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

Hello, and welcome to the Xenon Pharmaceuticals announces topline results from X-TOLE clinical trial conference call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Sherry Aulin, Xenon's Chief Financial Officer.

Good morning. My name is Sherry Aulin, and I'm Xenon's Chief Financial Officer, and I will be moderating the call this morning. Thank you for joining us on our call and webcast to discuss our topline results from the Phase IIb actual clinical trial of XEN1101 for the treatment of focal epilepsy. Joining me on today's call are Ian Mortimer, Xenon's President and Chief Executive Officer; Dr. Chris Kenney, Xenon's Chief Medical Officer; and Chris Von Seggern, Xenon's Chief Commercial Officer. For those of you on the webinar, there are slides accompanying this commentary from the executive team. At the end of the prepared remarks, we will open up the telephone lines for question-and-answer session. 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 and 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. A news release summarizing the actual topline results, which was issued this morning, will be filed with an accompanying Form 8-K the SEC and on SEDAR, and will be made available under the Investors section of our website at www.xenon-pharma.com. Now I would like to turn the call over to Ian.

Thank you, Sherry. Good morning, everyone. Thanks for joining us today to review the positive topline results from the XEN1101 Phase IIb X-TOLE clinical trial. This is an incredibly exciting day for the entire team at Xenon that has worked so tirelessly on this well-designed and well-executed clinical trial, and we couldn't be more pleased with the results. I want to touch on a few highlights from today's results before turning the call over to Dr. Chris Kenney, our Chief Medical Officer, who will review the X-TOLE efficacy and safety data in more detail. Then I will ask Chris Von Seggern, our Chief Commercial Officer, to comment on these data in the context of the extensive market research we have done in the adult focal epilepsy market. We have generated incredibly compelling evidence that supports the efficacy, safety and tolerability of XEN1101 and suggests high activity in the CNS. Importantly, we saw a statistically significant reduction of focal onset seizures compared to placebo across all dose groups, with a 52.8% reduction in monthly seizure frequency within the 25-milligram dose group compared to 18.2% in the placebo group. The strength of the efficacy data is confirmed by p-values of less than 0.001 for the primary efficacy analysis of the monotonic dose response as well as the 20-milligram and 25-milligram doses in the paralyzed comparison as well as the 50% responder analysis. The data from the primary efficacy analysis are markedly consistent across the efficacy endpoints and have exceeded our expectations. XEN1101 was generally well tolerated in this study with adverse events consistent with other commonly utilized anti-seizure medications or ASMs. There were no pigmentary abnormalities reported during the double-blind study or during the open-label extension to date with now 70 subjects treated more than 12 months. We are incredibly excited by these data, which suggests that XEN1101 has the potential to offer compelling efficacy combined with other ease-of-use attributes such as QD dosing in the evening, no titration and broad-spectrum activity. We believe these are key elements that could make XEN1101 a highly attractive agent in the future in the adult focal onset seizure market. With these results in hand, we will now turn our attention to developing XEN1101 as expeditiously as possible given the significant unmet medical need for adult patients with focal epilepsy. I'll provide some summary comments at the end of the call. But now, I'd like to turn the call over to Chris Kenney to provide some additional detail on today's data. Chris?

