All right, we're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for tuning in. It's my pleasure to have Ian Mortimer, CEO of Xenon. Welcome, Ian.
Thanks, Andrew. Thanks for having us. Thanks to you for hosting.
Of course. Exciting time coming up for you. For those in the audience a little bit less familiar with the Xenon story, maybe a couple of minutes talking about your programs and milestones we can expect over the next 6 to 12 months?
Sure, happy to. Yeah, it's a really exciting time for us coming up to unblinding our very first phase III clinical trial. I'll take a step back, give a little bit of a quick overview, kind of three key themes that I'd like to touch upon. One is the lead molecule is azetukalner in epilepsy. We'll talk about expansion into neuropsychiatry. We're getting more attention on our pain portfolio and spending some more time there. I'll touch upon that as well. For those that maybe don't know the company quite as well, we're a neurology company, deep expertise in drug and ion channels in the CNS. We've been building these capabilities for more than a few decades now. As I mentioned, the lead molecule is called azetukalner. This is a potassium channel modulator. It's in development both in epilepsy and neuropsychiatry.
I think the excitement that we have around the molecule is based off of our phase IIb X-TOLE data in patients with focal onset seizures. We had those data a few years ago. On a placebo-adjusted basis, it's the best efficacy ever seen in a clinical trial in the most severe population ever trialed in the most common form of epilepsy, which we call focal onset seizures. Really a nice setup into our first phase III readout, which is our X-TOLE2 study, which we've guided to early 2026. I feel really good about that. I think we'll probably get into in the Q&A just some of the attributes of the molecule, which I think is really special around the novel mechanism, the rapidity of onset, the overall tolerability profile, and the potential benefit for mood as well.
We've taken the same drug and we're expanding into neuropsychiatry. We had a phase II readout in a study that we called the X-NOVA study at the end of 2023. We've used that to build a large phase III psychiatry program in major depressive disorder and in bipolar depression. Currently, we have three phase III clinical trials ongoing in parallel, two in MDD called the X-NOVA2 and X-NOVA3 studies. We have a study called the X-CEED study in bipolar depression as well. That's progressing nicely in addition to the program in epilepsy. As I mentioned, we're starting to build kind of broader awareness of our pain portfolio. Two molecules that we've moved into phase I human clinical trials this year. Two INDs were filed this year on two different targets. One is on Nav1.7. We call the drug XEN1701.
That's currently in a phase I healthy volunteer study. Hope to move that into a human proof of concept study next year. The human genetics around Nav1.7 are absolutely remarkable. I know we can talk about that a little bit later. The second target we really like in pain is Kv7. Similar target, same target for azetukalner, a little bit of a different approach here in developing that as a novel analgesic. If you're interested more in the pain portfolio, we did an R&D webinar and R&D day just recently in the last couple of months that you can access as well. It really sets the company up nicely going into 2026.
Very helpful. Maybe a housekeeping question. You typically have an update in January of every year. Should we expect you to make some kind of splash during that time frame?
Yeah, I think like most companies, we like to do a press release at the beginning of the year, which is really just laying out what to expect from the company. I expect you'll see something again from us that will lay out all of the milestones upcoming in 2026 and beyond. Yeah, you'd expect to see something in terms of 2026 guidance as we put out that press release at the beginning of next year.
Maybe even a refinement of the X-TOLE data?
Yeah, so right now, maybe it's a good opportunity to talk about X-TOLE2 . X-TOLE2 is our phase III study in focal onset seizures. What we've communicated so far publicly is that the study is fully enrolled. It was designed to randomize 360 subjects in two active doses versus placebo, so a one-to-one-to-one randomization, looking at the 15 mg dose of the drug, 25 mg versus placebo. We have fully enrolled that study. We did communicate most recently on earnings that we had randomized 380 subjects. Those last patients are currently going through the double-blind period. We've also kind of walked through what are the next steps as they go through from double-blind to the end of the double-blind, then the patient has the opportunity to go to open- label extension.
Whether the patients go to OLE or not does have a little bit of an impact on the timeline. What we've said is that the phase III looks very consistent with phase II in terms of the types of patients enrolled in the study, so the baseline characteristics of the patients. We've also said that the rollover rate into open- label extension is very high as well. In phase II, it was 97%. We haven't guided specifically on phase III because the study is still ongoing. We are very comfortable that we're getting a high rollover rate. Most of those patients are going to open- label extension. Currently, the guidance for X-TOLE2 is data in early 2026. You're right, as we get closer to those events, we'll be able to narrow that guidance a little bit more.
