Welcome, everyone, to the 43rd Annual J.P. Morgan Healthcare Conference. My name is Tessa Romero. I'm one of the Senior Biotech Analysts here at J.P. Morgan. We're pleased to welcome to the stage our next company, Xenon, and presenting on behalf of the company, we have CEO Ian Mortimer. Ian, over to you.
Great. Thanks, Tess. Good morning, everyone. Always great to see everyone on Monday morning at J.P. Morgan. And a really big year in 2025 for Xenon. So excited to bring you up to date on our progress last year and some of the key and critical milestones for the upcoming year. So thanks to J.P. Morgan for hosting us. I am joined by some of my Xenon colleagues today in the front row, and Sherry Aulin, our Chief Financial Officer, and Chris Kenney, our Chief Medical Officer, will join for the Q&A period after the presentation. I will be making some forward-looking statements, so I do refer you to all of our risk factor disclosure that is filed with the SEC. So, as I mentioned, it's a really important time at Xenon.
We've been executing really well over the last couple of years, and we're coming into this year with our first phase III clinical readout for azetukalner. So there's kind of three key parts to the presentation this morning. I'm going to focus on azetukalner in epilepsy. We have really important phase II data. We're in a large phase III program with, as I mentioned, phase III data later this year. We've been broadening azetukalner into psychiatric indications, including major depressive disorder, and we're excited to announce this morning that the first phase III clinical trial in MDD has now been initiated. That was initiated last month. And then the third kind of key part to the business is really a nice maturing of our discovery portfolio and pipeline.
We've been working on drugging ion channels in the CNS for many years, and that has matured nicely. You are going to see multiple IND or equivalents and phase I initiations in 2025, so I'll touch upon some of that as well. We're really excited about azetukalner because this is the most advanced potassium channel modulator in development and the only one with really validating and de-risking data in both epilepsy as well as in MDD. We'll touch upon that throughout the presentation this morning. Really good balance sheet as well, supporting the company with cash runway into 2027. If we just look at a graphic of the pipeline, as I mentioned, a huge amount of focus at Xenon is on our lead program, azetukalner. This is a potassium channel or Kv7 modulator.
As you can see at the top of the slide, we have three phase III clinical trials ongoing in epilepsy, two in focal onset seizures, and one in primary generalized tonic-clonic seizures and as I mentioned, we have broadened this out into psychiatric indications as well, including our first phase III clinical trial called X-NOVA2 , which is now up and running in MDD. I'm not going to touch upon it in today's presentation, but you will see kind of in the middle of the slide, we have an ongoing IST with Mount Sinai, and we're going to see data from that study in the first half of this year, so some additional clinical data on azetukalner in MDD with our collaborators at Mount Sinai and at Baylor.
Then at the bottom of the slide, as I said, a really nice maturity of our discovery portfolio and pipeline, and I'm going to touch upon a few of those things later in the presentation. Let's start with azetukalner in epilepsy. This is our X-TOLE program as well as our X-TOLE 2 clinical trial in PGTCS. Just to set a little bit of context before we get into it, there's a significant unmet need in epilepsy. On this slide, we show all of the key markets and the epidemiology of epilepsy. If we just focus in the U.S., there's about 3 million Americans that are diagnosed with epilepsy. That's about 1 in 26 have a lifetime risk of developing epilepsy. The vast majority of those, about 60%, have FOS or focal onset seizures. The other significant category are those with generalized seizures.
This impacts both hemispheres of the brain, and the most common form of generalized epilepsy is primary generalized tonic-clonic seizures. The reason I mentioned that is because if you look at our phase III program, we're addressing all of the big markets in epilepsy, FOS and PGTCS. The other important thing to mention on this slide is the significant psychiatric comorbidities of these patients, so many epilepsy patients have psychiatric comorbidities, one of the common being depression, so there's really an intersection in the mechanism between seizure disorders and reducing seizures, and I'm going to show you some data, but also the opportunity to develop a medicine for major depressive disorder and also those patients that are suffering from the psychiatric comorbidity, those epilepsy patients that have depression and anxiety as well.
