Great. Thanks, everybody, for joining. It's my pleasure to be hosting a panel here with executives from Xenon Pharmaceuticals. With me, CFO Sherry Aulin and Chief Commercial Officer, former boss of multiple Stifel associates in the consulting world, Chris Von Seggern. Thank you both for joining in this panel today. Really appreciate it. Sherry, I'm sure most folks know the company well, but maybe I could just ask you to give a quick snapshot of Xenon, an overview of the 1101 programs in epilepsy and depression, and then we can do Q&A. So thanks again.
Yeah, absolutely. Thanks, Paul. And thanks to you and Stifel for hosting us today. Good afternoon, everyone. So I'll give you, as you mentioned, a high-level overview of Xenon for those of you who don't know us as well. So we're a neurology-focused company. We're in late-stage clinical development in epilepsy and depression with our lead molecule called XEN1101, which is a potassium channel modulator. We're now in a broad Phase III global program, which is ongoing. So we've got two studies in focal onset seizures. Those are called X-TOLE2 and X-TOLE3. They're similar in size and design to our Phase IIb X-TOLE study, which we ran and read out in late 2021. And I'll talk a little bit about the really compelling data that we generated from that study, which was the catalyst to us embarking on this broad Phase III program.
And then the third study that we're running in epilepsy is in primary generalized tonic-clonic seizures. That's a single study called X-ACKT. We did align with FDA on a single phase III study in that program in our end-of-phase II meeting, which took place a couple of years ago now. So we're really focused on X-TOLE2. That is our one of our FOS studies, and that's the critical path for us to file an NDA in the U.S. We have guided that we expect patient enrollment to complete in X-TOLE2 by late this year or early next year. So maybe just touching a little bit on the compelling data that we generated from our phase IIb study called X-TOLE. We saw the best placebo-adjusted efficacy in a trial in a clinical study in this patient population in focal onset seizures.
Since the study, we've generated, I'd say, a fair amount of additional very compelling long-term efficacy data through an open-label extension. Most recently, we released the 30-month cut of those data at the American Epilepsy Society meeting in December of last year, where we showed patients continuing to see, you know, incremental benefit on the drug. So importantly, in our double-blind period of the study, in our high-dose group, the 25-mg arm, we saw patients have 53% seizure reduction. And when you look at the 30-month cut of the open-label data, those patients are achieving more than 90% seizure reduction, which is really compelling, Paul, if you think about, you know, the seizure or the disease burden that these patients had going into the study.
As a reminder, the average patient had 13.5 seizures per month going in. Seeing patients with more than a 90% reduction is really, really compelling. We've generated some really compelling seizure freedom data as well. So as we look at patients who have been in the open-label extension for at least two years, actually a quarter of those patients are seeing 12 months or longer consecutive periods of seizure freedom. We know that's really important for this patient population because that's actually the threshold by which you can get, or patients can get, you know, a lot of their benefits, such as, you know, the ability to drive again. Then, importantly as well in the open-label extension, we've generated a lot of safety and tolerability data. We know a lot about the molecule now.
We have patients out more than four years on the drug. We've generated more than 600 total patient years of safety data. So a lot known now about the overall profile of XEN1101. So really, really excited to continue progressing in this phase III program in epilepsy. And then, as you mentioned, we are in an MDD program as well. So we generated data with the same molecule, XEN1101, in depression. That study called the X-NOVA study, which was a phase II proof of concept, read out late last year in November, where we saw clinically meaningful separation on the MADRS, which is a clinical scale of depression, at week six. And that has really sort of catapulted us down this path with depression. We've made significant headway since those data.
We have already planned an end-of-phase II meeting with the FDA in April, where we're planning on aligning on the key elements of the phase III program, which I'm sure we will we will touch on in the Q&A portion. We're anticipating to start our first of three phase III studies in depression in the second half of this year. Then touching a little bit on, you know, what else is happening in the pipeline, because I think we've, we've got, you know, a really broad and exciting preclinical pipeline at Xenon. We've got deep expertise in, in ion channel drug discovery. This is a space we've worked in for, you know, over 15 years on, on multiple targets, where we're looking both at, you know, broadening our capabilities within Kv7, but also looking at sodium channel inhibitors, including now Nav1.1 and Nav1.7.