Thanks. As we think about the efficacy bar, I mean, I think the street has very high confidence it's going to hit stat SIG. I'm going to ask, how have you designed the study to not only beat this 15% placebo-adjusted "bar"? Because in phase II, you did show best in class 35% delta with the top dose. How have you designed the study to ensure that similar 35% happens again?
Yeah, so happy. I think there's a bunch of kind of layers to your question as we think about phase II to phase III, the types of patients, maybe what our expectations are going into data as well. I mean, maybe to start off, the phase III trial is designed really exactly like the phase II study. So the inclusion-exclusion criteria in phase III are exactly the same as the phase II program. It is a 12-week double-blind. It was eight weeks of double-blind in phase II, 12 weeks in phase III. As you've seen from our open- label extension data that we've presented a number of times, it does look that that response does deepen a little bit over time. We're completely comfortable in moving from an eight-week double-blind to a 12-week double-blind. The inclusion-exclusion criteria are the same.
We feel very comfortable with the powering assumptions in phase III. We're using our phase II data to build the model. You know, that's the data we have with the molecule, both in terms of both effect size as well as variability or standard deviation. When we look at the phase II data and we look at the sample size and the way that phase III is designed, we have more than 99% power at the high dose and more than 90% power at the 15 mg dose. All of that lines up that we feel very comfortable going into the phase III trial. Most recently on earnings, there were some questions around just what are our expectations going into data. We provided a little bit of that information and some background.
I think it's generally well understood that drugs that are successful in phase II in epilepsy have good reproducibility in phase III. That again gives us confidence. You know, it's a reasonably small data set. If you look at the focal onset seizure drugs over the last 10 to 15 years, when you look at the phase II to phase III data set, that effect size comes in a little bit, but it's quite modest. That is why we believe reproducibility is high. The other thing that we've communicated, if you look at all of the drugs over the last 10 to 15 years and how they've done on a placebo-adjusted basis, which are some of the numbers that you've cited, the range is from the high teens and into the 30s. Obviously, at the high end of the range is our phase II data.
At the low end of the range is Vimpat. Everything else is in between. What we think is really interesting when you analyze those data is that placebo-adjusted efficacy is not a good predictor of commercial success. The question is why. You know, we've done a lot of work in primary market research. It's a more complicated prescribing decision than just one attribute. I think one of the things that we really benefit from with azetukalner is this will be the only time that a novel mechanism has been launched in epilepsy in quite some time, really since the days of KEPPRA. Perampanel or FYCOMPA was a novel mechanism, but in terms of a very clean profile, we're going back some years. The drug doesn't need to be titrated, and we don't have real DDI risk.
There aren't adjustments for background medications. When you don't need to titrate a drug, you don't have to make adjustments for DDIs. You've got a novel mechanism, and you've got the overall safety and tolerability and efficacy profile. We think we get really strong feedback from the epilepsy community. Although the phase III readout's important, the efficacy's important, you know, ultimately our phase II data or phase IIb data is going to be submitted. That will be study one on label. We're really excited about that. We will unblind the phase III study, and then we'll file an NDA next year. I feel really comfortable with the overall profile of the medication.
Understood. It is all about the totality of the profile, not just on efficacy?
That's right.
Yeah, understood. As we think about EMA, NDA definitely submitting in 2026, I think you've said six months after X-TOLE2 reads out, give or take. X-TOLE3 is the second identical phase III study. Is that needed for an EMA submission? What are the timelines for EMA?
Sure. Yeah, maybe this is a good opportunity just to talk about the overall phase III program for epilepsy. We are running three phase III clinical trials in epilepsy in parallel. To our knowledge, I do not think anyone has ever done that before, that have run the primary generalized tonic-clonic seizure study in parallel with the FOS studies. Usually, those are done sequentially. Given the profile of the molecule, we felt that it made sense for us to invest broadly throughout the phase III program. As you mentioned, we have two phase III clinical trials in focal onset seizures, X-TOLE2 and X-TOLE3 . Those are identical clinical trials. Inclusion-exclusion criteria, the design, the powering, everything is identical in those two studies. They are just run at different medical centers. With X-TOLE2 , we biased more of the sites from X-TOLE.
We biased more U.S. sites in that clinical trial, whereas in X-TOLE3 , we used clinical sites more outside of the U.S. You are right. We believe for ex-U.S. jurisdictions, including Europe, we will likely need both X-TOLE2 and X-TOLE3 . In addition to that, we are running what we call the X-ACKT study, which is a study in primary generalized tonic-clonic seizures. Those studies do take longer. It is a less prevalent form of epilepsy. These patients are also having breakthrough tonic-clonic seizures. Those studies do take a little bit longer to run. Our expectation is that would form the basis of an sNDA.