Actually, interesting in our phase III program, on an exploratory basis, we are looking at some of those endpoints in terms of depression and anxiety in the phase III epilepsy program. The reason that gives us a significant amount of excitement and confidence in the X-TOLE program is on the basis of our phase II-B data. So these data were first disclosed a few years ago. So this was a large phase II-B study, three active doses of the drug and placebo, and I'm going to walk through a little bit of data, not only the double-blind data, but we've been continuing to follow these patients in open-label extension now up to seven years. So every year at the American Epilepsy Society meeting in December, we're able to mature these data by a year, which we did last month, and I'm going to walk you through some of those data.
Both the baseline data, or sorry, the double-blind data, as well as the data that we're generating in open-label extension. These data were absolutely clear, as you can see on this next slide. On the left was the key primary endpoint of the phase II-B study. This is what we call the MPC. We're looking at a reduction in seizures of these patients. On the right, we're looking at a responder analysis. This was a key secondary endpoint in the study. This is the percentage of patients that have at least a 50% reduction in their seizure burden. Obviously, we expected these data to track left and right, and they do.
The reason that I show both of them on this slide is because on the left, this is the key primary endpoint for U.S. regulators, and on the right is the key endpoint for European regulators. If we look at the data on the left at the high dose, we had a 52.8% reduction in seizures. If we subtract that from the placebo group, this is the best placebo-adjusted efficacy ever seen in a focal onset seizure study when we look at the literature. And it's important to note this was in the most severe or refractory patient population that's ever been trialed based on our analysis of the literature. And we measure that three different ways.
One is the number of anti-seizure medicines that these patients failed before coming on study, the number of con meds they were on during study, as well as their background or baseline seizure burden, and it was quite significant for these patients. So these data within those contexts, I think, are extremely impressive and really form the basis of our phase III program. As I mentioned, we continue to look at these patients in open-label extension. We now have patients that have been dosed five years on drug. We have over 600 patient years of exposure. So we have a huge amount of safety data on the drug, and I'm going to come back to some comments on safety in a minute, but this is the efficacy data in open-label extension. What you can see is the patients on the left, they're in the double-blind.
This is a combination of all of the different arms of the study. So some of those patients are on placebo, some of them on 10, 20, or 25 mg of drug. As they transition into open-label extension, you see the population has a significant reduction in their seizure burden, and it looks like that's continuing to come down over time. The population has about an 85% reduction in seizures, which, again, based on those background characteristics of these patients, is extremely impressive. On this next slide, we actually look at seizure freedom. So this is a 100% reduction in seizures. So if we look at the data out three years, so these were the data that we were able to present to the epilepsy community last month. So the entire population from the phase II study has had the opportunity to be on the drug for three years.
If we look at that subgroup that has hit 36 months, so the N is 147, so quite a robust data set. If you look on the far left, about one in three patients are having seizure freedom for 12 months or more having been on the drug for 36 months. And I'd like to just put those data into context and into perspective. When I said that they had quite severe disease coming into the study, they had, on average, the median patient had failed six drugs already, they were on three background medications, and they still had 13.5 seizures per month. So if you think about 13.5 per month per 28 days, that's approximately a seizure every other day, and now we're getting one in three that are going a year with no seizures at all.
I think this is actually quite remarkable data, and it's data that we're getting extremely positive feedback from the epilepsy community and a clear differentiator when we compare us to other drugs that are both in development as well as on the market. As I mentioned, in terms of safety and tolerability, we have a huge amount of safety data on the drug now. What we see in open-label extension, so these patients that have been on the drug for many, many years now, the adverse event profile is consistent with what we see in the double-blind period. This is a very active drug in the CNS, and we see dose-dependent adverse events, the most common, which is dizziness. The vast majority of these patients, mild or moderate.
Usually, you see a lot of these CNS adverse events show up early in dosing, and then we see fewer of them as we move on. We also see a certain amount of somnolence and fatigue as well as we compare to the placebo group. But it's an adverse event profile in epilepsy that we're very comfortable with and very comfortable when we talk to the epilepsy community. All anti-seizure medicines that are active in the CNS have CNS adverse events associated with them. So let's move to the phase III program. As I mentioned, we've got two phase III clinical trials ongoing in focal onset seizures. We call this X-TOLE2 and X-TOLE3 . These are identical studies, and we're really trying to mirror the phase II. We had such good success in phase II that these studies are essentially the same as the phase II.
