Good afternoon, everyone. I'm Brian Abrahams, Senior Biotech Analyst at RBC Capital Markets. Thanks for joining us for our next session featuring Xenon. We have their CEO, Ian Mortimer, and their CFO, Sherry Aulin. Ian and Sherry, thank you guys so much for joining us today.
Thanks, Brian.
Great. Well, maybe kicking off, on your latest on the latest earnings call, you provided some updates on the ongoing phase III work for 1101, or the drug formerly known as 1101, I guess I should say. But can you maybe remind us what you guys are seeing with regards to enrollment trends? And then I guess even more than that, how are you guys feeling about the overall conduct of the phase III studies?
Sure. Yeah, I'm happy to kick off and maybe talk a little bit about the phase III program, and then Sherry can talk about some of our timelines and some of the trends we're seeing. So yeah, we're now referring to XEN1101 as the USAN or INN name of azetukalner. So as you know, we had really impressive data in our phase II program, the X-TOLE study. This was a couple of years ago. And I'm sure we'll have an opportunity to talk a little bit about the open-label extension data, which is coming in really strong, and we'll have another update later this year. And, obviously, we've had our end of phase II meeting with the agency in epilepsy, and we're now in our broad phase III clinical program for azetukalner in epilepsy.
We're running two phase III clinical trials in focal onset seizures, X-TOLE2 and X-TOLE3. Then we have a phase III clinical trial in primary generalized tonic-clonic seizures, or the X-ACKT study. But really getting to your question in terms of the phase III program and conduct and how we think about it, you know, the nice thing about epilepsy is we see really good reproducibility and consistency across studies. You know, that doesn't happen in, in, in all of the CNS indications, but we feel very comfortable and confident in epilepsy. And we're really trying to replicate, the phase II data in phase III. So very purposeful, we've called it X-TOLE2.
X-TOLE3 because it is being designed based on the X-TOLE study. So the same, the same endpoints, the same entry criteria, inclusion/exclusion criteria, are exactly the same. We are looking at the drug over 12 weeks versus 8 weeks. But if we go into the open label extension data, we know that over time the drug seems to be working even better in terms of seizure reduction. So that gives us a lot of confidence. But yeah, we're really trying to replicate, the phase II program, in our phase III studies, and we'd expect, you know, at least similar outcomes as we think about the completion of those studies.
And Sherry can walk us through some of the timelines as we think about the program. Okay.
Yeah. And just to add from a study conduct perspective, so not only are X-TOLE2 and X-TOLE3 designed very similarly to X-TOLE, but we're leveraging a lot of the sites that we used in X-TOLE and X-TOLE2. And a lot of the learnings and just broadly, you know, the conduct. So as you think about the jurisdictions, for example, you know, in X-TOLE, we had a split of patients coming from the U.S. and from Western Europe. And so we're biasing towards those same jurisdictions as we think about X-TOLE2. Just to remind everybody, we are really, obviously, both studies are now, you know, continuing to randomize patients. But we are really prioritizing X-TOLE2 as we think about critical path to our NDA.
So in our end of phase II discussions with FDA, we did talk to FDA about our intentions to file our NDA with efficacy data from X-TOLE and X-TOLE2. And that, therefore, our guidance has really been focused around X-TOLE2. And just as a reminder, we're expecting to have patient enrollment complete in X-TOLE2 late this year, early next year. As we think about sort of, you know, what drives us towards that guidance, you know, again, as a reminder, we target about 80-100 sites for each of these studies. And that's just the number of sites that we need in order to be able to recruit the patients in these studies. And again, that's very similar to what we did in X-TOLE.
It's really always a balance, Brian, between, you know, the timing, as well as study quality, right? As you go to more sites, that the quality may potentially suffer. We do believe that there's only a finite number of quality sites globally. And so we're really focused on going to the highest quality sites and making sure that we're conducting a high-quality study and really, you know, trying to replicate the exceptional results that we had in X-TOLE. So it's always a bit of a balance there for us.
Great. So look forward to that data. Sounds like the things are moving along, well there. Ian, you mentioned briefly the open label extension data. Would love to hear a little bit more about what your latest looks at the open label extension, studies, or database has shown, especially with regard to some of the side effects that have been seen with predecessor drugs like pigmentation and urinary retention on the safety side, and then also what you're seeing that gives you confidence on in areas like seizure freedom as patients continue to take the drug over time.
