Xenon Pharmaceuticals Inc. (XENE) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to today's conference call, Xenon Pharmaceuticals provides corporate update. [Operator Instructions] Please be advised today's conference may be recorded. [Operator Instructions] I'd now like to hand the conference over to Sherry Aulin, Chief Financial Officer of Xenon Pharmaceuticals. Please go ahead.

Good morning. Thank you for joining us on our call and webcast to discuss our XEN1101 program including Phase IIb X-TOLE clinical data that will be presented in a poster session and an Xenon-sponsored scientific symposium at the 2021 Annual Meeting of the American Epilepsy Society or AES. Joining me today are Ian Mortimer, Xenon's President and Chief Executive Officer; Dr. Chris Kenney, Xenon's Chief Medical Officer; and Dr. Chris Von Seggern, Xenon's Chief Commercial Officer. Ian will provide some opening remarks, Chris Kenney will provide a summary of the top line X-TOLE data, which was previously announced on October 4, as well as the additional completed sub-analyses to be presented at AES, and Chris Von Seggern will provide some commercial context for the X-TOLE data. Finally, Ian will provide a summary of our XEN1101 plans moving forward before opening up the call to your questions. Please be advised that during this call, we will make a number of statements that are forward-looking, including statements regarding the potential efficacy, safety profile, future development plans, addressable market, regulatory success and commercial potential of XEN1101, the anticipated initiation of future clinical trials for XEN1101, the timing and results of our planned interactions with regulators regarding XEN1101 and our ability to successfully develop and obtain regulatory approval of XEN1101. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings. Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward-looking statements, and news release summarizing our X-TOLE-related presentation at AES was distributed this morning along with a separate news release outlining our other scientific posters and activities at AES. To support our call this morning, a slide deck summarizing all of the X-TOLE data presented at AES has been uploaded to the Investors section of our website. Concurrent with our various AES activities, we will post additional materials, including the symposium slide deck and each of our scientific posters on the Publications page under the Medical Affairs section of our website. Now, I would like to turn the call over to Ian.

Thanks, Sherry, and good morning, everyone, and thanks for joining us today. We are incredibly excited to be in Chicago with a significant presence at AES built around our positive Phase IIb X-TOLE top line clinical data announced in early October. Our late-breaking abstract with lead author, Dr. Jackie French, was accepted by AES and will be presented in a session tomorrow afternoon. We are also hosting a scientific symposium this evening, highlighting the role of potassium channel openers in the treatment of epilepsy and depression. At both of these sessions, we will outline the X-TOLE top line data and share additional sub-analyses that have been completed since the release of top line data in October. These new analyses continue to support our high degree of confidence in XEN1101 and our belief that XEN1101 could play an important role in treating adult focal epilepsy, with potential and other indications as well. In addition to these events, we are participating in a joint industry scientific exhibit related to rare genetically defined epilepsies with a particular focus on our other KV program, XEN496. As Sherry mentioned, I encourage you to read today's news releases, download the slides accompanying this call and review our other posters at AES once they're posted on the website. I'll now turn the call over to Chris Kenney, who will comment on the X-TOLE data as presented at AES. Chris?