Okay. Thank you, Ian. It's a pleasure to be able to speak to everyone today and review the positive data generated from the X-TOLE clinical trial. Before I dive into the details, and as a reminder, X-TOLE was designed as a randomized, double-blind, placebo-controlled global multicenter Phase IIb study to evaluate the efficacy, safety and tolerability of XEN1101, administered as once daily adjunctive treatment in adult patients with focal epilepsy. The study result include a total of 325 randomized and treated subjects in the safety population, and 325 subjects in the modified intent-to-treat population for the efficacy analysis. Of the 285 subjects who completed the double-blind period, 96.5% entered the open-label extension to evaluate the long-term safety, tolerability and effectiveness of XEN1101. This high rollover rate provides important insight into the comfort of clinicians and their patients with the overall benefit and tolerability profile of XEN1101. As noted on this slide, the primary objectives of the X-TOLE study were to assess the efficacy of XEN1101 compared to placebo on focal seizure frequency while also assessing its safety and tolerability in adults with focal epilepsy taking 1 to 3 anti-seizure medications in the double-blind period. We're pleased to confirm that the trial met its primary efficacy endpoint with XEN1101 demonstrating a statistically significant dose-dependent reduction from baseline in monthly focal seizure frequency when compared to placebo. In other words, the monotonic dose response with a p-value of less than 0.001. Key secondary efficacy measures included a pair-wise comparison of each active dose to placebo and the proportion of patients who achieved a 50% or greater reduction in monthly focal seizure frequency from baseline. I'll go into more detail on these results in the following slide. Now when analyzing the demographics of the safety population, we believe the study arms were well balanced across age, gender and region. Subjects had an average age of 40.8 years and the median baseline seizure frequency across the study groups was approximately 13.5 per month. Of particular relevance, to put the efficacy data into context, approximately 50% of subjects were on 3 background antiseizure medications with about 9% and 40% on 1 or 2 background antiseizure medications, respectively. Subject to the X-TOLE study had failed a median of 6 previous antiseizure medications prior to study entry. Now when we analyze the literature, we've not been able to find another focal onset seizure study with half the subjects on 3 background antiseizure medications. And many studies actually excluded patients with 3 ASMs. In this context, it was very difficult to treat patient population. The XEN1101 efficacy data are quite remarkable. Turning now to the positive efficacy results. As noted, the primary objective of this study was to assess the dose response trend of XEN1101 in reducing monthly focal seizure frequency based on a ranked ANCOVA model. The median recent reduction in monthly focal seizure frequency was 52.8% in the 25-milligram group, 46.4% in the 20-milligram group, and 33.2% in the 10-milligram group compared to 18.2% in the placebo group. As stated earlier, the monotonic dose response relationship between XEN1101, active dose groups compared to placebo was statistically significant with a p-value of less than 0.001. These data suggest a clinically meaningful dose response relationship for XEN1101 in the adjunctive treatment of focal seizures in adult patients. As I mentioned earlier, we believe these data are even more impressive when taking into consideration the history of these patients in terms of their exposure to previous antiseizure medications and the number of concomitant antiseizure medications while on study. In addition, XEN1101 demonstrated a statistically significant reduction from baseline in monthly focal seizure frequency compared to placebo for all 3 XEN1101 doses in pair-wise comparisons between each dose and placebo with 2-sided p values of less than 0.001 for 25 milligrams versus placebo, a p-value of less than 0.001 for 20 milligrams versus placebo, and a p-value of 0.035 for 10 milligrams versus placebo. These efficacy data strongly suggests that XEN1101 is highly active in the central nervous system. A key secondary endpoint of the study was a responder analysis, which compares the proportion of study subjects treated with XEN1101 who achieved a 50% or greater reduction in monthly focal seizures versus placebo. The percentage of subjects who achieved a 50% or greater reduction in monthly focal seizures was 54.5% in the 25-milligram group, 43.1% in the 20-milligram group, and 28.3% in the 10-milligram group compared to just 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 25 milligrams versus placebo, p less than 0.001 for 20 milligrams versus placebo and a p-value of 0.037 for 10 milligrams versus placebo. Additional secondary endpoints evaluated the clinical global impression of change and the patient global impression have changed scale. These results show that 46.4% of clinicians rated their patients as having much improved or very much improved in the 25-milligram dose group with 2-sided p-value less than 0.001. A similar result was seen with the patient global impression of change scores with 42.9% of subjects reporting much improved or very much improved in the 25-milligram group with a 2-sided p-value less than 0.001. In addition, the XEN1101 20-milligram dose was statistically significant in patient global impression of change, while the XEN1101 20-milligram in clinical global impression of change and XEN1101 10-milligram dose for both clinical global impression of change and patient global impression of change showed numerical improvements over placebo, but were not statistically significant. As a clinician, these data are extremely important as it takes into consideration the benefit for the patient in an overall composite endpoint and speaks not only to the strength of the efficacy, but also the overall safety and tolerability profile of XEN1101. Turning now to the safety and tolerability profile of XEN1101, which was generally well tolerated in the study regarding adverse events that were consistent with other antiseizure medications. The incidence of treatment emergent adverse events was higher in the treatment groups as compared to the placebo group with 62.3% of patients in the placebo group, 67.4% of efficiency in the 10-milligram group, 68.6% of patients in the 20-milligram group, and 85.1% of patients in the 25-milligram group experiencing at least one treatment-emergent adverse event. It's important to note -- very important to note that the incidence of treatment-emergent serious adverse events, or SAEs, was similar in all 4 arms of the study with 2.6% of patients in the placebo group, 4.3% of patients in the 10-milligram group, 3.9% of patients in the 20-milligram group, and 2.6% of the patients in the 25-milligram group experiencing at least one SAE. Furthermore, the vast majority of AEs in the treatment groups were mild or moderate and consistent with the XEN1101 mechanism of action exerting its effect within the central nervous system. Regarding adverse events leading to study discontinuation. There were 3.5% of subjects in the placebo group, 2.2% of subjects in the 10-milligram group, 13.7% of subjects in the 20-milligram group, and 15.8% of subjects in the 25-milligram group that had an adverse event leading to study discontinuation. To provide a bit more color on the AE profile, the most common treatment-emergent adverse events across all XEN1101 dose groups were dizziness, 24.6%; somnolence, 15.6%; fatigue, 10.9%; and headache, 10.0%. The treatment-emergent adverse event rates are in the range that are consistent with other antiseizure medications and rates that were expected. Two treatment-emergent adverse events of urinary retention were reported in the active treatment groups from a total of 211 treated patients on active drug. Importantly, these were of short duration, one required a dose reduction and both subjects remained on drug with no other changes or intervention. This is in contrast with ezogabine, which cause urinary retention to the extent that some patients required catheterization hospitalization. Therefore, overall, we're not concerned with these urinary symptoms given the 1% rate, transient nature and no need for intervention. Electrocardiogram interval changes were infrequent and evenly balanced between placebo and active treatment groups. There were no pigmentary abnormalities reported during the double-blind study or during the open-label extension to date with 70 subjects now treated more than 12 months in the open-label extension. Overall, the safety and tolerability profile of XEN1101 is in line with other antiseizure medications and what is expected, given XEN1101 appears highly active in the central nervous system. The X-TOLE results generated from this large multicenter controlled trial are truly exciting because they demonstrate impressive efficacy of XEN1101 for adult patients with focal epilepsy, including those seizures that are deemed difficult to treat when compared to other clinical trials. In addition, patients will benefit from XEN1101's other important attributes such as once-a-day dosing in the evening with no need for titration. Given XEN1101's unique potassium channel mechanism of action, and the strength of these data, we believe XEN1101 could play a very important role when treating focal epilepsy in the future. With these compelling topline results in hand, we're eager to work with FDA to plan for an expedited development path moving forward. I think it's a good segue to turn things over to Chris Von Seggern who's going to comment on the commercial potential for XEN1101 based on insights from key opinion leaders and prescribing physicians. Chris?