Yeah. So, X-TOLE, as we mentioned, was run as an eight-week double-blind. If you finish the double-blind period, you have the opportunity to go into open-label extension. We had 97% of patients that completed the double-blind period rollover. So, you know, almost everyone. And we've been tracking those patients over time. You know, open-label extension gives us a number of things to consider. You've talked about safety and efficacy as kind of being two critical. And so let's talk about each of those in turn. On the safety side, what it has allowed us at the macro level is just to get a huge amount of comfort around the molecule. We now have over 600 patient years of exposure. We have patients that have been treated out more than four years.
And so that should give us a lot of confidence as we're seeing the safety data. What we're seeing in open-label extension is consistent with what we see in the double-blind period in terms of the types of adverse events. And you mentioned a couple that there was some concern about a predecessor molecule, around pigmentation. We don't expect to see any of that in terms of the chemistry of azetukalner, and and we can confirm that we haven't seen anything in open-label extension. So I think that should give us some comfort that I think we're at a point now that we can kind of put that question to rest.
In terms of urinary retention, again, there was some urinary retention for a predecessor molecule. We've seen it very infrequently with azetukalner. And really, not at any concerning levels, patients, you know, we saw two in the double-blind period. That was less than 1%. We've seen a couple in open label. And given the amount of exposure in open label, it's really quite a rare event that we're seeing anything on the urinary side. So it's nothing that's really concerning from our perspective. In terms of the efficacy, obviously, this doesn't have a control arm, but we can still look at efficacy over time. There's kind of a couple of key things that we're looking for on the efficacy side. We're looking for overall seizure reduction of the population. And what we find is that patients that stay on the drug for longer do even better.
So just as a reminder, the seizure reduction in the double-blind period at the high dose was just over 50%. We now see the population with over a 90% reduction. The most recent data that I'm referencing right now was published and presented at the American Epilepsy Society meeting last December. That was a 30-month cut of the data. And this year we'll mature that data another 12 months, and we'll have a 42-month cut of the data for AES this year. We're now presenting those data on an annual basis. You had mentioned seizure freedom. I think that's obviously an important thing to track as well. And the data is actually quite remarkable. You really need to go back to the patient baseline characteristics and demographics. These patients, on average, the median patient coming into this study had failed six drugs. They were on three background medications.
So on average, or the median patient, this was the 10th drug that they had exposure to. And they were still having 13.5 seizures per month, or about a seizure every other day. We now, for those patients that have been dosed for two years on the drug, about one in four of them, just under 25%, is having 12 months of no seizures at all. So when you think about, the demographics and just how refractory and severe these patients were coming in, and we measure that, how many drugs they had failed or were on, and that background, seizure burden, and then seeing these patients, a subset of these patients, go, significant periods of time with no seizures at all, it's actually quite remarkable. And so that's the feedback that we're getting from the epilepsy community.
As I mentioned, later this year, we'll mature that data another year.
And speaking of feedback, as you're continuing to present the data and analyses of X-TOLE and open-label updates, and speak with physicians at these conferences and in market research, what's the latest that you guys are hearing with regards to, I guess, what aspects of XEN1101's profile that resonate the most, and where the level of interest may be? Is it where's the most enthusiasm? Is it around having a new mechanism, the rapidity of onset, ease of use, safety profile? What resonates the most?
Yeah, I think you've hit on a lot of them, right? And you know, there are lots of drugs available to treat patients with epilepsy. And so physicians are always making trade-off decisions. And the types of patients that are going to be treated with a branded medicine are going to be treated in polypharmacy. And so I think a novel mechanism is always going to be part of those criteria, as you mentioned. The rapidity of onset's really interesting. A lot of drugs in neurology, and specifically in epilepsy, need to be titrated. So you start on a non-therapeutic dose, and you have to slowly titrate up. That's usually because of side effects. Azetukalner does not need to be titrated. And so we see statistical significant efficacy at week one. So that rapidity of onset, I think, is really important, as you've mentioned as well. I think the ease of use attributes.
The one thing that you didn't mention that we've now tested in market research just over the last couple of months, because it's a little bit newer, is the antidepressant effects. Right? So obviously, these patients have the primary diagnosis of either focal onset seizures or primary generalized tonic-clonic seizures. But you'll find for those refractory patients or the patients that are not getting good seizure control, there's significant comorbidities as well. So a lot of these patients have comorbid depression, the vast majority of them. And so for the epilepsy community and the treating physician, the epileptologist, or the neurologist, to have a drug that lowers seizure burden but can have antidepressant effects can be really important for the patients that they're treating.
We have now tested that in market research post our X-NOVA data, which is our data in major depressive disorder at the end of last year. And we're getting really good feedback there. So we think the commercial opportunity for azetukalner in epilepsy has gone up post the X-NOVA data.