Thanks, Ian. We're excited to present detailed clinical data from our XEN1101 X-TOLE Phase IIb clinical trial at the AES meeting. Importantly, data from additional analysis of subgroups in the X-TOLE study are consistent with the top line data set, which demonstrated strong evidence supporting the efficacy, safety and tolerability of XEN1101. The study results include a total of 325 randomized and treated subjects in the safety population and 323 subjects in the modified intent-to-treat population for the efficacy analyses. Beginning first with the efficacy results. The trial met its primary efficacy endpoint showing a monotonic dose response relationship between the XEN1101 active dose groups compared to placebo, which was statistically significant. In other words, a p-value less than 0.001. XEN1101 also demonstrated a statistically significant reduction from baseline and monthly focal seizure frequency and pair-wise comparisons to placebo from all 3 XEN1101 doses with 2-sided p-values of less than 0.001 for both high doses, 20 milligrams and 25-milligram doses. A prespecified secondary endpoint of the study was a responder analysis, which compares the proportion of study subjects treated with XEN1101 who achieved a greater than 50% reduction in monthly focal seizures versus placebo. The percentage of subjects who achieved a greater than 50% reduction in monthly focal seizures was 54.5% in the XEN1101 25-milligram group, 43.1% in the XEN1101 20-milligram group and 28.3% in the XEN1101 10-milligram group compared to 14.9% in the placebo group. Statistical significance was achieved for all dose groups compared to placebo, with 2-sided p-values of less than 0.001 for both the 20-milligram and 25-milligram doses. Additional sub-analyses of these top line data have been completed and are being presented at AES, including an analysis of the proportion of patients with at least a 75% reduction in monthly focal seizure frequency from baseline, along with the proportion of patients who achieved 100% reduction in monthly seizure frequency from baseline. Some of these sub-analyses were performed in subgroups of patients with varying baseline characteristics, given that X-TOLE included a difficult-to-treat patient population as defined by the number of prior failed anti-seizure medications, concomitant antiseizure medications while on study and baseline seizure burden. Upon review of the scientific literature, we believe that the X-TOLE demographics represent one of the most severe patient population studied in an adult focal epilepsy clinical trial to date. Even in the context of this very difficult-to-treat population, XEN1101 demonstrated impressive efficacy. More than half of the patients in the 25-milligram group experienced at least a 50% reduction in monthly focal seizure frequency from baseline. And further, the majority of these patients actually experienced a 75% or greater reduction in monthly focal seizure frequency from baseline. Seizure freedom was attained in a subset of patients, consistent with other anti-seizure medications despite the higher level of disease severity in the X-TOLE population compared to other focal onset seizure studies completed to date. At 20 milligrams and 25 milligrams, the seizure freedom rates were 7.8% and 6.3%, respectively. Importantly, in those patients with less severe seizure burden at baseline less than 8.5 seizures per month, we saw a seizure freedom rates of 17.6% and 13.8% in the 20-milligram and 25-milligram dose groups, respectively. These data suggest that seizure freedom rates might be higher in a population of patients with less disease severity. Building on these analyses of the less severe patients, we analyzed the median reductions from baseline in monthly focal seizures at 25 milligrams based on the number of previous anti-seizure medications failed, the number of concomitant anti-seizure medications and the baseline seizure burden. Across the board, we see increases in seizure reduction in patients with less disease severity. For example, the median reduction of seizure frequency was 58% in patients who had failed less than -- less than a median of 6 anti-seizure medications prior to study initiation and 64.5% in patients who are on 1 or 2 concomitant anti-seizure medications. In patients who had less than 8.5 monthly seizures at baseline, the data was even more dramatic, with a median reduction of seizure frequency of 70.6%. Another interesting sub-analyses looked at seizure reduction across seizure subtypes, including Type 4 seizures defined as focal seizures that lead to the more severe generalized tonic-clonic seizures. These data showed a median percent reduction in monthly focal seizure frequency of 86.9% in Type 4 seizures in the 25-milligram dose group. Overall, we believe these data continue to support our confidence in the significant efficacy of XEN1101 in the potential clinical use population. Turning now to XEN1101 safety profile. XEN1101 was generally well tolerated in the study, with adverse events consistent with other commonly utilized anti-seizure medications. The complete adverse event table will be presented at AES. In summary, the most common treatment emergent adverse events, or TEAEs, were dizziness, somnolent, fatigue and headache, and these were seen in a dose-dependent manner. Dizziness was the most common adverse event, seen in 31.6% of patients in the high-dose 25-milligram group. As a reminder, the vast majority of these AEs are mild or moderate, and with additional analysis now complete, we know that the majority of these occur in an early treatment period. In addition, we do observe other adverse events consistent with an active CNS drug, and these are generally seen in a dose-dependent manner, were expected and consistent with a highly active anti-seizure medicine. As discussed in October with our top line results, the incidence of treatment-emergent serious adverse events was balanced across the 4 arms of the study. AEs that led to treatment discontinuations was also presented in October and was seen in a dose-dependent manner with 3.5% of subjects in the placebo group, 2.2% of subjects in the XEN 10-milligram group, 13.7% of subjects in the XEN1101 20-milligram group, and 15.8% of subjects in the XEN1101 25-milligram group that had an adverse event leading to treatment discontinuation. A few additional comments on safety and tolerability. As we disclosed previously, there were 2 transient adverse events of urinary retention that were reported in the active treatment groups, one of which required a dose reduction, and both subjects remained on drug with no other changes or interventions required. We now have additional data from the American Urological Association Symptoms Index completed by all patients, which showed no evidence of urinary retention based upon mean differences across treatment groups in either the total or individual items. There were no cardiovascular -- there was no cardiovascular signal of concern based on vital signs, including orthostatic tests. There were no safety signals of concern from physical or neurologic exams, and there was no signal of concern from ECG, safety labs or urinalysis. Weight changes were modest, with an increase noted in all treatment groups. The mean increase of 0.2 kilograms was noted in placebo, 0.6 kilograms in the 10-milligram group, 1.6 kilograms in the 20-milligram group and 1.9 kilograms in the 25-milligram group. There have been no treatment-emergent adverse events of pigmentary abnormalities reported during the double-blind phase of the study or in preliminary analysis during the ongoing open-label extension to date, with approximately 80 subjects now treated more than 12 months. So overall, now that we've spent a significantly more time with the safety data and completed additional analyses, we are very comfortable with the AE profile of XEN1101 given the impressive efficacy and that AEs seen to date are predictable, dose-dependent, the majority are mild or moderate and occur early in treatment. This adverse event profile is in line with other anti-seizure medications and as expected, given XEN1101's high degree of activity in the central nervous system. So based on the totality of these extol results and given XEN1101's ease-of-use attributes and unique potassium channel mechanism of action, we believe XEN1101 could play a very important role in treating focal epilepsy in the future. Which is a good segway to turn the call over to Chris Van Seggern, who will share some insights from our primary market research. Chris?