Again, I'm sure we'll talk about some of those programs in the Q&A. And we're excited about progressing multiple molecules across these targets into IND-enabling studies over the next year or two. And then just lastly, to wrap things up, very strong position from a cash perspective. We did an additional raise late last year, which bolstered our balance sheet. We ended the year with $930 million in cash that fully funds our phase III epilepsy program as well as the phase III MDD programs I described and gives us cash into 2027. So we're excited to be able to chat a bit more with you today, Paul, about these programs in our pipeline.
Awesome, Sherry. Thanks for the great overview. So boiling it down, the phase II data is excellent for 1101. The mechanism is already kind of partially or arguably partially, arguably mostly de-risked, right, from ezogabine at the outset of this program. I guess going into phase III, like when you guys discuss and work to mitigate risk internally, what are the things that are top of mind from an execution perspective and ensuring that you can replicate the phase II effect size in, in two larger pivotal trials?
Yeah, Paul, it's a great question. And I think importantly, given that the X-TOLE data were as strong as they were, the guiding principle here is to minimize changes from X-TOLE as we transition to X-TOLE2 and X-TOLE3. So how does one do that? You can think about, you know, similar sites and similar geographies, selection of the same clinical endpoints and selection of the same patient population, so not deviating from inclusion/exclusion criteria. And in reality, most of what we're doing with X-TOLE2 and X-TOLE3 is really a replica of X-TOLE, that gives us a really high strength and conviction. The most important piece that is different is the time point at which the endpoint is measured. So we're moving from an 8-week to a 12-week time point, to satisfy European regulatory requirements.
As we look at the open-label data stemming from X-TOLE, we actually see continued benefit or continued improvement as patients transition into that open label, which just further strengthens our conviction on the ability to replicate the findings coming out of X-TOLE2 and X-TOLE3.
That's great. And, you know, recently you did announce some change to the enrollment guidance where, I believe it was mid-year to late this year previously, and now it's complete enrollment late this year, early 2025. Anything behind that change? I mean, I guess at pace, right, are things progressing slower than you expected? Is this still kind of within the standard deviation? And, you know, what's your confidence that you're gonna meet this updated timeline and that everything's on track?
Yeah, that's a great question, Paul. And I mean, we articulated this as really a refinement of our estimates, and, and that's how we see it. So, you know, we're, we're always trying to give the street the best estimate of, of based on the, the, the information that we have on, on when we expect to complete the study. So I guess first and foremost, you know, we've, we've provided guidance on X-TOLE2 because, again, that's the study that's really critical path to our NDA filing. And so we're really biasing towards ensuring that that study completes, so that we can we can, you know, progress the program in, in, in, in with our NDA. So if we look back to X-TOLE, I mean, we've got a we've got obviously experience in the space.
We enrolled 325 patients in the X-TOLE study, and we've said previously that that, you know, was across about 80 sites. So, we're consistently applying that framework to X-TOLE2, where we've targeted 80-100 sites. And if you think about trying to enroll 360 patients across that number of sites, you're actually randomizing only a handful of subjects per site. So we're constantly getting information from sites, you know, on a daily basis, and there's just natural ebbs and flows as we think about the rate of, you know, patient screening and randomization. And so we provide the best information that we have at the time, which was, you know, second half of 2024. And just based on our most recent estimates and information that we have, we've refined that to late 2024, early 2025.
But there's nothing, you know, there's no key drivers or anything that we're really seeing within those data, that impact our confidence. I mean, I think we're comfortable with the revised timing, and we just like to be transparent on these things and make sure that the street has, you know, the most recent available information that we have.
Okay. Makes sense. Thank you. You know, I guess from a filing perspective, right, when you get the data, assuming it's positive, you should technically have two pivotal studies per your discussions with the FDA. You know, at that point, I could think of two potential things that would be rate limiting. One is X-TOLE3 is close enough where filing before that data doesn't kind of make sense because it just would be almost confusing, and the FDA might, you know, want it, or maybe I'm thinking about this wrong. Maybe you could talk about that. And then the second thing is just the kind of need for ICH guidelines safety data. So can you sort of talk about these two components of this and, and how you're thinking about it, assuming, again, this first phase III does read out favorable?