All of the inclusion-exclusion criteria are the same. A few more patients in terms of sample size per arm. These are 360 subjects, 120 subjects per arm in placebo, in the 15 mg arm and 25 mg arm, and then patients have the opportunity to go into open-label extension. As I mentioned, the first phase III readout for this program will be in the second half of this year. As I mentioned, we're also expanding the opportunity outside of FOS into PGTCS, and we have, this is very common in epilepsy. Usually, you focus on the focal onset seizure population first, and then you expand into PGTCS, usually with a single phase III clinical trial at the highest dose, and that's what we're doing in this program. This is very common in epilepsy drug development for adult patients.
We're using a single dose of 25 mg of azetukalner versus placebo. This clinical trial is ongoing. We haven't given guidance yet, but we expect that these data would form the basis of an sNDA after the NDA in FOS. So that's a summary of the epilepsy program. Really nice progress over the last couple of years on the cusp now of phase III data in the second half of this year, and the open-label data from our phase II program is maturing very nicely, and we've had the opportunity to continue to provide those updates at the American Epilepsy Society meeting every year. So let's move into kind of the second key message for today, which is really the expansion of azetukalner in major depressive disorder.
So this was based, we ran a smaller phase II study in MDD that read out just over a year ago. It was called the X-NOVA study. We tested two doses of azetukalner, 10 mg and 20 mg versus placebo. Key endpoint was a clinical scale of depression called MADRS. There's really two scales that the regulators look at. You can choose either of them based on the guidance. One is called MADRS. The other is called HAM-D17. We did look at both of these in this study. We did choose MADRS as the primary, and we had HAM-D17 as one of the secondary endpoints. I think that's important because based on the data, we're actually going to move to HAM-D17 as the phase III endpoint, and I'll come back to that in a second.
Based on the mechanism of the drug in terms of modulating potassium channels, especially in the reward circuitry of the brain, we're also looking at a key secondary endpoint called the SHAPS scale. And the SHAPS scale measures anhedonia, which is a key comorbidity in patients with moderate to severe depression. So we're continuing to monitor that in phase III, and I'll show you some data from the phase II program as well. So I'm going to go through a couple of data slides on MDD from the X-NOVA study. As I mentioned, this was a smaller phase II proof of concept study, just over 150 subjects, so just over 50 subjects per arm. This was the primary endpoint on MADRS at week six.
A couple of things from this, you can see a clear separation in dose response from placebo to 10 mg to 20 mg, and we had a clinically meaningful separation of just over three points between active, the high dose of 20 mg and placebo at week six. If we look at HAM-D17, we also had about a three-point separation, but the p-value for HAM-D17 was less than 0.05, and that's because we saw less variability, and this is supported from the literature as well. We saw less variability in the endpoint of HAM-D17 versus MADRS, and so we will be using HAM-D17. We've done our end of phase II meeting with FDA, and as I mentioned, we've just initiated our phase III program in MDD with the first phase III trial initiated last month using HAM-D17 as the primary endpoint.
As I mentioned, for these patients, a key comorbidity and a key differentiator when we look at the SSRIs and SNRIs and the drugs that are currently used to treat these patients is the comorbidity of anhedonia. So often the existing drugs can help treat the underlying depression, but the patients aren't feeling better on scales of anhedonia, and so we did measure this. It's called the SHAPS scale. Again, you see a clear dose response between placebo, 10 mg and 20 mg, and a p-value less than 0.05. In terms of safety and tolerability, what was interesting is we actually see that the drug is better tolerated in the MDD study than in the epilepsy setting. Obviously, this has the caveat of a cross-trial comparison, and in depression, this is monotherapy where it's polypharmacy in the epilepsy setting.
But going into this, we actually weren't sure how an MDD patient would tolerate the drug. A couple of key messages here. One, we're seeing the same types of adverse events in depression that we saw in the epilepsy program and that we saw in all of our clinical pharmacology and healthy volunteer studies. We're just seeing them at a lower level in the depression study. So we think this drug is being very well tolerated in the MDD setting, which I think is important for this patient population as well. So it was the totality of all of these data that put us into the phase III program that I mentioned has just been initiated. We're going to run three phase III clinical trials in major depressive disorder, essentially in parallel. They will be a little bit staggered in terms of them getting up and running.