Thanks, Chris. We continue to share our XEN1101 data with epileptologists and neurologists to gather feedback and shape our thinking going forward. As a reminder, following the X-TOLE results, we surveyed 148 prescribing epileptologists and neurologists in the U.S. to understand their perspectives on the XEN1101's anticipated product profile and to build upon the learnings we gained from earlier primary market research with 50 clinicians across the U.S. Overall, the profile of XEN1101 was very well regarded. Both neurologists and epileptologists view the efficacy and tolerability of XEN1101 as potential differentiators. In particular, differential efficacy was cited as a driver of use for XEN1101 across all lines of therapy. As Ian and Chris noted, XEN1101 showed a dose-dependent, highly statistically significant and clinically meaningful seizure reduction in a patient population that could be characterized as very difficult to treat. For context, this heavily pretreated patient population failed a median of 6 ASMs, and 50.8% were on 3 background ASMs. Further, in a patient with less severe disease at baseline, XEN1101 demonstrated improved efficacy, suggesting a very strong profile in the patient population that we believe is most likely to receive XEN1101, if approved. In light of the strong efficacy in the overall product profile, physicians indicated comparable utilization of XEN1101 to Vimpat, which, if approved, would position XEN1101 to compete for the first branded opportunity for patients with residual seizure burden. Given the substantial efficacy demonstrated in the X-TOLE results, combined with all that we have learned from our market research, we believe the profile of XEN1101 has the potential to significantly improve the standard of care for patients with residual seizure burden. And, if approved, would represent a meaningful advancement in a therapeutic armamentarium for this disease. I'd now like to turn the call back to Ian for an outline of our future development plans with XEN1101 and closing remarks. Ian?

Thanks, Chris. Since announcing the top line data, we focused on building out our Phase III development plans for XEN1101. We believe the X-TOLE data package provides compelling evidence of XEN1101's activity in the CNS, and our team is focused on finalizing the clinical development plans for XEN1101, including a Phase III program in adult focal epilepsy and likely other epilepsy indications. We expect to conduct a planned end of Phase II meeting with the FDA in the second quarter of 2022, followed by the initiation of our Phase III adult focal epilepsy program anticipated in the second half of 2022. In addition, the X-TOLE open-label extension, which has been expanded to 3 years, is expected to generate important long-term data for XEN1101. We are also advancing the clinical development of XEN1101 in major depressive disorder through an investigator-led Phase II proof-of-concept study with collaborators at Mount Sinai, and we intend to initiate a company-sponsored MDD clinical trial in the first half of 2022. In addition to these clinical advancements, we also continue to expand the intellectual property portfolio covering XEN1101, and we've made excellent progress on this front with 2 new U.S. patents issued to Xenon this year that we believe provides long exclusivity for XEN1101. We are excited to have the opportunity at AES to further educate and inform leading epilepsy clinicians and physicians about XEN1101. With its differentiated potassium channel mechanism of action, strong efficacy data and ease of use attributes, including once-a-day evening dosing and no titration, we believe XEN1101 could play an important role in treating adult focal epilepsy. For those of you who are attending AES, we look forward to connecting with you in person. And as always, you can set up virtual meetings to discuss the progress and plans for XEN1101 and the other innovative neurology-focused therapeutics in our pipeline. So I'll now ask the operator to open the line for any questions. Liz?