Yeah, absolutely. And as Sherry's already mentioned, X-TOLE2, we believe, is rate limiting for filing. That would be, in our opinion, the confirmatory study on the back of X-TOLE. So, Paul, you've raised a good point about the timing of X-TOLE3 vis-a-vis X-TOLE2 could create some confusion from an FDA standpoint, but it's not gonna necessarily prevent us from filing. It's probably more of a review issue, if at all, depending on when data come in. The FDA doesn't love it when you throw new data at them within a month or two of your PDUFA. So, that's probably the biggest risk is a flood of new information at that point in time. On the safety side, though, we have a ton of safety data, as Sherry's already mentioned here.
So we have patient over 600 years of patient exposure, patients out up to 4 years. We've just extended the open label from 5 to 7 years, and we'll just continue to generate important safety data for this molecule. And the typically the rate limiting components of ICH guidelines are the 6-month and 1-year exposures. And we're well north of those already from the dataset that we have. So we don't believe that safety data are going to or safety exposures are going to be rate limiting for us, again, given the body of evidence we have to date, as well as the ongoing studies in epilepsy and the additional exposures that can be generated through the MDD program. So we think we're well clear in that regard.
Okay. So just to make sure I understood kind of what you were saying, Chris, it sounds like the plan would be to file with X-TOLE2, and X-TOLE3 most likely would be updated as like a major amendment or something like that. Is that like a base case, or is it too early to say what a base case is?
Yeah, no. So our plan is to file on the back of a positive X-TOLE2. And then from additional data, we do have a requirement to share those with FDA, but we have always thought about X-TOLE3 as really being to satisfy European regulatory requirements. So we don't view that to be a rate limiting step here in the US.
Okay. Okay. Great. Do you wanna talk about commercial analogs? You know, I think on the Wall Street side, right, people look at different AEDs, and they can find, you know, brand drug launches where the brand sells $a few hundred million over $1 billion easily in the case of Vimpat and Keppra. And then there's this more recent analog, cenobamate, which, you know, I feel like cenobamate has done well. But the expectations, including my own, right, for XEN1101 or higher. I guess when you think about analogs and kind of stack up historically the past 10 years of launches in the epilepsy space, does anything stick out that looks similar to XEN1101? And what specifically do you think of cenobamate as a good or bad analog, Chris?
Yeah, absolutely. So, historically, we've talked about Vimpat as being really a successful molecule in this space that has many of the attributes, but not all of the attributes of XEN1101. It's a bit more modest potency, but it does offer some of the ease-of-use characteristics that we have. We've often thought about its positioning as really the first branded agent that's used within the range of generics as being something that we strive for with XEN1101.
What we've heard from our market research is the totality of the evidence associated with 1101, the very potent and very strong efficacy data, the inline AE profile, and then importantly, these ease-of-use attributes of no titration, one pill once a day at night, and the lack of material DDIs are things that are really engaging for this for our physician community. I think things have changed a bit in terms of our thinking and what we're hearing from our market research as well, on the backbone of the MDD data. When we think about now the preponderance of the evidence or the totality of the evidence of XEN 1101 potentially moves us into a different analog to consider, which is lamotrigine. So lamotrigine is the second most utilized medicine, behind Keppra in our category.
Despite the fact that it has an exceptionally long titration period and is objectively less efficacious than some of the alternatives, found a really material role in this space on the backbone of being perceived as the mood and epilepsy medicine. The product was approved in bipolar depression and is often thought of as the choice of anti-seizure medication for a patient that either has preexisting mood conditions or who has mood exacerbation or the symptoms that can be associated with Keppra. So Keppra, the most utilized medicine in this space, does have an AE that can tend to exacerbate some of the mood, depression, and anxiety conditions. lamotrigine really found a home, being the alternative to that product.