Thanks, Chris. Briefly, by way of background, prior to the X-TOLE topline readout, we conducted primary market research in a blinded fashion with 50 clinicians ranging from academic epileptologists to high-volume prescribing neurologists and epileptologists across the U.S. Those interviewed indicated that an enduring unmet need remains despite the availability of numerous antiseizure medications for the treatment of adult focal FLS. Physicians emphasize that high clinical unmet need exists, particularly among patients who are not well controlled despite being treated with multiple drugs in a polypharmacy approach. Our research suggested that the majority of patients are exposed to 1 of 2 commonly prescribed antiseizure medications, either levetiracetam or lamotrigine early in treatment. These agents use either as monotherapies or in combination with additional ASMs are insufficient to address the seizure burden in approximately 50% of adult FOS patients. Patients next frequently cycle through multiple therapies, seeking improved seizure control. And it is typical at this point when branded ASMs enter the equation. With the impending off of exclusivity for [ VIMPAT ], we believe an opportunity exists for XEN1101 to compete for first branded use for these patients. The results of our prior market research suggested that the potential profile of XEN1101 was compelling, given an anticipated efficacy profile that was in line with current standard of care. As a reminder, we modeled 35% reduction in the 25-milligram treatment group, a comparable safety tolerability profile to existing ASMs along with the differentiated ease-of-use attributes such as QD dosing and no titration. Given the substantial efficacy demonstrated in the external results, combined with all that we have learned from our prior 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 the therapeutic armamentarium for this disease. In summary, we believe XEN1101 has a very compelling overall profile and to summarize this value proposition below. XEN1101 has demonstrated compelling efficacy in X-TOLE, and this efficacy is even more impressive given the history of the patients in their prior current ASM use. With a novel mechanism of action, XEN can facilitate combination use with other drugs in a polypharmacy approach. XEN1101 has strong ease-of-use characteristics, including one pill once a day, no titration and forgiving PK for mystosis. The safety and tolerability profile today is predictable and is as expected and in line with other ASMs. Given its mechanism of action, combined with clinical evidence of CNS activity, XEN1101 may have an impact on mood, which could be another differentiator in epilepsy given the significant comorbidity of depression in this patient population. Overall, the profile of XEN1101 is very compelling, and we are excited for its continued development and the opportunity to have a meaningful impact on patients. I'd now like to turn the call back over to Ian for some concluding remarks. Ian?