[Operator Instructions] Our first question comes from Brian Abrahams with RBC Capital Markets.

Congratulations on the continued promising data and appreciate all the details in the slides. Just a couple of questions for me. I guess, first off, on dosing and how you're thinking about dosing going forward. I mean if it looks -- if you take a look at the response rate analyses, the 75% and 100% responders, 20 milligram seems to be tracking about as good as 25 milligrams. And it also seemed to show a large drop in monthly seizures even though -- even if the medians were maybe a little bit less robust on the change versus the 25 milligrams. So just given what you're seeing there on efficacy with these -- with some of these new sub-analyses as well as some of the lesser AEs in terms of dizziness and weight gain, where do you -- how do you think about 20 milligrams as a potential go-forward dose? What's your latest view on what you might be taking into Phase III based on what you're seeing emerge here as well as maybe some of the other PK that you're looking at as well? And then I have a follow-up.

Okay. Thanks, Brian. I'll start, and Chris will add as well. So we haven't -- I mean, great question, and probably what we're spending most of the time internally is figuring out the final Phase III program, including the dosing. I think we were comfortable that we'll take 2 doses into the Phase III program. We haven't yet finalized the 2 doses, but obviously, in the range in which we've presented data so far between the 10 and 25 milligrams. I mean, your comments, I think, are good ones on starting to tease apart the differential between 20 and 25 milligrams, but we're just not there yet in terms of the final dose selection. But we do feel when we have the product eventually commercially marketed that there will be more than 1 dose available as obviously, we're seeing increased efficacy at the higher doses, but we need other doses for patients to go to if there are tolerability concerns or any AEs that are -- Chris, more detail?

Yes, sure. I mean, I think as I said when we presented the top line data, I think we're in a luxury position where we have 3 doses, all of which or any of which go forward into Phase III. To your point, comparing and contrasting 20 and 25, I think both doses behaved really well. Sort of both exceeded ezogabine, as an example. But when I look at the totality of the data, 25 milligrams, at least in my mind, outperforms 20 milligrams across the board. So as you look at the mean percent change in seizure frequency, as you look at the responder rates at 50%, as you look at clinical global impression of change, patient global impression of change. Across the board, all these sub-analyses that we shared today, 25 always outperforms 20 from an efficacy standpoint. And then on the safety side, there is a small cost for that increase in dose in terms of dropouts and common AEs like dizziness. But at least in my mind, as a clinician, I think that the benefits outweigh the downside by a substantial margin. That said, I think they're both good doses. And as Ian said, we're working through trying to figure which doses should go forward in the coming months.

Got it. That's really helpful. And then just maybe one more quick follow-up on the safety side. It looks like there was a little bit of blurred vision that seemed to be highest at the 25-milligram dose. Just wanted to clarify whether the patients, I guess, whether this was more related to kind of the spectrum of dizziness, somnolence and CNS AEs or whether -- and whether you had done any particular ophthalmologic exams on those patients, just given the pigmentation history with ezogabine?

Yes. So in terms of the safety, I mean this was a large trial, over 300 patients, but you think in the scheme of things in terms of figuring out what sort of safety signal is real or not, it really is on the lower side. And so I think that something like blurred vision, I would want to sort of pool a larger number of patients before I was convinced that anything was going on. I think what's behind that question, and tell me if I'm wrong, is could this be an indicator of something more ominous from an ophthalmologic standpoint? So as many of you know, ezogabine can dimerize because of its chemical structure, not because of its mechanism of action. And our chemical structure differs from ezogabine in an important manner that makes us think that this drug cannot dimerize. That said, we're in a enormous amount of effort in checking ophthalmologic examinations for all patients prospectively. And we haven't seen any pigmented changes in the retina in any of these patients from the ophthalmologic standpoint with like 80 -- more than 80 patients treated for over a year. So we're pretty confident, based upon the data set, at least where it is right now, that we're not having any ophthalmologic toxicity. And then the -- so does that answer your question?