So as we think about the evolution of the story of XEN1101, we think we have a profile that looks a heck of a lot like lamotrigine, but better because of some of the ease-of-use attributes. A 16-week titration period is an extraordinarily long period of time where patients remain at risk. And it's something that we're hearing from our market research is a hook. On cenobamate, 'cause I do wanna answer that. Cenobamate's the, you know, emerging as the market-leading, branded agent in this space. And they're doing a good job, I would say. They launched during COVID, and they had to establish themselves in this space. Cenobamate offers a really interesting profile, but again, is hampered with this really long titration period.
Unfortunately, during their clinical studies, had very severe allergic reaction or DRESS that resulted in patient deaths in the study. And that has correspondingly made the drug really reserved for last-line patients. So it's an interesting analog for us, but what we hear from our research is the profile elements of XEN1101 move us up in the treatment paradigm by comparison to cenobamate. So while their success, I think, begets our success, we're looking at positioning and placement in the treatment paradigm well ahead of where cenobamate is today.
Okay. Makes sense, Chris. Can I ask one question about lamotrigine? So I randomly spent a lot of time on the lamotrigine depression data. And I think I remember that there were four or five acute studies run for lamotrigine that actually, like, didn't meet their primary endpoint, and it worked in two randomized withdrawal studies. And there's a whole other interesting drug development rabbit hole you can go down there. But I guess the reason why I asked that question is for lamotrigine to establish itself as an AED with mood benefits, did it actually need a labeled indication, or did that happen earlier when there was initial data?
I guess as it relates to 1101, you know, the question I think from people is, let's say the phase III data comes out mixed, right, and it's not filable, and there's a signal, but it's kind of less clear. Like, does that still have relevance in epilepsy?
Yeah, this is a great question. And you're right. lamotrigine has a very checkered clinical history. As is often the case, depression studies don't always work out favorably. So, for them to eventually secure the label, it did require a number of studies. They don't have a specific label of depression in epilepsy. And it is the broad clinical experience over time, as well as the communication of those benefits through medical channels, that has really established this product as the go-to mood product. And going way back to the launch of this product, which is now well over a decade ago, it was part of the story through medical communication channels that has become widely known and appreciated in this space.
So, it is certainly not a requirement that one has depression and epilepsy-specific data for the appreciation of the antidepressive effects of a molecule to be appreciated. The question you asked about what happens if, you know, depression studies are mixed moving forward, we believe that we have a very clear antidepressive effect stemming from X-NOVA. And despite the fact that there wasn't statistical separation in the primary efficacy, there is a very clinically meaningful benefit and secondary endpoints lining up. That benefit is likely to persist. And even with the absence of statistical significant improvement, we do not make mood worse. And that's a very important component that is the baseline here. Failure of clinical studies is different than saying we're exacerbating mood like levetiracetam.
We think that this is something that will carry with us, for as we march towards commercialization in the epilepsy space.
Yeah. Okay. Okay. Great. So to this point, you announced that you're gonna do three studies in depression, which I think is a logical risk mitigation move. Beyond that, can you talk about the design elements of these studies that you're considering to try to mitigate risk? Like, how are you thinking about the number of dose arms? And, you know, I think what I'm sort of getting at, right, is this phase II study certainly shows an encouraging signal, but the placebo effect was pretty big. And in depression studies, it can often get bigger going into phase III. So how at Xenon do you kind of try to control for all that?
Yeah, I think that's a great question, Paul. You know, as a reminder, as you said, the X-NOVA study, you know, we saw clinically meaningful separation. That's, you know, charged us ahead to get into phase III. I think importantly, we did look at two active doses in X-NOVA. So we looked at the 10 milligram and 20 milligram doses versus placebo. We saw a clear dose response there, but we really saw the clinically meaningful separation with the 20 milligram dose. We're planning to move ahead with that higher dose in phase III. What that will partially help us achieve is to minimize that placebo rate that you mentioned. So what we do know from our review of the literature is when you go from two active arms to one, you do reduce the placebo rate by a full point.