I see. Let's just say successful, file NDA in 2026, approved in 2027. I remember Potiga, which is the predecessor drug, I believe got DEA scheduled. Would you expect a similar DEA schedule?
Yeah, I think it's, yeah, I'll come back to what the scheduling is. Yeah, all anti-seizure medicines are essentially scheduled. Ezogabine was a Schedule V. I think it's premature to try to comment on scheduling today when we don't have the final data set. Yeah, it's very common for anti-seizure medicines to be scheduled medications. The prescribers are completely comfortable with them.
Understood. Bottom line, with the totality of data that you've produced and will likely reproduce again, the positioning of this drug ultimately should be in the earlier line of treatments. Is that correct?
Yeah, I mean, this is maybe a good opportunity to just talk a little bit about the market. In the U.S., there are 3 million Americans that have epilepsy. 60% have focal onset seizures. About half of them are not getting good seizure control. If you add in some adolescents and pediatric patients, we roughly talk about a million patients that we think could benefit from a new medicine, a new mechanism, and a new branded drug. That is when we think about the total market opportunity. Most newly diagnosed patients are going to be on a single generic drug. The drugs that have done very well in focal onset seizures, a couple of hallmarks. One, yeah, they generally get used earlier in the treatment paradigm. When we look at the clinical trial population, that is a very severe population.
As we mentioned in phase II, the average or the median patient had failed six ASMs. They were on three background medications, and they were still having 13.5 seizures per month per 28 days, so approximately a seizure every other day. We expect, obviously, from once the drug is available commercially, that patients that are less severe will have access to the medicine. As we mentioned, with a novel mechanism, the opportunity to combine it with an SV2A drug or a sodium channel inhibitor makes a lot of sense.
Great. Why don't we move on to depression then for the same asset? Is it three phase III MDD studies, or is it two? Three of them.
Yeah, so our plan is to run three phase III clinical trials in major depressive disorder. Two of them are up and running. The first one, which we call X-NOVA2 , started at the end of last year. It was probably Q1 of this year when we had the majority of sites up and running. The second phase III clinical trial was staggered by about six months. X-NOVA2 started in the summertime. And then, you know, maybe as we're talking about psychiatry, we just recently, in the last few months, initiated a phase III clinical trial in bipolar depression as well.
Great. For the first phase III MDD study, when do we get that data? Is 2026 a possibility?
We haven't yet guided on, you know, we're a couple of quarters in. We usually like to try to get a little bit further into a clinical study to provide guidance. If we look at the phase II study, which was a much smaller study, our X-NOVA, it was really a proof of concept study. We looked at two different active doses of the drug, 10 and 20 mg versus placebo, at just over 50 subjects per arm. This is significantly larger because we're looking at 450 subjects in phase III in each of the MDD studies. We are going to many more clinical sites. Usually, these trials, in our expectation, both based on experience when we look at other sponsors as well, usually about two to two and a half years to get these studies completed.
Thanks. Ultimately, how are you also trying to position this drug? Is it similar to epilepsy, where it's about the totality of evidence, or is it more SKU'd towards a strong efficacy delta?
When we look in psychiatry, the prescribing decision is less around efficacy as a single driver. As we think about azetukalner in psychiatry, I think there's a number of things that we're getting positive feedback when we do our market research, when we talk to psychiatrists. One, it's a novel mechanism. There hasn't been a lot of novel mechanisms developed in psychiatry over the last number of decades. To be able to come with a completely novel mechanism is something that is very well received. It has rapidity of onset. What we've seen in both epilepsy and in psychiatry is we get separation between active and placebo at week one. The first time that we look at those data, we get separation.
If you look at some of the more traditional psychiatry drugs, like the SSRIs or SNRIs, those can take weeks and weeks, if not months, to show efficacy. If you're in a major depressive episode and these patients have other risk factors, something that can work more quickly is also well received. The other thing is it looks like, based both on the mechanism as well as data that we've generated, is that this mechanism has an impact on anhedonia. Often, the drugs that are used to treat psychiatry right now can treat certain aspects of the disease, but often do not have an impact on anhedonia. These patients really don't feel the motivation or the enjoyment. What we think is, again, with a novel mechanism, a rapidity of onset and having a benefit on anhedonia.
Maybe the last thing is the adverse event profile. It's different. Again, a lot of the drugs to treat psychiatry either have weight gain or sexual dysfunction as side effects. Again, coming to the psychiatry field with a different adverse event profile is something that's well received. A little bit different than in epilepsy in terms of what are some of those factors that would impact a prescribing decision. I think we have things that are clearly differentiated from the drugs that are currently used.
Speaking of anhedonia, you'll be assessing that in the study. What is a clinically meaningful delta, placebo-adjusted delta?