That does.

[Operator Instructions] Our next question comes from Andrew Tsai with Jefferies.

Okay. Great. Thanks for sharing all these data sets. So I think the breakdown by efficacy -- by line of therapy, I mean, is interesting and might be underappreciated. So as I think about your Phase III studies and the design, would you guys consider enrolling a slightly less severe patient population? Or would you try to keep the aspect all the same? Maybe talk about that dynamic.

Thanks, Andrew. Yes, I think maybe just some high-level comments. Going into the X-TOLE study, I'm not sure we expected the type of patients in terms of kind of the difficult to treat -- the heavy pretreatment and failed ASMs and the high proportion of Con-Meds and the high amount of seizure burden at baseline that, going in, I don't think we expected that. And so once we saw the data and over the last month or 2, that we've had opportunity to kind of dig in and also review the literature, I mean, our comments that we believe this is probably one of the most difficult, if not the most difficult to treat patient population, and then you start to tease apart some of the efficacy by that disease severity. And as you see, the efficacy continues to improve, which I think is logical. Those with less failures and less Con-Meds and less baseline disease, we see those seizure reductions go even higher. So I think we're really pleased to see that. It really continues to add to our confidence that we're seeing remarkable consistency in the data set. As we think about the Phase III program, we haven't finalized the design, so I think it's a good question. I would say, overall, probably unlikely that we're going to make material changes. We had a very, very successful study, and so kind of our baseline going in is that the next study, the Phase III study will look very similar to the Phase II X-TOLE study, but maybe some adjustments kind of on the edges. But for the most part, it will probably look very similar. But as Chris Von Seggern has mentioned, we believe that the profile and some of these sub-analyses give us confidence in where the drug will be used eventually from a commercial perspective.

Can I add on that?

Yes. Of course you can.

Yes. So this is Chris. I would like to add on that a little bit, just kind of go kind of higher level. I mean, the critical path for this drug to approval is to get through the Phase III program, and so we want to get there as quickly as we can. And so any sort of restrictions that are made along those lines could slow us down. That's one thing. And I think more importantly, we're looking at X-TOLE -- we're positioning X-TOLE as the first pivotal trial in focal onset seizures. And we have yet to know whether FDA agrees with that position, but we'll find out soon. And so the more we deviate from that study design that was used in X-TOLE, the more it puts that approach at risk. And so you always want to kind of fine-tune things. There are some things that we can do, but we want to kind of keep that to a minimum because we're coming off a success. So don't fix it if it's not broken kind of thing.

Our next question comes from Paul Matteis with Stifel.

This is Alex on for Paul. Just wondering if you could provide a little bit more context on the dose-dependent weight gain you saw here? Curious how that compares to other anti-seizure medications, how you're thinking about it and whether -- I guess, in the high-dose group, you saw any association with cardiovascular signals?

Yes, sure. So this is Chris. Yes. So as I said, from the mean perspective, there was a modest increase. If you want to compare the -- the high dose of 25 milligrams to placebo, it was 1.9 kilograms versus 0.2 kilograms, so you have a difference of 1.7 kilograms, something on the order of 3 or 4 pounds in the high dose versus placebo. To add a little bit of color to that, we have looked at that data in the open label and that increase doesn't -- it tops out there. It doesn't continue to trend upwards. So it's -- to put it in the context of other anti-seizure medications, this is nothing along the lines of what has been seen with valproic acid, that's for sure. And then -- and so we're characterizing it as a modest increase in weight gain since it's sort of capping out on a mean level around less than 2 kilograms. So I don't think that this is any -- this isn't anything that we're concerned about. If you're -- I think the question about cardiovascular perhaps is tying it into are there any more ominous issues ongoing. So if you were causing excessive weight gain, could you end up with glucose intolerance? Could you end up with an exacerbation of obstructive sleep apnea or cardiovascular events? We're not certainly seeing anything along those lines. If your question was -- if those 2 questions were tied together, if the question about cardiovascular risk was just sort of a question on its own, we're not seeing anything in terms of imbalances on any of the interval changes on ECG, vital sign changes at rest or orthostatic, anything like that. So the cardiovascular signal as of yet is completely clean. Honest increases in weight, nothing that we think will slow down the development of this drug.

Our next question comes from Laura Chico with Wedbush.