That just makes sense if you think about patients going into the study knowing that they have a 2/3 chance of getting an active arm versus a 1:1 randomization, which is what we're looking at in the phase III program. We're gonna continue to employ a lot of the other strategies that we know help to minimize placebo rates in these studies. But ultimately, as you suggested, you know, there's no magic bullet here. So we are for that reason running three studies to help mitigate risk because we know that even drugs that work in depression are not always successful. But we feel confident given the signal that we've seen and now moving from two active doses to one that we should be able to manage the placebo rate quite well. We're making other incremental changes as well.
I mean, I think there's a lot of learnings that we can take away from X-NOVA as we think about the phase III program. So another factor here is that we are looking to move from MADRS, which was our primary endpoint in X-NOVA, to the HAM-D scale in phase III. They're both FDA-recognized, you know, scales of depression that can be used as a primary endpoint. We measured both in X-NOVA, and we were statistically significant on HAM-D, but not on MADRS. And really the driver there was the standard deviation was much lower on HAM-D. And that is actually consistent with what we see across other studies in the literature. And so we do plan to move to HAM-D as our primary endpoint for phase III, in addition to actually raising the bar a little bit or the entry criteria on HAM-D.
So we know again that, you know, patients typically respond better in these studies as they're more severe. And so we had a cutoff of 20 on HAM-D for entry into X-NOVA, and we're gonna raise that by a couple of points to just ensure that we're really targeting the most severe or mostly moderate to severe patients. And then we're gonna continue to look at some of the key endpoints that we did in X-NOVA, which we think are really important differentiators of 1101 versus the standard of care and what's available today. So we looked at SHAPS, which is a scale for measuring anhedonia, which is a common comorbidity seen in depression where patients feel less depressed, but they still don't feel, you know, better and kind of that motivation. And so we're gonna look at SHAPS in Phase III.
Again, we were statistically significant on that scale in X-NOVA, as well as week 1 efficacy. So consistent across both epilepsy and depression, we're seeing a rapid onset. And I think that can be an important differentiator for us in both efficacy and in both epilepsy and depression. So we're gonna look at week 1 efficacy as a key secondary endpoint in the phase III program.
Okay. Great. Obviously, there's a lot more we could talk about here, but I wanted to touch upon one more thing before we're out of time, and that is just the Nav1.7 program. Since you started talking about your efforts here more explicitly, right, there's a lot of interest in the investor community, especially given the data that Vertex has generated. Can you just briefly talk about Vertex's efforts here? Sorry, excuse me, Xenon's efforts here. And, you know, I guess it's preclinical. Like, how, how ready is this for prime time? When do you think you could actually have something in the clinic?
Yeah, great question, Paul. I think the focus of a lot of our investors since we started to talk about this recently. I think people who've known Xenon for a while know that we have a history with this target. We had a multi-year collaboration with Genentech. We've been working on this target for many, many years and can leverage a lot of those learnings to take the opportunity to develop more selective 17 inhibitors. You know, we know that genetic validation on this target is really strong. As you mentioned, Vertex has now validated the 18 target with their clinical data, but we feel that 17 is, is, you know, remains a strong target given the, the, the genetic validation. We've made a lot of progress internally over the last couple of years.
So we have what we think are very advanced candidates that meet our requirements internally for development. And we think about, you know, the criteria, in terms of efficacy, potency on target, pharmaceutical properties, and therapeutic index as all factors that we look at. We're continuing the preclinical work. So I'll say we've again got interesting molecules that we've identified. We do anticipate we'll probably have multiple candidates that could enter IND-enabling studies over the next couple of years. And, you know, we know that there's obviously a huge commercial, huge medical need that drives a commercial opportunity here. And, you know, importantly as well, I think the opportunity to generate important early kind of de-risking human proof of concept data is important as well in this area.
So, you know, we're excited about continuing to make progress, and hopefully we'll be able to say more about it, as we identify molecules and move them into IND-enabling studies.
Awesome. All right. Well, thank you, Sherry. Thank you, Chris. We appreciate your time. And, thanks, everyone, for listening. We'll see you on the next one.
Thanks, Paul.
Thank you.