There is less information on anhedonia, for sure. We use a scale that is called the SHAPS scale. If you look through the literature, obviously, there is a huge amount of information on the clinical scales of depression, which is either the MADRS scale or HAM-D17 or the 2N FDA guidance. There is really less information available on SHAPS. I think what we are looking for there is clear separation and statistical significance.
Thanks. Then separately, you mentioned X-CEED, which is your bipolar depression compound for the same asset, also in phase III. This is a unique design, as how I understand it, because there's an interim analysis baked into it. When did you start the study? When could the interim occur?
We started the study just in the last couple of months. We do not currently have data with azetukalner in bipolar depression patients. This is the first study that we're going to run. Obviously, we have a huge amount of information on the molecule in terms of the overall profile. We feel very comfortable moving into a bipolar depression study. Because it's the first time we've run this mechanism in this indication, we did build in an interim analysis where we could resize. It is actually quite late in the program where we have the opportunity to increase sample size if necessary. We haven't given guidance on this. I think this is going to take longer, based on experience when we look at the literature, to run bipolar depression than it is to run the MDD studies.
Okay. It doesn't feel like a 2026. Yeah. When I think about bipolar depression drugs, I mean, it's just really antipsychotics for the most part. Some work in bipolar I, some don't work in bipolar II. Is your end goal here to work in both bipolar I, bipolar II? Is the end goal to be used mono and adjunctively in bipolar depression?
Yeah, so you're right. The first part of your question is that there's fewer medicines available for bipolar depression patients. I think there's a massive medical need. We're not trying to treat the mania associated with bipolar. We're really focused on the depressive symptoms. These patients can be either characterized as bipolar I patients or bipolar II. That's just how their mania presents, whether they're truly manic or hypomanic. Both bipolar I and II are part of the inclusion criteria. We will stratify for those just to make sure that we have balances between the arms.
Thanks. Okay. Lastly, in the last four minutes, pain program catching a lot of attention. Maybe starting with the macro, what have you seen in the maybe FDA landscape to suggest that the FDA is really going after novel pain assets and supporting the pathway there?
Yeah, I think it's broader than just what regulators are saying. I think we all know that the need for a non-opioid oral chronic pain drug is significant. We think we probably have experience and an angle and differentiation that's really different from most. We're an ion channel company. That's how we've built our capabilities. Prior to that, we were a genetics company. We were the first in the world to clone the Nav1.7 gene, which has remarkable genetics. If you're a homozygous loss of function in Nav1.7, you do not feel pain, regardless of noxious stimuli. It has been a target that many of us, pharma and biotech, have been trying to drug for the past two decades with challenges. We believe we have chemistries that have never yet been tested. The profile of our chemistries have never been tested in a human.
We have just transitioned into a phase I clinical trial. It is exciting times on Nav1.7. As I mentioned, we have Kv7 as well, which we think is an important pain target. Both Kv7 and Nav1.7 are involved in pain signaling and are expressed along the pain pathway. Now we have two molecules that have transitioned into phase I. We hope to be in a position to start phase II proof of concept studies next year.
In the healthy volunteer phase I studies for Kv7 and Nav1.7, respectively, what kind of receptor occupancy do you need to see for you to move forward?
Yeah, for Kv7, what we're really looking for in phase I is that we have enough exposure that we can model that it would be at a level that we would see an analgesic effect preclinically. For Nav1.7, it's a little bit different. We believe, based on the human genetics, we need to probably get somewhere between 75%-85% receptor occupancy. What we'll be measuring in phase I is the exposures we're getting. We'll be able to then model, based on our preclinical work in multiple species, to be able to ensure that we believe we're getting high enough receptor occupancy that we have a good shot of success in the phase II proof of concept study.
The phase II proof of concept studies, presumably in acute pain to start, what types of acute pain would you be interested in?
Yeah, I think the first phase II proof of concept studies will be standard. We have not yet finalized which proof of concept study we will use for which molecule. When I say standard, it would be studies like bunionectomy or abdominoplasty. We will design those. You're right. The first proof of concept studies we do in a postoperative acute setting. Really, the opportunity here is much broader, we think, as in chronic pain. We would run the chronic pain studies after the acute studies.
Okay. Last question then is, what is your best guess when we get some kind of data in actual patients, not healthy volunteers, but phase II?
Yeah, kind of rough timelines is right now we're in the SAD MAD portions of the phase I studies for both XEN1701 as well as XEN1120. Those phase I should wrap next year. We should get into phase II proof of concept studies. The nice thing about pain proof of concept studies is they can move quite quickly. In rough terms, I'd expect that we'd probably see some data in patients in 2027.