I think the responder analysis looks pretty impressive. So I just have one follow-up on the weight changes, and I know you were just talking about this, Chris, but it sounded like this is also a bit variable in terms of gain and loss. And APA reported earlier this year that 61% of adults experienced undesired weight changes during the pandemic. And among those, the medium weight changes were plus/minus 12 to 15 pounds. So I guess my question would be, is what you're observing in these weight changes in X-TOLE, are these solely related to 1101? Or could this also be an effect of the pandemic?

Yes, I do think that -- so there's a lot of different ways of looking at weight gain, right? So we're talking about mean changes in the population. You can also look at outlier analysis, and we're presenting some of that at AES. So typically, in epilepsy, there's somewhat of an arbitrary cutoff of 7% used to define that. And so we are seeing more patients in the high dose group compared to placebo who had a greater than 7% change in weight. Most of those, almost all of them were an increase, not a decrease. But we did, to your point about the pandemic, half of those patients actually gained weight between screening and baseline, and so it's sort of artificially elevated, that number that's being presented at AES. That said -- so I think that some of this can be contributed -- attributed to the pandemic or whatever weight gain in general. But there is an imbalance in the treatment arm, so I don't think that you can completely chalk this up to COVID. And as you look at patients who were in placebo and then went into the open label, there is a similar pattern that we're seeing, sort of a 1 to 2-kilogram increase in weight. So we think that there is a real signal outside of COVID, where there's 1 or 2-kilogram increase over time that plateaus after exposure to XEN1101.

Laura, just to add to Chris' point, just so it's not losses. Just the way in our statistical analysis plan that weight gain was done is you average. So we go through -- patients go through a screening and then as you know, this baseline, this 2-month baseline period. And so the weight was averaged over visits, over those 2 to 3 months into the study before randomization and then through the double-blind portion. And so some of the weight gain may have happened before someone was actually randomized and on drug. But as Chris mentioned, I think the other -- so just to be clear on how the analysis is done. But as Chris mentioned, when we look at the kind of broader data set, including open label, we believe we're seeing a modest amount of weight gain with the drug.

And then -- and just to build on that, because of COVID, the baseline, we had to be flexible in terms of the duration of that baseline prior to randomization. And so some -- so it was, in some patients, substantially longer than what was planned. So more time for that weight gain to occur.

Our next question comes from Yatin Suneja with Guggenheim Partners.

Just a couple for me. Can you just put in perspective the seizure free rate that you are seeing with 1101 versus current channel of care? And then for patient with less than 8.5%, you gave us the number for 20 and 25-milligram arm. Can you maybe tell us what the number is for placebo? And then maybe one final question. Can you just talk about the -- Is there a mechanistic reason why we see a little bit different response depending on the motor seizure type you have? If you look at the data that you presented, I think Type 3, you are seeing a lower response but -- but very high in Type 4. Can you just talk about what the mechanistic reason there is?

I actually don't have that placebo number at hand right now. I have the difference between active and placebo, so I simply can't provide it to you even though I would like to.

Yes. Although the -- I mean, the overall seizure freedom rate in placebo is 1.8%. And so if we -- even if we looked at those with less seizure burden, it's still going to be a very low number because it's starting from a low number. We don't have that cut in front of us yet, but I think it's -- we really didn't see a lot of seizure freedom, obviously, in the placebo group. When we've looked at the literature very -- obviously, it varies, and our analysis suggests that it varies based on those characteristics of the patients. And so when you look at other clinical trials, often you see kind of low to mid-single digits in terms of seizure freedom. But these aren't perfect comparisons because they're cross-trial comparisons. And as we showed that our seizure freedom rate is into the teens, if you look at patients with -- with less severe seizure burden at baseline, which is probably more consistent in the range of what other studies had. So again, I think the for us, given the patient population, I think the data are very competitive and impressive overall. Chris, I don't know if you have anything on seizure freedom, but we should just talk about maybe the types of different seizures that we measured in the study and the Type 3 versus Type 4.