Thanks, Chris. So in summary, we believe that these data generated from the X-TOLE study suggests XEN1101 could be a highly competitive ASM in the future adult focal seizure market. Further, we believe that the strong efficacy demonstrated by XEN1101, combined with its unique mechanism of action and other desirable attributes that are sought after by physicians when treating adult patients with focal seizures, clearly differentiates XEN1101 from other ASMs. Additionally, the strong efficacy data signal activity in the central nervous system, which further supports our plans to develop XEN1101 in other indications including major depressive disorder and potentially broaden the opportunity in other types of epilepsy. So in closing, I'm incredibly proud of the entire Xenon team. I'd like to take a moment to thank our XEN1101 X-TOLE steering committee members, the clinicians who participated in X-TOLE and their patients, and for all of our Xenon employees for their support that helped us reach this important milestone today. I believe that the results announced today mark a transformational moment for us as a company and I'm excited to keep you updated on our progress as we continue to advance XEN1101 and the rest of our neurology focused pipeline. I will now ask the operator to open the line for questions. Given that we do have limited time, please limit to one question each. We will end the Q&A session at 8:15 Eastern Time, but we'd be happy to follow up with each of you throughout the rest of the day. Operator?

[Operator Instructions] And your first question will come from the line of Paul Matteis with Stifel.

Great. And congrats and team on the data. Just one question on safety. Can you just talk a little bit more granularly about the SAEs and also the adverse events that led to treatment discontinuation. What drove the imbalance in SAEs? I know it's small, but is there any sort of pattern there to keep in mind? And how are you kind of thinking about that more broadly?

Thanks, Paul. So maybe I'll make a couple of comments, and then I'll pass it to Chris Kenney to provide his perspective. So as we stated in the release and on the call, we don't think there's any imbalance in SAEs across the different treatment groups. For the -- just as a reminder, for the 10-milligram and 20-milligram arm, smaller number of patients than in the 25-milligram arm in placebo, and we have the exact number of SAEs in 25 milligrams in placebo. And there wasn't any trend there. It was just we -- just different SAEs throughout. So no trend and no concern from our perspective. On the discontinuation in terms of the overall adverse event profile, Chris can comment on that. It's really driven by, as we would expect, some of the AEs that we're seeing in the study. But Chris, maybe you can give a bit more color and anything you wanted to add on the SAE side.

Yes. On the SAE side, I'm very confident and we've shared this data with our steering committee as well that there really is no imbalance in SAEs. That's our position. Regarding the adverse events leading to discontinuation, there's -- you'll see, Paul, that there's sort of a dose response -- that there's an increase in the total number of adverse events as you go across from placebo with increasing dose. And then we've also sort of given the overall numbers for the adverse events that were most common and there's a dose response within those as well. And so we're going to be sharing all that detailed data in an upcoming medical conference. But what I can assure you is that the details of that don't change the overall risk benefit profile of the drug.

And your next question comes from Andrew Tsai with Jefferies.

Okay. Great. Congrats on the data. Props on the execution, especially during COVID. So my question is about next steps for 1101. What do you plan to discuss specifically with the FDA? How quickly could we hear resolution on next steps? And as a corollary, given the strength of the data, high p value, I mean, could it make sense to see if the FDA would be willing to let you file on Phase II data? Is that a scenario you are willing to entertain with the FDA, given that you are looking for an expedited path forward?

Thanks, Andrew. So maybe a couple of comments from me, and then I think Chris should jump in on this one as well. Obviously, these data are extremely compelling. And the consistency is remarkable across the different efficacy endpoints. So we're still at topline. So we need to continue to obviously get to a final CSR and then get ready to get in front of the agency and other regulators as well. As we said in the past, we will go -- we'll get to an end of Phase II meeting, and we'll have that discussion with FDA on what the path would be forward. I think it's unlikely to answer the last point of your question that we could file on these data. I think that's highly unlikely. But we do believe that these data are compelling and we will make all of the arguments that this could be one of the 2 registration studies. But obviously, that will be a discussion with the agency. And then even more broadly in terms of the development of 1101. With these type of data, obviously, we're -- we've committed to doing work in depression. The Mount Sinai study is now initiated. And we're working hard to get our own company-sponsored study up and running. And as I mentioned in the prepared remarks, we are looking at other types of epilepsy as well given the profile of 1101 and the compelling data. Chris, anything to add to those comments?