Great. Thanks for all the color. All right, we're going to get started with our next session.
Thanks, to you, for hosting.
Of course. Exciting time coming up for you. For those in the audience a little bit less familiar with the Xenon story, maybe a couple of minutes talking about your programs and milestones we can expect over the next 6 to 12 months?
Sure, happy to. Yeah, it's a really exciting time for us coming up to unblinding our very first phase III clinical trial. I'll take a step back, give a little bit of a quick overview, kind of three key themes that I'd like to touch upon. One is the lead molecule, azetukalner, in epilepsy. We'll talk about expansion into neuropsychiatry. We're getting more attention on our pain portfolio and spending some more time there. I'll touch upon that as well. For those that maybe don't know the company quite as well, we're a neurology company, deep expertise in drug and ion channels in the CNS. We've been building these capabilities for more than a few decades now. As I mentioned, the lead molecule is called azetukalner. This is a potassium channel modulator. It's in development both in epilepsy and neuropsychiatry.
I think the excitement that we have around the molecule is based off of our phase IIb X-TOLE data in patients with focal onset seizures. We had those data a few years ago. On a placebo-adjusted basis, it's the best efficacy ever seen in a clinical trial in the most severe population ever trialed in the most common form of epilepsy, which we call focal onset seizures. Really a nice setup into our first phase III readout, which is our X-TOLE2 study, which we've guided to early 2026. I feel really good about that. I think we'll probably get into in the Q&A just some of the attributes of the molecule, which I think is really special around the novel mechanism, the rapidity of onset, the overall tolerability profile, and the potential benefit for mood as well.
Then we've taken the same drug and we're expanding into neuropsychiatry. We had a phase II readout in a study that we called the X-NOVA study at the end of 2023. We've used that to build a large phase III psychiatry program in major depressive disorder and in bipolar depression. Currently, we have three phase III clinical trials ongoing in parallel, two in MDD called the X-NOVA2 and X-NOVA3 studies. We have a study called the X-CEED study in bipolar depression as well. That's progressing nicely in addition to the program in epilepsy. As I mentioned, we're starting to build kind of broader awareness of our pain portfolio. Two molecules that we've moved into phase I human clinical trials this year. Two INDs were filed this year on two different targets. One is on Nav1.7. We call the drug XEN1701.
That's currently in a phase I healthy volunteer study. Hope to move that into a human proof of concept study next year. The human genetics around Nav1.7 are absolutely remarkable. I know we can talk about that a little bit later. The second target we really like in pain is Kv7. Similar target, same target for azetukalner. A little bit of a different approach here in developing that as a novel analgesic. If you're interested more in the pain portfolio, we did an R&D webinar and R&D day just recently in the last couple of months that you can access as well. It really sets the company up nicely going into 2026.
Very helpful. Maybe a housekeeping question. You typically have an update January of every year. Should we expect you to make some kind of splash during that time frame?
Yeah, I think like most companies, we like to do a press release at the beginning of the year, which is really just laying out what to expect from the company. I expect you'll see something again from us that'll lay out all of the milestones upcoming in 2026 and beyond. You'd expect to see something in terms of 2026 guidance as we put out that press release at the beginning of next year.
Maybe even a refinement of the X-TOLE data?
Yeah, so right now, maybe it's a good opportunity to talk about X-TOLE2 . X-TOLE2 is our phase III study in focal onset seizures. What we've communicated so far publicly is that the study is fully enrolled. It was designed to randomize 360 subjects in two active doses versus placebo, so a 1-1-1 randomization, looking at the 15 mg dose of the drug, 25 mg versus placebo. We have fully enrolled that study. We did communicate most recently on earnings that we had randomized 380 subjects. Those last patients are currently going through the double-blind period. We've also kind of walked through what are the next steps as they go through from double-blind to the end of the double-blind. The patient has the opportunity to go to open- label extension.
Whether the patients go to OLE or not does have a little bit of an impact on the timeline. What we've said is that the phase III looks very consistent with phase II in terms of the types of patients enrolled in the study, so the baseline characteristics of the patients. We've also said that the rollover rate into open- label extension is very high as well. In phase II, it was 97%. We haven't guided specifically on phase III because the study is still ongoing. We are very comfortable that we're getting a high rollover rate. Most of those patients are going to open- label extension. Currently, the guidance for X-TOLE2 is data in early 2026. You're right. As we get closer to those events, we'll be able to narrow that guidance a little bit more.
Thanks. As we think about the efficacy bar, I mean, I think the street has very high confidence it's going to hit stat sig. I'm going to ask, how have you designed the study to not only beat this 15% placebo-adjusted "bar"? Because in phase II, you did show best in class 35% delta with the top dose. How have you designed the study to ensure that similar 35% happens again?