Yes. I mean, what I would say about the seizure freedom. I mean, if you think about the chance that somebody is going to respond to an anti-seizure medication. After they filled one, there's a pretty big drop and then even further drop. And once you get to 3 failures, I mean, you're sort of down into single digits in terms of the response rate for anti-seizure medication. So when you think about that, and you think about the fact that this population had a median failure of ASMs of 6, it's really quite amazing that there was anybody who was seizure-free, frankly. So I think that this is on par with other ASMs and perhaps better, even if you take into consideration the population. With regard to the seizure types, I would just be cautious having looked at a lot of clinical trials and slice the data in multiple different ways. You have to be careful when numbers get small. And so we saw a substantial improvement in Type 4 seizures, the secondary generalization. And that was definitely a real signal, we believe, in the 25-milligram and 10 for that matter. But I would be cautious about saying it's less effective in Type 3 just because of the numbers of patients. But I mean, even if it is, I mean, if I had the choice, I would certainly want to decrease generalized seizures given the risk with SUDEP and so forth.

Our next question comes from David Hoang with SMBC.

And thanks for providing this really great update. So I just had -- I had a question here, if you can bear with me. I'm just trying to eyeball some of the data from the cenobamate studies. And again, I recognize there's a caveat of cross-trial comparisons. But if I look at the cenobamate data, the seizure freedom rate, I think they're reporting like mid-20%, maybe like 25%, 28%, something like that. But the placebo rate is also, I guess, relatively high. You have about 9% of patients reporting seizure freedom. So can we kind of just, again, is that probably mostly stemming from the -- maybe the baseline population enrolled in the trial where maybe you have a more severe population? Is that sort of perhaps the right way to think or contextualize this data?

Yes. Yes, I'll make some comments and then Chris can jump in as well. Yes. I mean, we get a lot of questions on trying to compare to cenobamate and maybe a couple of comments. When we look at the prescribing information for cenobamate, they had 11% seizure freedom in their 200-milligram dose, and I think it was in the low 20s. I think it was like 20% or 21% in the 400-milligram dose. I mean, when you talk to clinicians and KOLs and we didn't add board yesterday where we spent a good part of the day. Really, it's 100 or 200 milligrams is the dose that's being used in the real world, so I think that's the comparison that we should be thinking about. And if we looked at their 2 studies, their median baseline seizure was 8.5%, and that's why we've done the 8.5% cut. So if you look at the 8.5% cut, we're -- for the 20 and 25 milligrams, we have a seizure freedom rate in the teens. And so again, with all the caveats of doing cross-trial comparisons that we just talked about, we're very comfortable in terms of kind of the competitive rate of seizure freedom that we're seeing with 1101. Chris?

Yes. Just a few things come to mind in terms of the comparison with cenobamate, I mean, first of all, you think about the mechanism. We believe, based upon preclinical data and the mechanism that we could have benefits beyond focal onset seizures, and so we're considering other options within the development plan. So based upon the mechanism, we see more flexibility there. Two, we -- to date, we don't have any sort of idiosyncratic safety issue which -- of concern that could emerge in the future, but it has not done yet, we don't have to worry about that. We don't -- we did not titrate this drug. We went right to the effective dose and saw benefits in the 25-milligram group within 1 week. And all the extent of the benefit that you're seeing at the end of the study was also 100% prevalent -- present at 1 week. And then the other thing I would say in terms of the comparison to cenobamate is if you look at like, let's say, median percent change in frequency -- a median percent change in seizure frequency, at the high dose, it's on par, but our placebo effect was actually less. So if you look at the delta between the 2, and I agree with you, it's difficult to compare clinical trials, although we do it all the time. The actual -- the delta there is on par, perhaps even bigger.

Got it. If I could just sneak in one quick follow-up. Just a comment on the American Urological Association Symptoms Index. If I'm reading that correctly, is this to say that those urinary retention events are reported may not sort of be so-called, I guess, real events if you go by I guess, the AUA classification? Is that sort of where that is coming from?

This is sort of an analogous situation to the weight gain, right? There's like a lot of different ways to look at safety. And I think you can look at a population and then you can also look at sort of an outlier analysis. And the scale that you're referencing, I would put it a little bit more on the crude side in terms of being able to detect a signal, so it's good that we're not seeing any changes. But I do want to -- I don't want that to diminish the fact that we did see urinary retention in 2 patients. One of whom had to decrease the dose, the other didn't. I mean, those patients didn't have to stop study drug. They didn't require any intervention. There were a long ways from being catheterized. But still, I don't want to minimize the fact that there were 2 patients with urinary retention. So this could change in time, but I think that there may be a signal in terms of urinary retention in 1% of patients. And I don't think it's anything that will slow down the development of the drug, but it's certainly something that we want physicians and investigators to be aware of so that there is no delay in a reaction sort of be more substantial in some patients.