Well, I would just say that, obviously, this is a historic moment for Xenon. And the data, as Ian has stated, are really quite incredibly compelling. And so there's going to be a huge amount of effort placed on trying to get -- to go to the next step from a regulatory perspective and getting to an end of Phase II meeting as soon as possible. So you can be sure we're doing everything we can to get there as quickly as we can. And then as far as the pivotal question, is this study going to be considered adequate and well controlled from a regulatory perspective. We're certainly going to position it in that manner. And I personally haven't come across anything that has suggested that we shouldn't do that. So -- but it's all dependent upon how the conversation goes with FDA.

And your next question comes from the line of Marc Goodman with SVB Leerink.

This is Rudy on the call for Marc, congrats on the data readout. I think the efficacy data looks pretty robust. So regarding baseline characteristics for the patients who enrolled in the trial, how does that compare with the patient study in the clinical trials of other products like lacosamide and cenobamate?

Thanks, Rudy. So Chris made these comments in his prepared remarks, but I think they're worth reemphasizing, and Chris and his team have done more work on looking at the literature as well, so he can go into more detail. But at least on our look at whether it be cenobamate or other drugs that have been developed and our look at the literature, we believe this was a much more difficult to treat population. A higher number of prior ASMs that they had failed and a higher number of ASMs that they were on at baseline, that stable dose coming into the study. Just as a reminder, we had about 50% of the patients were on 3 background medicine. We haven't seen that level of background medication and background ASMs when we've looked at -- when we were spending the weekend looking at the literature. So I think the data, when you put into the context of the types of patients that were treated in the study even more impressive. But Chris, I know you guys watched it in more detail. Any comments to add?

Well, if you sort of compare this study to the Phase IIb study that was done with ezogabine just as one example, 1/3 of the ezogabine patients were on one ASM and about 2/3 on 2. And almost no patients on 3. So it was really much less sort of treated in terms of the overall population. And then in cenobamate, I don't think it's quite as dramatic. But if you take a look at the number of ASMs and you look at the number of median seizures at baseline, our population, I think, is more impaired from a disease severity perspective. And so I mean, like I said, we haven't been able to find a study that was more aggressively treated in focal onset seizure. It doesn't mean that we couldn't be missing one, but we haven't been able to find one yet.

That's very helpful. And congrats again on the data.

Your next question comes from Yatin Suneja with Guggenheim Partners.

Really very good results. Better than I would say most of us were expecting. So congrats on a great execution. Question on the AE profile. I know you disclosed the blended data for all the arms in terms of the key AEs. Could you maybe give us a sense of, was there any meaningful difference between, let's say, 20-million and 25-milligram versus the overall? So that's one question. And then anything on the mood effect that you saw or are you able to absorb? If so, how was that measured or how was that measured?

Maybe I'll take -- Chris, maybe I'll take the last one on the mood effect and then if you want to just talk about the kind of dose dependency in the adverse events. I think we've touched upon that earlier in the Q&A, but we can address it again. So just to remind people because we've had a lot of questions, we know that about 30% to 50% of patients with adult focal epilepsy have the comorbidity of depression. And we know that the potassium channel mechanism of 1101 has strong validation in depression with ezogabine, both preclinically and also clinical studies that were run in patients with depression and anhedonia. For the X-TOLE study, there were no scales of depression or anhedonia that were done at baseline or during the double-blind portion. One of the exploratory endpoints was on quality of life, and there is some well-being characteristics of the quality of life measures. That's an exploratory endpoint. It's not part of our top line analysis, and we're still working through those data. So we've got nothing to provide an update at this time. Maybe -- but obviously, we're -- now that we have the data overall in terms of the activity in the CNS, we're really excited to get going on the depression work and seeing the breadth of -- the potential breadth of the efficacy of 1101. Chris, maybe you can just talk a bit about the AE profile overall?