Yeah, so happy. I think there's a bunch of kind of layers to your question as we think about phase II to phase III, the types of patients, maybe what our expectations are going into data as well. I mean, maybe to start off, the phase III trial is designed really exactly like the phase II study. So the inclusion-exclusion criteria in phase III are exactly the same as the phase II program. It is a 12-week double-blind. It was 8 weeks of double-blind in phase II, 12 weeks in phase III. As you've seen from our open- label extension data that we've presented a number of times, it does look that that response does deepen a little bit over time. We are completely comfortable in moving from an 8-week double-blind to a 12-week double-blind. The inclusion-exclusion criteria are the same.
We feel very comfortable with the powering assumptions in phase III. We are using our phase II data to build the model. That is the data we have with the molecule, both in terms of both effect size as well as variability or standard deviation. When we look at the phase II data and we look at the sample size and the way that phase III is designed, we have more than 99% power at the high dose and more than 90% power at the 15 mg dose. All of that lines up that we feel very comfortable going into the phase III trial. Most recently on earnings, there were some questions around just what are our expectations going into data. We provided a little bit of that information and some background.
I think it's generally well understood that drugs that are successful in phase II in epilepsy have good reproducibility in phase III. That, again, gives us confidence. It's a reasonably small data set if you look at the focal onset seizure drugs over the last 10 to 15 years. When you look at the phase II to phase III data set, that effect size comes in a little bit, but it's quite modest. That is why we believe reproducibility is high. The other thing that we've communicated, if you look at all of the drugs over the last 10 to 15 years and how they've done on a placebo-adjusted basis, which are some of the numbers that you've cited, the range is from the high teens into the 30s. Obviously, at the high end of the range is our phase II data.
At the low end of the range is Vimpat. Everything else is in between. What we think is really interesting when you analyze those data is that placebo-adjusted efficacy is not a good predictor of commercial success. The question is why. We have done a lot of work in primary market research. It is a more complicated prescribing decision than just one attribute. I think one of the things that we really benefit from with azetukalner is this will be the only time that a novel mechanism has been launched in epilepsy in quite some time, really since the days of KEPPRA. Perampanel or FYCOMPA was a novel mechanism, but in terms of a very clean profile, we are going back some years. The drug does not need to be titrated, and we do not have real DDI risk. There are not adjustments for background medications.
When you do not need to titrate a drug, you do not have to make adjustments for DDIs. You have got a novel mechanism, and you have got the overall safety and tolerability and efficacy profile. We think we get really strong feedback from the epilepsy community. Although the phase III readout is important, the efficacy is important, ultimately, our phase II data or phase IIb data is going to be submitted. That will be study one on label. We are really excited about that. We will unblind the phase III study, and then we will file an NDA next year. I feel really comfortable with the overall profile of the medication.
Understood. It's about the totality of the profile, not just on efficacy?
That's right.
Yeah, understood. As we think about EMA, NDA definitely submitting in 2026. I think you've said six months after X-TOLE2 reads out, give or take. X-TOLE3 is the second identical phase III study. Is that needed for an EMA submission? What are the timelines for EMA?
Sure. Yeah, maybe this is a good opportunity just to talk about the overall phase III program for epilepsy. We're running three phase III clinical trials in epilepsy in parallel. To our knowledge, I don't think anyone's ever done that before that have run the primary generalized tonic-clonic seizure study in parallel with the FOS studies. Usually, those are done sequentially. Given the profile of the molecule, we felt that it made sense for us to invest broadly throughout the phase III program. As you mentioned, we have two phase III clinical trials in focal onset seizures, X-TOLE2 and X-TOLE3 . Those are identical clinical trials. Inclusion-exclusion criteria, the design, the powering, everything is identical in those two studies. They're just run at different medical centers.
With X-TOLE2 , we biased more of the sites from X-TOLE, and we biased more U.S. sites in that clinical trial, whereas in X-TOLE3 , we used clinical sites more outside of the U.S. You are right. We believe for ex-U.S. jurisdictions, including Europe, we will likely need both X-TOLE2 and X-TOLE3 . In addition to that, we are running what we call the X-ACKT study, which is a study in primary generalized tonic-clonic seizures. Those studies do take longer. It is a less prevalent form of epilepsy. These patients are also having breakthrough tonic-clonic seizures. Those studies do take a little bit longer to run. Our expectation is that would form the basis of an sNDA.
I see. Let's just say successful, file NDA in 2026, approved in 2027. I remember Potiga, which is the predecessor drug, I believe got DEA scheduled. Would you expect a similar DEA schedule?