The first one, our guidance was to get up and running at the end of last year, which we've achieved. This is a one-to-one randomization. We think that'll help manage the placebo rate. We've chosen 20 mg versus placebo. Significantly larger studies, obviously, in phase III versus the phase II proof of concept, about 225 subjects per arm. Primary endpoint, the change at week six in the Hamilton scale or HAM-D17. Key endpoints including at week one and SHAPS and a number of other endpoints that you would expect in a depression study. So overall, if we kind of summarize azetukalner, both in epilepsy and MDD, I think we have robust clinical efficacy in multiple indications. As I mentioned, the placebo-adjusted efficacy in epilepsy is the best that's ever been seen based on our review of the literature.
One of the things I haven't mentioned yet this morning, but I will mention it on this slide, is that we're also seeing a rapidity of onset. So the nice thing about azetukalner, it has quite a long half-life. The drug doesn't need to be titrated. Most CNS drugs, you start low and go slow. This drug, you're on your active dose on day one. And how that translates in the clinic is we see statistically significant efficacy at week one. We've seen that both in the epilepsy setting as well as in the MDD setting. I think that's, again, a key differentiator. So we have a novel mechanism. There are no potassium channel modulators on the market today to treat epilepsy or depression. We have very compelling efficacy. We have rapidity of onset, and we have a number of other ease-of-use attributes.
This is one pill once a day with no titration. So either from the physician's perspective or from the patient's perspective, this is an easy drug to add to some of the other therapies that they're on. And I think the safety profile is now clearly differentiated from the other drugs in development, given that we now have patients that have been dosed more than five years on therapy, and we have over 600 patient years of exposure. So let's move in the last few minutes to our pipeline programs. And as I said, we started highlighting actually for the first time a year ago at this conference some of the work that we were doing in our early stage pipeline, and it's matured very nicely. We really believe we are experts in drug and ion channels in the CNS, and we've got ongoing programs in both targeting potassium channels.
These are continued molecules on the same target, which is Kv7 of azetukalner. This is an opportunity to go even broader than epilepsy and psychiatry, also to have continued life cycle management and other molecules following behind azetukalner. I think some of the new information that we're getting much more attention from is actually on the right-hand side at the bottom, which is our sodium channel program. There's two key channels that we're targeting. One is NaV1.1, and the other is NaV1.7. 1.1 is critical in an epilepsy, a DEE, a developmental and epileptic encephalopathy called Dravet Syndrome. We had some really impressive preclinical data in our NaV1.1 program at the AES meeting last month that I think had some really strong attention. Then I would say we're spending most of our time with investors on our NaV1.7 program.
I think we have some really exciting chemistries that are going to move into human clinical development this year. So from our entire discovery portfolio, you're going to see multiple INDs in 2025 as these molecules transition from drug discovery and preclinical development into human clinical development. And we're really excited about these maturing over the next couple of years. So just in summary, before we get into some Q&A, as I mentioned, I think it's an incredibly exciting time for Xenon in terms of where we are in our maturation as a company. As we've talked to many of you about, our objective and our strategy is to forward integrate and to launch azetukalner ourselves in the U.S. And we're on the cusp of phase III data in our epilepsy program, which will be followed by an NDA and commercial launch.
So we can look forward to, over the next couple of years, significant clinical data in both epilepsy and MDD from azetukalner. And then, as I mentioned, a really nice maturing of our discovery portfolio over the next couple of years as well. And at the beginning, I said we have a strong balance sheet with cash runway into 2027 to support all of these programs. So thanks very much. And Tess, maybe we can invite Sherry and Chris up, and we can get into Q&A. Tess, do you want to go here?
So a little bit of a housekeeping question for me to start. Did the phase III X-TOLE2 trial complete enrollment?
So great question. Obviously, we're going to get, I think, a lot of questions this week on just where we are in the phase III program. Today, we're comfortable with our guidance and confident in our guidance, which we're going to have phase III data for in FOS in the second half of the year. We haven't provided any more detail on that in terms of the completion of patient screening or patient randomization or even narrowing the guidance within the second half of the year. That'll come as the year unfolds.
How are you thinking about what is a win in that dataset versus a home run in terms of safety, tolerability, and also efficacy? And really, what attributes of those data do you think drive more or less adoption of the product?
Sure. I'm happy to start, and then Chris and Sherry can add to my comments. You know, one of the things that I think we're in a very fortunate position is just the X-TOLE data, right? I don't think we can lose sight that we've completed one of what we believe is going to be the first study to file on, which is our X-TOLE program. I walked you through the data this morning.