Just a quick comment on mood. I mean, just for those of you who don't know ezogabine, which has a similar mechanism in action, they completed a proof of concept in major depressive disorder and suggest that there may be some activity. So I mean, we're going to do the same with XEN1101. So our position -- we want to see if the drug actually improves mood. With regard to the current study in terms of the adverse events, all I can tell you is that there's nothing that suggests that XEN1101 is worsening mood from a depression or an anxiety perspective. You'll have to forgive me, but the answer to the adverse event is basically the same one I gave, Paul. So if you take a look at the overall treatment emergent adverse events, you'll see that the total amount went up as you go from placebo to the higher dose. And we also shared the most frequent adverse event. And there's a similar trend that you see with those most frequent adverse events as to the overall similar to the overall treatment emergent adverse events. And we're going to share all that data in great detail, but does it change the overall risk benefit profile of the stroke.

Your next question comes from Tim Lugo with William Blair.

And congratulations on just really incredible data. I know you settled in on 20 mg for the OLE portion of X-TOLE and whether the X-TOLE is fileable or not, I know there's probably going to be a lot of additional exploration. Can you just talk about where you think the 25 mg dose will fit in for future studies? And if future studies are in patients with less concomitant ASMs. Are you going to explore lower doses for that population? Or if the 25 mg will continue to be kind of explored going forward?

Thanks, Tim. Great question and a question that's had a lot of debate over the weekend, have seen on, which is what are the doses that we move forward with. And I don't think we have -- we don't have a final answer for you. I can give a little bit of information and then Chris should weigh in with his perspective. I think what was really remarkable about the data was the dose-dependent profile we saw. We had questions going in on, would 10 milligrams be efficacious based on exposure? And obviously, it is. And then we also had separation -- clear separation between 20 and 25 milligrams. So the team absolutely nailed the doses going into the study with the dose response that we're seeing across the efficacy endpoints. So I think we have a lot of flexibility as we think about the future development of 1101. We don't have PK data yet from the study. So as we get PK data and exposure, that will obviously be something that we'll take into consideration as we think about the doses going forward. But that's maybe a little bit of background. And Chris, you've thought about this a lot also.

Yes. Well, you can imagine, things are moving pretty quickly with the data that we have in hand and everybody is sort of expressing their opinion about what we should do going forward. I think we're in a luxury problem, which is pretty much what Ian just said, which is that, I mean, you can make an argument to move any or all of these doses forward. What's clear to me is that I think the tolerability and safety of the 10-milligram dose is pretty much identical to placebo, which is nice, and that the efficacy of the 25-milligram group is the best. And the totality of the data on 25 milligrams, if you look across the seizure reduction endpoints and then also CGI and PGI, it's clearly from an efficacy standpoint, the best, but there was a slight increase in dropouts because of adverse events, but there was a small price to be paid there. So you can imagine that we're discussing it, and that's one of the things we need to figure out as we kind of make our way to end of Phase II. So luxury problem. Any one of those doses could be moved or all of it.

It's a great problem to have. And congratulations on incredible data. Maybe if I could just sneak one more in. Can you talk about suicidal ideation? I know that you were kind of pointing to quality of life in terms of getting some signs on mood benefit, but I think suicidal ideation was also being captured in the study?

Yes, we -- sorry, Ian, go ahead.

No, no, no. Keep going, Chris.

Okay. Suicidality for sure, it was captured. It wasn't part of the topline. And so there wasn't anything that emerged from a blinded perspective leading up to database lock that we were concerned about, but we still need to look at that. You can be sure that we're going to tease that apart as well as we can. Based upon the mechanism -- well, based upon the AEs, we're seeing no worsening of depression or anxiety. And we're going to take a close look at the CSSR. I mean, the drug is in development for major depressive disorder. So we actually have a hypothesis that the reverse is true. And obviously, suicidality is something that's in the label for all of these antiseizure medications, and there's recent facility publication recently within the past week or 2, but there's a lot of pushback from the academic world that's inappropriate. So you can be sure we're going to be going to the table with FDA with all of that data and trying to make the argument that you can imagine.

And your next question comes from David Hoang with SMBC.

And like everybody else, congratulating you on the data. [indiscernible] in terms of the high-dose 25-milligram efficacy you're seeing there, can you remind us a little bit as to how that compares to some of the other agents out there? I know agents such as [indiscernible] on some of their efficacy endpoint, maybe just help set in the context for us?

Yes. Thanks, David. Sorry, you're cutting in and out a little bit, at least, on my line. I think the question was -- just put the 1101 efficacy into context with other ASMs. Is that the gist of it?

Yes, you got it.