Yeah. I think it's, w hat?
Yeah, I'll come back to what the scheduling is. All anti-seizure medicines are essentially scheduled. Ezogabine was a Schedule V. I think it's premature to try to comment on scheduling today when we don't have the final data set. Yeah, it's very common for anti-seizure medicines to be scheduled medications. The prescribers are completely comfortable with them.
Understood. Bottom line, with the totality of data that you've produced and will likely reproduce again, the positioning of this drug ultimately should be in the earlier line of treatments. Is that correct? Or you're?
Yeah. I mean, this is maybe a good opportunity to just talk a little bit about the market. In the U.S., there's 3 million Americans that have epilepsy. 60% have focal onset seizures. And about half of them are not getting good seizure control. If you add in some adolescents and pediatric patients, we roughly talk about 1 million patients that we think could benefit from a new medicine, a new mechanism, and a new branded drug. That's when we think about the total market opportunity. Most newly diagnosed patients are going to be on a single generic drug. The drugs that have done very well in focal onset seizures, a couple of hallmarks. One, yeah, they generally get used earlier in the treatment paradigm. When we look at the clinical trial population, that's a very severe population.
As we mentioned in phase II, the average or the median patient had failed six ASMs. They were on three background medications, and they were still having 13.5 seizures per month per 28 days, so approximately a seizure every other day. We expect, obviously, from once the drug is available commercially, that patients that are less severe will have access to the medicine. As we mentioned, with a novel mechanism, the opportunity to combine it with an SV2A drug or a sodium channel inhibitor makes a lot of sense.
Great. Why don't we move on to depression then for the same asset? Is it three phase III MDD studies? Or is it two? Three of them?
Yeah. So our plan is to run three phase III clinical trials in major depressive disorder. Two of them are up and running. The first one, which we call X-NOVA2 , started at the end of last year. It was probably Q1 of this year when we had the majority of sites up and running. The second phase III clinical trial was staggered by about six months. X-NOVA2 started in the summertime. Maybe as we're talking about psychiatry, we just recently, in the last few months, initiated a phase III clinical trial in bipolar depression as well.
Great. For the first phase III MDD study, when do we get that data? Is 2026 a possibility?
We have not yet guided on. We are a couple of quarters in. We usually like to try to get a little bit further into a clinical study to provide guidance. If we look at the phase II study, which was a much smaller study, our X-NOVA, it was really a proof of concept study. We looked at two different active doses of the drug, 10 and 20 mg versus placebo, at just over 50 subjects per arm. This is significantly larger because we are looking at 450 subjects in phase III in each of the MDD studies. We are going to many more clinical sites. Usually, these trials, in our expectation, both based on experience when we look at other sponsors as well, take about two to two and a half years to get these studies completed.
Thanks. Ultimately, how are you also trying to position this drug? Is it similar to epilepsy where it's about the totality of evidence? Or is it more SKU'd towards a strong efficacy delta?
When we look in psychiatry, the prescribing decision is less around efficacy as a single driver. As we think about azetukalner in psychiatry, I think there's a number of things that we're getting positive feedback when we do our market research, when we talk to psychiatrists. One, it's a novel mechanism. There hasn't been a lot of novel mechanisms developed in psychiatry over the last number of decades. To be able to come with a completely novel mechanism is something that is very well received. It has rapidity of onset. What we've seen in both epilepsy and in psychiatry is we get separation between active and placebo at week one. The first time that we look at those data, we get separation.
If you look at some of the more traditional psychiatry drugs like the SSRIs or SNRIs, those can take weeks and weeks, if not months, to show efficacy. If you're in a major depressive episode and these patients have other risk factors, something that can work more quickly is also well received. The other thing is it looks like, based both on the mechanism as well as data that we've generated, is that this mechanism has an impact on anhedonia. Often, the drugs that are used to treat psychiatry right now can treat certain aspects of the disease but often do not have an impact on anhedonia. These patients really don't feel the motivation or the enjoyment. What we think is, again, with a novel mechanism, a rapidity of onset and having a benefit on anhedonia.
Maybe the last thing is the adverse event profile. It's different. Again, a lot of the drugs to treat psychiatry either have weight gain or sexual dysfunction as side effects. Again, coming to the psychiatry field with a different adverse event profile is something that's well received. A little bit different than in epilepsy in terms of what are some of those factors that would impact a prescribing decision. I think we have things that are clearly differentiated from the drugs that are currently used.
Speaking of anhedonia, you'll be assessing that in the study. What is a clinically meaningful delta, placebo-adjusted delta?