On a placebo-adjusted basis, we think it's the best efficacy that we've ever seen when we review the literature in a very severe and refractory population. So that doesn't change. I mean, we have those data, which we're really excited about. You know, the nice thing about epilepsy is you do get high reproducibility and consistency across studies. So our expectation is that the drug is going to perform well in phase III. But I don't think we're too concerned with what the very specific data are going to be. I think the data in the package in totality is going to be really important for the epilepsy community.
You know, in terms of safety and tolerability, as I mentioned, we have a huge amount of comfort with the molecule now, just given that we have patients over five years of exposure as well as 600 patient years of exposure. So again, you know, I think on the safety and tolerability side, we would expect consistency in the dataset from phase III with what we've already seen. Chris?
Yeah, I would just add, so just to take a step back, so X-TOLE, Ian just showed you the X-TOLE data of the phase II-B study, which we view as incredibly robust. We're positioning that as our first pivotal trial in focal onset seizures. So that should be study one in the label. And now the second study that will come along will be study two.
So in order to get to the point where we can submit that NDA, we need this next study. And ultimately, what we really need is a positive study. So stat sig, that's what I would call a win, stat sig on that study. Now, in terms of, you know, trying to be able to repeat that robust dataset, what we did is we tried to change as little as we could going from X-TOLE to X-TOLE2. So, I mean, there was a change in dose. There was a little bit of a change in the double-blind period, which could potentially work in our favor. But in general, the studies are very similar geographically and in terms of study design. So hopefully, that will parlay into favorable results. I mean, if you look, there are no two studies that are exactly the same.
I would expect some degree of difference, but to what degree it should be minimal based upon the consistency of how epilepsy studies perform going from phase II to phase III. Sherry, do you want to talk about the commercial opportunity?
Yeah, absolutely. I mean, as a starting point, I think Ian went through some of the EPI data. I mean, this is a significant population of individuals who have epilepsy, three million adults in the U.S. In addition to that, there's about 500,000 children who have epilepsy. We're targeting the two largest segments of that population being FOS and PGTCS. I mean, what we think about from a commercial perspective, obviously, a lot of the questions we get are often on sort of expectations for sales curve and trajectory as well as peak. It's important to think about the treatment paradigm for these patients.
Oftentimes, when a patient is first diagnosed, they'll be put on a generic agent. Most often, we'll see levetiracetam, which is generic Keppra, or lamotrigine, generic Lamictal, are often early choices. Then from there, second line would generally be a monotherapy, but trying a different agent because patients either don't have good seizure control or they're not tolerating the drug well. From there, we would see in third line is where you would have patients start to move towards polypharmacy and the introduction of branded agents. Patients will generally have to go through one or two generics before they'll be eligible for a branded product. As we look at the epilepsy space, I mean, obviously, there's a lot of anti-seizure medications out there.
There has really been a bifurcation of drugs that have performed extremely well in the space, multi-blockbusters and those that have not done so well. It really comes down to the very specific attributes of each drug. There have been very successful drugs, as I mentioned, Vimpat, which is a very easy-to-prescribe medication, Keppra, which was a novel agent when it was first introduced into the marketplace, and then drugs that haven't performed as well because of some serious adverse events or challenges with respect to titration and management from both the physician as well as the patient's perspective.
When we look, and Ian went through all of the elements of azetukalner, as we look across all of the attributes, we feel that azetukalner, based on the data that we've generated thus far, as we look at the efficacy, the safety tolerability profile, the fact that it's a novel mechanism, we have seen to date rapidity of onset as well as potential mood benefit. All of those attributes really lead us to believe that azetukalner should be, as we think about the branded space, the first drug of choice. And we expect that if and when we do launch azetukalner, that the only other branded agent at that time will be a drug called XCOPRI, which does come with some challenges around prescribing. It does have a long titration period, and it is not a novel mechanism.
For that reason, you know, we're optimistic and feeling confident about the commercial opportunity here. And we really do think that azetukalner stands out. You talked a little bit about this already here, but I think just to put a little bit of a finer point on it, you know, what are you hearing really from the patients in terms of what they're looking for in a new treatment option? And does that deviate at all from what prescribers might be looking for?