Okay. Right. Maybe I'll make a couple of comments and then Chris Von Seggern and the work that you and the commercial team have done in terms of looking at where 1101 would fit in, would love to hear your perspective on this. As many of you know, because we spend many hours talking about this coming into data, we thought that efficacy really didn't differentiate when you looked at the broad group of ASMs that are labeled or available for this patient population. And we expected that we would clearly differentiate on the ease-of-use attributes. And if we were in range of efficacy in that 30 to 40 median, the NPC, that we would be -- we'd have a very compelling profile. Obviously, we've really blown through that in terms of efficacy. So we believe efficacy now is clearly differentiated from the group as well as the ease of use attributes. And as Chris Kenney spent a fair bit of time, we believe that the AE profile is really what you would expect when we think about those large categories. But Chris Von Seggern, can you provide your perspective as well?

Yes. Ian, to build on this, I think, again, as Ian had mentioned, we're definitely at the high watermark from an efficacy standpoint. And in particular, when you compare placebo-adjusted efficacy for the 25-milligram arm, we're in a position that is, again, at the very high end of the category, particularly for the most recently launched products as we've seen those numbers come down over time given the use of background antiseizure medications and clinical trials. So we feel that this product, again, as Ian just mentioned, is going to be amongst the best in the category from an efficacy standpoint. And then when combined with other attributes, will, in fact, very significantly differentiate us from an ease-of-use standpoint, onboarding patients and the ability to use the product in combination for difficult-to-treat patients. We think the profile is going to stack up very favorably against the competition that exists in that space.

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

I'd like to also offer my congratulations on the solid data. I guess, a question for Ian. You said you had over 90% of patients in the trial that were at least on 2 antiepileptic drugs. Can you just maybe comment on which one -- which were the most common of these AAVs?

Thanks, Serge. I actually don't have that data in front of me. Chris, do you have any of that information? If not, that's something that obviously we can disclose as we go into a deeper data release at future medical meetings. But I don't know if you have any commentary on the types of drugs. I think it would be everything that we would expect these patients to be on in terms of the other drugs that are available.

Yes. I mean, we're obviously going to be sharing that in great detail, but there weren't any surprises from that perspective or any significant sort of regional differences either for that matter.

Okay. Maybe if I can sneak one more. Just trying to figure out what was the overall COVID impact on the trial, mostly on the enrollment delays and just trying to get an idea of if you had to repeat a similar trial, what would be the more regular time line post-COVID that you could complete such a trial?

Yes. I mean, we've talked about COVID with the Street over a number of different quarterly calls. COVID had a material impact on screening and enrollment really in the summer months of last year. And that's because patients couldn't get to their clinics in terms of the randomization visits or even some of the screening visits. So there was a period of time -- pre-COVID screening was going really well, and then we mentioned we had a number of months where it was very, very challenging. And then the screening picked up again towards kind of last fall at the end of last year. And as a reminder, we completed screening in the spring of this year. So it really did pick up. I think very difficult to predict what the COVID impact is going to be in a study that would start in the future, although we all are getting used to living in the pandemic. So I expect that as we saw in the last part of last year and the first part of this year that, that screening really picked up. The other benefit, obviously, that we have is we now have these data. And so the ability to get clinicians excited to participate in the clinical trial on the backs of these data. I think our perspective is that the next study will be easier to run definitely the next, more or less.

And I'd just like to add on to that, if you don't mind, which is that, I mean, if you think about the fact that this study was ran so well during a pandemic, you can be sure that what we're going to try to do when we go back for a subsequent study is to lean on the same sites that did a good job, right, trying not to reinvent the wheel. I do have a better answer to your question about the concomitant antiseizure medications because I pulled up the table in the interim. So the top medications that were used procedures in this trial were lamotrigine, lacosamide, coluracetam, clobazam, levetiracetam, basically your sort of usual suspects.

Your next question comes from the line of Laura Chico with Wedbush Securities.

Congrats on the data. Just real quickly, given the responder rate analysis data, I'm curious to when we might get any insight into seizure freedom results? And then I'm not sure if I missed it, but any additional color on what doses at which the urinary retention happened?

Thanks, Laura. So yes, we -- in the top line press release, we got it out as quickly as we could in terms of the primary and the secondary efficacy analyses. And these are the results that we said that we would put in the top line press release. Obviously, we are -- on the responder analysis, you can break them into quartiles on how the patients have done, whether they've gotten worse or whether they've gotten better and in which quartile they got better in terms of seizure reduction. So we'll be in a position to present that data in the future. In terms of -- what was the, I apologize, second question was on...