That makes a lot of sense. And then you've made the decision not only to explore epilepsy, but also to really go full on in major depressive disorder. Can you talk about some of the aspects of those data that really have prompted your enthusiasm, and then maybe additionally, some of the feedback that you've gotten from both KOLs and regulators that have shaped your decision to invest in a full phase III program in MDD as well?
Sure.
Yeah. I mean, our X-NOVA data were really interesting. You know, although we didn't hit on the primary statistical significance on the primary endpoint, there was a lot in those data that we found very compelling. You know, against our primary endpoint, which was MADRS at week six, we saw a clinically meaningful separation between the 20 mg dose and placebo. That was a 3-point separation. We were statistically significant across a number of other endpoints, including HAM-D, which is another clinical scale of depression across, you know, other endpoints, such as week 1 efficacy, which is consistent with what we saw in our epilepsy data. Rapidity of onset, again, being an important potential differentiator, not only in epilepsy, but also in depression, where standard of care agents can take five-six weeks to actually see efficacy.
And then on a different component or aspect called anhedonia, we were also statistically significant. And that's important because anhedonia is a key comorbidity that comes along with depression, where patients on standard of care may feel less depressed, but they're still not feeling motivated or happy. And there's good scientific or mechanistic rationale with potassium channel openers in anhedonia. We did see again stat sig on that endpoint, and we'll continue to evaluate that in phase III. So overall, as we looked at the totality of the data in X-NOVA, we felt like we saw a really strong signal, Brian. And you know, another aspect of this is the tolerability profile, which I think we were, to some extent, surprised by. You know, a really good tolerability profile and better tolerated in these patients than in epilepsy.
One hypothesis is that these patients are on monotherapy versus in epilepsy. You know, they're on multiple background medications, and there could be some effect there of the additional medications. So you know, we decided, obviously, to move forward. I think we made significant progress over the last few months since our top-line data. We did just recently announce that we had our end-of-phase II interaction with FDA, where we did review with FDA our full development plan for MDD for phase III. And really aligned on the key elements of our phase III program, as well as just our broader development program. One of the benefits that we have here is we do get to leverage a lot of the work that we're doing in epilepsy.
So as we think about the broader clinical development program, which includes our clinical pharmacology studies, you know, toxicology and CMC work that we're doing for our epilepsy package, we have the benefit of leveraging a lot of that for MDD. So overall, you know, we're now making our way towards initiating that program. So we're excited to do that. And our first phase III, first of three phase III studies will initiate later this year.
As you think about the design of the studies, I know you're using a relatively traditional study design. How will the patient population that you plan to enroll, I guess, how does that align with where you expect the drug to potentially fit into the future MDD treatment paradigm?
Yeah, I'm happy to review some of the elements of the phase III program. And then, Sherry, if you want to go through the treatment paradigm and where we think that this would fit in as a novel mechanism. So you know, we've given a bunch of the information on phase III. We're gonna choose one dose to move ahead, which is 20 milligrams. So this is gonna be a one-to-one randomization, active versus placebo. 20 milligrams. We haven't yet gone through the sample size, but these will be well-powered phase III studies. We are gonna use HAM-D17 as the primary endpoint. We are, as Sherry mentioned, gonna continue to look at rapidity of onset and also the endpoints of anhedonia.
I think both of those are really interesting in order to differentiate azetukalner from other drugs that are available. Looking at what we learned from X-NOVA, we are going to increase the criteria in terms of the scores in baseline moving into the study. So we're looking at a HAM-D17 cutoff of 22. It was 20 in the phase II program. So we're gonna adjust that slightly. But those are the major components. And like I mentioned, we'll have the final sample size calculations out here in the next couple of months in advance of initiating the phase III program.
Yeah. And maybe just to add to what Ian mentioned, these are gonna be monotherapy studies, so consistent with X-NOVA. We're really focused here on approval in the US, and monotherapy does allow us to get, you know, into that future treatment paradigm, even used in combination with other antidepressants. I think there's a lot of parallels to be made between the treatment paradigm in epilepsy and in depression, where they're, you know, it's a highly genericized market. There are the sort of mainstays, SSRIs and SNRIs, and most first line patients will go through, you know, at least one SSRI, SNRI, maybe multiple. And at that point, be eligible for a branded product. There's still this massive unmet medical need.
You know, we all know that there's north of 20 million Americans that suffer from depression, and about half of them are actually not well controlled or not kind of well treated on the current available medication. So critical here are agents that have novel mechanisms so that where patients have failed prior lines of treatment, they can try something with a novel mechanism that perhaps works, just given the heterogeneity of the population. And then we touched already on some of the other differentiators, where we think 1101 in the branded market should really stand apart as we think about rapidity of onset, potential benefit on anhedonia. And the safety and tolerability profile, where we have not to date seen significant weight gain or any sexual side effects.