Our next question comes from Tim Lugo with William Blair.

This is Lachlan on for Tim. So I was obviously looking at all the various subgroup analyses you've got there, and I was wondering from your perspective, both as a clinician but also from the market research, are there any there that kind of stand out as particularly meaningful or differentiated from that perspective?

Yes. So I guess in terms of the differentiators, specifically that stand out, clearly, the efficacy is what's been pointed to beyond the thing that's going to drive utilization. And we've heard that time and time again, even in recent ad boards is what [ Ian ] had mentioned, just really compelling interest in that efficacy data. Particularly as you move to earlier lines of therapy, where the data just get increasingly impressive. And when you think about true clinical use in the future, patients on 1 or 2 ASMs showed a markedly improved seizure reduction. And we imagine that that's the primary audience that would receive XEN1101 in the future rather than the more difficult-to-treat clinical trial population that has to, by nature, pass through many more therapies ultimately to get on a clinical product. In light of that efficacy, the other thing that clinicians point to is, and Chris mentioned this earlier, we see efficacy very quickly. And you have to put yourself in the frame of the patient, in the frame of the clinician, time that they're writing the product. This patient is likely seeking an additional therapy because they recently had a breakthrough seizure. That's why you changed drugs. And our product works remarkably quickly given the lack of titration. We're talking 1 or 2 weeks, you see therapeutic benefit. And that's simply unseen with other products where you can have to wait weeks, sometimes months, potentially still seeing seizures while you're going through that titration period. The combination of really significant efficacy combined with rapid onset of action and other candid ease-of-use attributes make clinicians really excited. Again, it's because of what they're looking at. This patient is seeking alternatives because they're having breakthrough seizures, and we have that ability to address that need very quickly. The last component, and we don't spend a lot of time talking about this, but it's important, it's often considered in this marketplace, one of the reasons for breakthrough seizures is missed doses. And in fact, there are several products that the clinicians will point to that if you miss 1 of your doses, 4 hours later, you're likely to have a seizure. We don't have that issue. We have protection for misdosage and it provides another level of comfort for the most concerning features in its marketplace of having a seizure. We have an attribute that potentially offers us a little bit of coverage and benefit in the event that a patient unfortunately misses a dose.

Yes. And I think all of this is coming from the mechanism, right? I mean, this is an entirely different mechanism than any of the other drugs are using. So that's why we're seeing the benefits in these patients who are heavily treated at baseline.

Our next question comes from Serge Belanger with Needham & Company.

A couple of questions for me. First one on the survey work that you've recently done with epileptologist. Chris mentioned that from that survey work, 1101 was viewed as potentially playing a role on par or similar to Vimpat. Just curious if that is in line with your expectations? And how it could guide your future Phase III trial design plans?

Well, I can answer the survey aspect of it. We saw coming out of the survey comparable utilization or expectations based on the 1101 profile without actually some of the more sophisticated analysis we've done over the last several weeks. And apples-to-apples comparison and from a profile, clinicians were pointing to utilization that it's in line with Vimpat, which as you know, is the commercial market leader today. And that does guide our thinking in terms of both expectations is where -- as well as where we're likely to play in a clinical use population. Vimpat is widely used as add-on therapy after patients pass through 1 or 2 generic medications and still has residual seizure burden.

Yes. I would just -- this is the other -- Chris. The only thing I would add is that we think we're differentiated in terms of the more novel mechanism of action. And again, there are always caveats with comparing clinical trials, but we're seeing what on the surface looks like more robust efficacy in a population of patients who has more -- more severe disease severity at baseline.

And a follow-up. Regarding the open-label extension trial, I think Ian mentioned that 80 patients have now been in that trial for 12 months. Curious when you expect to start reporting data from that trial?

So the trial is ongoing. As we mentioned, we based on feedback and asks from clinicians, we had extended that to 3 years. I had mentioned on our Q3 quarterly call that we will be doing a more formal cut of that data as we prepare for our end of Phase II meeting with the agency, and so I'd expect that you'll see some more of the open-label data in 2022.

That concludes today's question-and-answer session. I'd like to turn the call back to Sherry Aulin for closing remarks.

Great. Thanks, everyone, for joining us on our call today. Operator, we'll now end the call.

This concludes today's conference call. Thanks for participating. You may now disconnect.