Yes. Sorry. Just on urinary retention, I don't how I missed it, but just the doses at which that was occurring and just maybe quickly recap of elimination efforts for 1101 versus ezogabine?

Yes. Thanks, Laura. I'll start and then Chris can add his perspective. So we got 2 patients with urinary retention. They were in 2 different groups. We haven't disclosed the actual doses, but they were in 2 different groups. And as Chris mentioned in the prepared remarks, we've had -- we had 200 patients on active drug in the study. So it's a less than 1% rate. One patient needed a dose reduction. The other didn't. These were transient. And both patients stayed on drug. So I think when we look at that overall, very difficult to understand whether that's signal or noise. We will continue to monitor it, but there's nothing either from our perspective or from the steering committee's perspective that concern them in terms of looking at those data, specifically for urinary retention. Your last question was on root of elimination. We had always said that we thought that the risk for urinary symptoms with 1101 was likely lower than ezogabine and that's proven out. And we don't know exactly why, whether it be based on the Kv7.4 expression in the smooth muscle of the bladder or that ezogabine is primarily renally excreted and 1101 is not. So it may be a combination of those things. But Chris, anything to add on the specific AEs and any concern?

Well, just the ezogabine data, the frequency was a little bit higher. I mean, they had a larger safety database, but the frequency was higher and the sequela were more serious, right? Some patients had to be catheterized. In fact, there was one patient that required self-catheterization, I believe on a permanent basis. What was seen with ezogabine was that there was a dose response to the urinary retention. We're going to share all that data in a subsequent medical conference. But I think it's important to keep in mind that both subjects stayed on study medication. They didn't -- they weren't hospitalized. -- did catheterized. It was very manageable. But it did occur in 2 patients.

And your final question comes from Antonia Borovina with Bloom Burton.

Just want -- everyone say, congrats again on the -- data. My question is related to the pigmentation side of that. So you mentioned you didn't see any instances of that. I'm just wondering what measurement did you look at to come to the conclusion? And given the fact that now we have 70 patients that have proceeded to the 1-year mark in the open-label extension, do you believe this concern is largely defined at this point?

Thanks for the question. Maybe I'll answer the second part of it. And Chris, you can go through the first part in terms of what measures we have to pick this up if there was a signal. Look, we've been very clear since the beginning that we believe, and we believe that there is strong scientific support, that the pigmentation with ezogabine was related to the chemistry and the dimerization of that molecule under oxidative conditions. And our position has always been that 1101 doesn't -- can't dimerize. It doesn't have the structure that allows it to dimerize. So from our hypothesis going in is that we wouldn't have seen any pigmentation based on the chemistry of 1101 and obviously, that's proven out. How big a database do we need to convince everyone, I think we're very comfortable with. Obviously, we now have more than 70 patients that are out more than 12 months. And if you look at the ezogabine data for when they were -- when they knew that it was a risk and they were looking for it, that it would have been picked up in this time frame. But Chris, maybe you can just walk through some of the tools we use to make sure that we're monitoring this.

Yes. So I mean, obviously, we're looking at adverse events. That's the key thing. And then on top of that, the ophthalmologic examination is the other component that's very important. Just keep in mind that mechanisms of action don't dimerize, chemicals do, and I'm not a chemist, but based upon what our chemists are saying that this drug really shouldn't dimerize. That said, it obviously happened with ezogabine and played a major role in terms of it not being on the market right now. So we're going to keep an eye on it. And I would just say that I don't think we can say that it's a done deal at this point, that we want to keep following these patients long term the beauty of this open-label study is that it's going to be 3 years long, and then we'll have an open-label extension for the Phase III work that's done as well. So I think -- I'm not saying -- I don't think now, but I think by the end of the day, we'll be able to put this issue to rest. And I would say this, I think that it's more -- the fact that we're looking at systematic ophthalmologic examinations is a lot better in terms of picking up a potential signal than what they were doing with ezogabine, which they didn't know what was going on and they were looking for clinical science, which took a while to manifest.

We have no other questions in queue at this time. I would like to turn the conference over back to Ian Mortimer for final comments. .

Thanks very much, operator, and thanks, everyone, for joining us today. This was, as we said at the beginning, these results exceeded our expectations and we're excited to continue to accelerate the development of XEN1101 in patients with adult focal epilepsy. We'll be around all day, so I'm sure we'll talk to many of you throughout the day. So thanks very much. We'll end the call now. Thanks, operator.

This does conclude today's conference call. You may now disconnect your lines.