase two Xnova study, and I’m gonna bias my comments a little bit more.

I will comment on the IST, but I’m going to bias my comments a little bit more to our ex Nova study just because it was significantly larger than the IST. We had two active doses, and so at least we can think about a dose response. And it was really those data where we saw this consistency in terms of separation between active and placebo, looking at both clinical scales of depression using MADRS as well as HAM D17 and this clinical scale of, of anhedonia called SHAPs. Right? I think we got really nice data.

I think the side effect profile was milder than we saw in epilepsy. In that study, we we did see a dose dependency both in efficacy and in the adverse event profile as well. We looked at ten milligrams and twenty milligrams. So it was really those data, that drove us to run a large phase three program in MDD. And so the IST data, although I think interesting and we’ll talk about it, wasn’t decision relevant for us in terms of the phase three program in MDD.

And to that end, we’ve already started the phase three program. Right. We started our first phase three MDD study, which we call Exnova two, a few months ago. How’s that going? It’s going well so far.

Still early days, but, so far, the study, is meeting our expectations in terms of execution and the types of patients that we’re enrolling. We’ll have the second phase three MDD study, which we’re calling Exnova three. That’ll start in the next couple of months. We’re also going to start a phase three program in bipolar depression. That’ll also start in the next couple of months.

So we’re going to have an incredibly large and robust phase three program in psychiatry, both in MDD and in bipolar depression as well. In the IST, so the IST, you know, small number of patients. It was only about 30 subjects per arm. It was a single dose at twenty milligrams. And the primary endpoint was actually not a clinical scale.

It was a functional MRI endpoint, and it didn’t look like there was separation on the functional MRI endpoint. What we’ve said in terms of the clinical scales of depression, they use MADRS as the scale. As a reminder, in our phase three program, we’ve moved to HAMDI 17, and I think there’s some really good reasons on why we changed to the Hamilton scale. But they looked at MADRS, and then they looked at the scale of anhedonia, which is the Schapf scale. They had some other exploratory endpoints as well in terms of the some of the clinical global impression scales.

What we were able to say on MADRS and on SHAPs is that the twenty milligrams outperformed placebo at every single time point. I wouldn’t say that this was a well powered study, so we didn’t see significance, but we did see separation at every point. We saw the greatest separation on the clinical scale of depression at week six. Right. We saw a little bit of that, that separation come back together at week eight.

You were that might be tachyphylaxis or just variability? No. I I I yeah. We’re not concerned about tachyphylaxis at I mean, we we now have so much data with this molecule and this mechanism both in epilepsy and depression that we do not see any change in the signal over time. Actually, I think our epilepsy open label data seeing how robust that, that is in the long term is that we’re not seeing any any change in the signal.

We actually know because we’ve seen the patient level data, and we said this on our earnings call, is, it was actually caused by a couple of patients that had quite significant changes in their scales between week six and week eight. And that’s quite frankly just the challenge of a small study. Yeah. Right? And an academic study at that.

On the adverse event profile, yeah, I think, you know, one of the important things in terms of adverse events in depression, I agree we need to be, well aware of that. Important, we haven’t seen with this mechanism through multiple studies any material changes on weight gain and any sexual dysfunction, and I think if we think about standard of care in depression, I think that’s really important that we haven’t seen that. Overall in the IST, the adverse event profile was consistent with what we’ve seen in other studies. We’re seeing the same types of adverse events. In terms of kind of their, you know, mild and moderate, there was one SAE that was in the drug arm.

It was deemed unrelated. It actually happened 45 after the last dose, so it’s not something that we’re concerned about. But if we look at the overall What was that?

Brian, Analyst, RBC: Sorry? What was the SAE?

Operator: The SAE, I don’t think we’ve disclosed. James, Doctor. Murrows, I think, will disclose in a couple of weeks. But as I mentioned, it was weeks and weeks after the last dose, so and it was deemed unrelated. So it wasn’t something that we were concerned about.

You know, some of the adverse event in terms of the rates, some are higher than we’ve seen in the past, some are lower, and that’s, again, I think just the, you know, the the law of small numbers and small sample size where you do see more variability in the data.

Brian, Analyst, RBC: Maybe in the last thirty seconds because I know we’re bumping up on time, but, there’s a lot more in the pipeline, and that pipeline is starting to mature than pain, epilepsy, other other syndromes. I think you’ve talked about having an Investor Day later this year where you’re gonna talk about that in a little more detail. Anything you can sort of quickly preview there and what we should be looking for, what you’re most excited about? Yeah. I mean, yeah.

Operator: I’ll I’ll I’ll be really, really brief. I we’re incredibly excited about the the portfolio of targets we’re looking at, and those are maturing now. We have the first of those, which is a KV drug called XEN110. We’re just in a phase one clinical trial now, and we’ll get NAV1.7, a drug we call, XEN1101. That’ll be in clinical development in a couple of months as well.

So that discovery portfolio is maturing nicely. As you mentioned, we’re going to do two, at least two investor kind of webinars later this year. One focused on NAV1.7 and KV7 in the treatment of pain and really understanding that from a mechanistic perspective and the profile of our molecules. And then we’re very excited about, a program we have on a target called Nav 1.1, and we’d like to do a little bit of a deeper dive with the Street on that mechanism and some of the early preclinical data that we’ve generated as well.

Brian, Analyst, RBC: Good. We’re out of time, Ian. Thanks so much. Great to have

Operator: you here. Thank you, Brian. I appreciate

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