Yeah, so we've spent a lot of time talking to healthcare providers and reaching out to the patient community. I mean, one of the, you know, cenobamate has lifted the bar in terms of what level of efficacy is expected. And it's gone from like, well, how many patients improve by 50% to how many patients are seizure-free.
And so that's what we hear a lot. From like a pure seizure perspective, they don't want to have any more seizures. They want to be able to navigate their life without the fear that they could have a seizure at any given moment, you know, and put them in a difficult predicament or an unsafe predicament. So we're hearing a lot about seizure freedom. And so if you, you know, that's why that data that Ian presented in the long term with one in three patients being seizure-free despite having pretty severe seizures at baseline is really, you know, I think in keeping with the message that we're hearing from patients. And then the other thing that, you know, that clearly is a major issue with them is mood, both depression and anxiety as a common comorbidity of epilepsy.
Right now, you know, there are anti-seizure medications that are mood neutral, and there are some that can actually make it worse. You know, being able to check both of those boxes we see is, you know, a really major opportunity for the patients and potentially something that this drug can bring forward. From the prescriber perspective, I would say that we're hearing the same, those two themes. I just think that within the prescriber, you know, the patient cares about their mood, period. I think some neurologists are more in tune with mood as an issue in epilepsy than others. I see a huge educational opportunity within the healthcare providers to educate on this and hopefully bring forward a therapy that can help out with both.
Yeah, maybe just to add to that. If, for those, and I know Tess, you were at the American Epilepsy Society meeting for those that didn't have the opportunity to attend. I mean, Chris's point on just this kind of underdiagnosis of the mood-related disorders and epilepsy, I think is really something that needs to change in that education. You really saw Xenon lean in at the AES meeting in terms of trying to raise the profile of the mood disorders and the psychiatric comorbidities in epilepsy, and will continue to do so.
Yeah, I think like a follow-up for me on this is just as you think about, you know, zooming ahead to the product being available. Like where do you think physicians are in terms of awareness of the product today, the class overall? Where do you think that needs to ultimately get to by the time you're ready to launch?
Sure, I can start, and Chris and Sherry can add their perspective as well. I mean, we do measure it. You know, we do measure on kind of terms of, you know, the awareness of Xenon and the awareness of azetukalner, and that's increasing, you know, every year that goes by. You know, this was a really important American Epilepsy Society meeting for us. We had a huge presence last month in Los Angeles to raise the profile, and I think we really did stand out as an important partner in the epilepsy community moving forward. So yes, we'll, as a newer entrant into the field, we're going to continue to have to raise the profile of Xenon and azetukalner, but we're well into that.
You know, we have been investing in a small commercial organization in terms of some key hires there, and also an MSL in Field Force in 2024 to continue to raise the awareness of Xenon and azetukalner. So we're well, we believe we're in really good shape as we think about the timeline right now before we get to commercial launch, but we've been thinking a lot, not just about the clinical development of azetukalner, but also raising the profile and ensuring that when we're ready to launch this drug, that there's good awareness.
And maybe just to add, one thing that has become a, we've become aware of, Tessa, is that, you know, people do know about Xenon more these days than they did a couple of years ago. In our conversations with people, as Ian said at AES, for example, you know, people have real awareness of Xenon, of azetukalner in our data. And we find that as well as we're out there recruiting some of these important hires into the organization, whether it be on the commercial or the medical side, where people want to be engaged and working with the company that has the molecule with the best epilepsy data, if that's their field. And so we find that from a talent attraction perspective, that has been something that we've absolutely noticed recently.
Yeah, and I guess to summarize what both Ian and Sherry said, I think we're entering a positive feedback loop where it just keeps feeding on itself. For me, the first American Epilepsy Society meeting I attended was 2021 with the phase II-B data just come out. The difference between 2021 and 2024 in terms of name recognition, both for Xenon and the drug, is through the roof. We had over a thousand meaningful interactions at AES with healthcare providers, key opinion leaders, patient advocacy groups, and so forth. So, and now that we have a full, you know, field-based medicine team with boots on the ground, it's just going to continue to feed back on itself in terms of word of mouth.
A question we often get from investors is, how does this launch, Tess? So how do you respond to that? I missed that.
Can you say that again?
How does the product launch?