There's less information on anhedonia, for sure. We use a scale that's called the SHAPS scale. If you look through the literature, obviously, there's a huge amount of information on the clinical scales of depression, which is either the MADRS scale or HAM-D17 or the 2N FDA guidance. Really less information available on SHAPS. I think what we're looking for there is clear separation and statistical significance.
Thanks. Then separately, you mentioned X-CEED, which is your bipolar depression compound for the same asset, also in phase III. This is a unique design, as how I understand it, because there is an interim analysis baked into it. When did you start the study? When could the interim occur?
We started the study just in the last couple of months. We do not currently have data with azetukalner in bipolar depression patients. This is the first study that we're going to run. Obviously, we have a huge amount of information on the molecule in terms of the overall profile. We feel very comfortable moving into a bipolar depression study. Because it's the first time we've run this mechanism in this indication, we did build in an interim analysis where we could resize. It's actually quite late in the program where we have the opportunity to increase sample size if necessary. We haven't given guidance on this. I think this is going to take longer, based on experience when we look at the literature, to run bipolar depression than it is to run the MDD studies.
OK. It doesn't feel like a 2026. Yeah. When I think about bipolar depression drugs, I mean, it's just really antipsychotics for the most part. Some work in bipolar I, some don't work in bipolar II. Is your end goal here to work in both bipolar I, bipolar II? Is the end goal to be used mono and adjunctively in bipolar depression?
Yeah. You're right. The first part of your question is that there's fewer medicines available for bipolar depression patients. I think there's a massive medical need. We're not trying to treat the mania associated with bipolar. We're really focused on the depressive symptoms. These patients can be either characterized as bipolar I patients or bipolar II. That's just how their mania presents, whether they're truly manic or hypomanic. Both bipolar I and II are part of the inclusion criteria. We will stratify for those just to make sure that we have balances between the arms.
Thanks. OK. Lastly, in the last four minutes, pain program catching a lot of attention. Maybe starting with the macro, what have you seen in the maybe FDA landscape to suggest that the FDA is really going after novel pain assets and supporting the pathway there?
Yeah. I think it's broader than just what regulators are saying. I think we all know that the need for a non-opioid oral chronic pain drug is significant. We think we probably have experience and an angle and differentiation that's really different from most. We're an ion channel company. That's how we've built our capabilities. Prior to that, we were a genetics company. We were the first in the world to clone the Nav1.7 gene, which has remarkable genetics. If you're a homozygous loss of function in Nav1.7, you do not feel pain regardless of noxious stimuli. It has been a target that many of us, pharma and biotech, have been trying to drug for the past two decades with challenges. We believe we have chemistries that have never yet been tested. The profile of our chemistries have never been tested in a human.
We have just transitioned into a phase I clinical trial. It is exciting times on Nav1.7. As I mentioned, we have Kv7 as well, which we think is an important pain target. Both Kv7 and Nav1.7 are involved in pain signaling and are expressed along the pain pathway. Now we have two molecules that have transitioned into phase I. We hope to be in a position to start phase II proof of concept studies next year.
In the healthy volunteer phase I studies for Kv7 and Nav1.7 respectively, what kind of receptor occupancy do you need to see for you to move forward?
Yeah. For Kv7, what we're really looking for in phase I is that we have enough exposure that we can model that it would be at a level that we would see an analgesic effect preclinically. For Nav1.7, it's a little bit different. We believe, based on the human genetics, we need to probably get somewhere between 75%-85% receptor occupancy. What we'll be measuring in phase I is the exposures we're getting. We'll be able to then model, based on our preclinical work in multiple species, to be able to ensure that we believe we're getting high enough receptor occupancy that we have a good shot of success in the phase II proof of concept study.
The phase II proof of concept studies, presumably in acute pain to start, what types of acute pain would you be interested in?
Yeah. I think the first phase II proof of concept studies will be standard. We have not yet finalized which proof of concept study we will use for which molecule. When I say standard, it would be studies like bunionectomy or abdominoplasty. We will design those. You are right. The first proof of concept studies we do in a postoperative acute setting. Really, the opportunity here is much broader, we think, as in chronic pain. We would run the chronic pain studies after the acute studies.
OK. Last question then is, what is your best guess when we get some kind of data in actual patients, not healthy volunteers, but phase II?
Yeah. Kind of rough timelines is right now, we're in the SAD MAD portions of the phase I studies for both XEN1701 as well as XEN1120. Those phase I should wrap next year. We should get into phase II proof of concept studies. The nice thing about pain proof of concept studies is they can move quite quickly. In rough terms, I'd expect that we'd probably see some data in patients in 2027.
Great. Thanks for all the color. Thanks, everyone, for listening in.
Great. Thank you, Andrew.