Any sense at all as to when we may see that investigator-sponsored study from Mount Sinai read out? I know it's not in your hands, but just kind of curious what and whether or not there's anything we should be looking for there that could shape how you think about future development.
Yeah. So as a reminder, there is an ongoing investigator-sponsored study with azetukalner in MDD. They're looking at the 20 milligram dose of azetukalner versus placebo. The study is being run at two sites, and they're targeting enrollment of 60 patients. So we do actually expect to have those data sometime this year. They're nearing completion of that study. I will just remind everybody that they are, as a primary endpoint, looking at a functional fMRI endpoint. However, secondary endpoints do include the clinical scales of depression as well as anhedonia. So we'll be interesting to see those data. But you know, as we've said in the past, the results of that study are not going to change our course. So we are committed to our phase III development program. But obviously, we'll share those data once available.
We are working closely with our collaborators or the investigators of that study, and we'll align on our publication plan. We'll announce, you know, once the data are available.
What's your latest thinking on international plans for 1101? Is this something that you would be interested in pursuing on your own, or are there sort of major differences in the treatment paradigms in epilepsy and/or MDD that might shape your decision on how much to focus the regulatory and future commercial investment in?
Yeah, great question, Brian. I'm I'm happy to start, and feel free to add in, Ian. You know, we've said for some time our strategic objective is to commercialize ourselves in the U.S. Obviously, that's the biggest commercial opportunity as we think about epilepsy and MDD. So really, our efforts are are focused around the U.S. At this stage in the company's lifecycle, we're not looking to enter into, you know, other geographies. I think importantly there, we would think of Europe as a big market, Asia Pacific, with Japan being, you know, a significant market as well. But but at this stage, we're not interested in doing that ourselves, just from a capital, you know, perspective. And the challenges and complexities that come with, you know, market access and payer dynamics in those geographies.
So likely that we would look for a partner, Brian, that has, you know, capabilities in those geographies, whether that's one, you know, ex-U.S. partner or potentially regional players, is yet to be seen. So it's something that's absolutely on our radar. We haven't guided on timing. But that's our plan.
Okay. Good. Maybe just before we wrap up, maybe on the rest of the pipeline, you've talked about work that you guys are doing on a number of different earlier stage ion channel targets, Nav1.1, Nav1.7 candidates, and having followed the story a long time. I know there's a lot of enthusiasm now about Nav channel modulators for pain, but you guys were really the originators many years ago. So there's a lot of key learnings, I guess, you could potentially apply here in terms of how to overcome some of the historical challenges. Where do we stand with those assets, and when might we learn more?
Sure. Yeah. Definitely not, you know, the driver or the focus of the company, obviously, with a phase III program with azetukalner and epilepsy and moving into depression. But I think the discovery portfolio at Xenon has matured nicely kind of behind the scenes, and we're just starting to give it a little bit of daylight now. So three targets that we're really interested in, obviously, we're continuing to prosecute new chemistries on Kv7. I think that's really important, given the lead program. And then you mentioned two sodium channels, Nav1.1 and 1.7. 1.1 is a potential target in Dravet syndrome. Most of the children with Dravet syndrome are haploinsufficient in Nav1.1 , so they have 50% of the protein. And so we have oral small molecules that we can potentiate the channel or increase current through the wild type channel.
And so we're showing some, and we've published some of that data at epilepsy meetings. We're seeing some really interesting preclinical data in that Nav1.1 program. And the Nav1.7, I would say, is, yeah, near and dear to our heart. We were the first to clone the gene many, many years ago. And I think, you know, we've had a ton of learnings over the past 15 years or so. And I think we have some really interesting chemistries. We really like the target. We think the genetic validation has always been exquisite on the target. And now I think we've learned a lot on the right types of chemistries that really could have some breakthroughs here.
So whether it be the Kv7 molecules, Nav1.1 or 1.7, what we've said is we're kind of a candidate selection for in all of those programs, which means for us, what we call a DTC or development track candidate is moving the candidate into formal IND-enabling or GLP toxicology studies. So a lot of that'll happen this year and next, and then that'll be followed by IND or CTA filings. So the opportunity to move multiple molecules into human clinical development over the next few years.
Great. Well, with that, we're out of time. Ian, Sherry, thank you guys so much. Great.
Thank you, Brian.
Thanks, Brian.