Yeah, I think I touched on this a little bit earlier, Tess, is, you know, two questions are sales curve and then peak. So, you know, we just think from an attribute perspective azetukalner really stands out.
Again, as you compare to cenobamate or XCOPRI, we have a novel mechanism. We have no need for titration and therefore rapidity of onset, which is important as patients are likely looking to another agent because they're experiencing breakthrough seizures. So for all those reasons, you know, as we think about the ability of azetukalner to perhaps outperform what we've seen from, you know, other drugs or perform as well as what we've seen from those very successful drugs is something that we're confident in. Obviously, this is not a space where there is sort of this massive pent-up demand just because of the number of agents that are available. So you don't see these, you know, hot out of the gates type of situations with, you know, other therapeutic areas.
But we are optimistic about how azetukalner could perform from a sales ramp perspective, again, given all of the attributes, as well as from a peak perspective, given there's still a massive unmet medical need. So of those patients that we mentioned in both FOS and PGTCS, upwards of 50% of patients do not have good seizure control despite the number of available therapies. And azetukalner can really potentially provide that for many patients, given the data that we've presented in a very difficult-to-treat population.
Helpful, thank you. So switching gears now to the product and MDD, can you talk a little bit about how confident you are in kind of mitigating some of the key risks that we all know well inherent in these types of studies? You know, what were those kind of key activities that you've been, you know, working on over 2024 and into 2025 to try and mitigate those key risks?
Yeah, so several. So first of all, you know, okay, so in contrast to epilepsy, the consistency of going from phase II to phase III is less in MDD than epilepsy. That's an understatement. And so there are a number of things that we've tried to do to increase our chances of success. So probably the biggest one is the phase II data that Ian showed you, had two active arms. We've now decreased that to one as we make this transition to phase III. So in general, if you look at the literature, that usually saves you a point in terms of a placebo effect.
Also, we're putting in a lot of effort in terms of compliance using a video app to make sure that patients are actually taking their medication. We're using an even more rigorous criteria to enrich the population. So instead of needing a HAM-D of 20 to come into the study or more, we're requiring that it be 22 because sometimes those patients who are on the milder end of the moderate to severe spectrum can bring down your signal. You know, as with epilepsy, the quality of the sites must be high, period. And so we want experienced coordinators, experienced investigators, and we're working with a CRO that has lots of experience in MDD as well. So lots of different things that we're trying to do to, you know, maximize our chances of success as we go from phase II to phase III.
Just to add to what Chris mentioned, the other piece of our risk mitigation strategy is that we are running three robust studies that are well-powered, and of course, we would need two of those studies to be positive to be successful within sNDA.
And just in the last couple of minutes here, can you just talk a little bit about for the broader pipeline at Xenon, where you think the greatest opportunities are and how should we be thinking about those preclinical programs moving into the clinic in terms of cadence and, you know, give us a little bit of a framework?
Sure, yeah, I mean, we're excited about all of the preclinical programs that we're working on for very different reasons, so let's go through them quite quickly. We have said that the Kv7 program preclinically and our NaV1.7 program are a little bit more advanced. To answer your question specifically around cadence, when we think about INDs and transitioning into human clinical development, you're going to see that from the Kv7 program and from our NaV1.7 program before you'll see it from our NaV1.1 program.
You know, we think that there's absolutely a pipeline and a mechanism with potassium channel modulation. So we're going to have a rich amount of chemistries that we're going to be able to develop and move forward. So that's really the focus on Kv7. NaV1.1, I think there's been a lot of, you know, overall for these pediatric epilepsies, we're trying to move in addition to seizure reduction into the opportunity for disease modification. And I think this is an on-target, a small molecule oral opportunity to really be on-target. The Dravet children are haplo-insufficient in NaV1.1, and this small molecule is potentiating the channel.
And the data that we had at AES, you know, last month was really, really strong supporting that program. And then obviously NaV1.7, I think there has been a renewed interest in selective sodium channel inhibition as an analgesic. And the NaV1.7 program is something that we've been working on for some time. The nice thing about NaV1.7 is that program can move quite quickly in the clinic in terms of moving through healthy volunteer studies and then into an early proof of concept study. So I would say the NaV1.7 program is probably of the three the one that we get the most attention on and the most questions on.
All right, great. Well, thank you for joining us, everyone. I hope you have a great rest of the conference.
Thank you.
Thank you.