Study Result

Oct 4, 2021

Hello, and welcome to the Xenon Pharmaceuticals Announces Top Line Results from Xtol Clinical Trial Conference Call. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Sherry Allin, Xenon's Chief Financial Officer. Good morning. My name is Sherry Allin, 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 top line results from the Phase 2b EXTEL 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 Doctor. Chris Kenny, Xenon's Chief Medical Officer and Chris Von Seggen, 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 a 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, 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 statement. A news release summarizing the Ectol top line results, which was issued this morning, will be filed with an accompanying Form eight ks with the SEC and on SEDAR and will be made available under the Investors section of our website at www.xenonpharma.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 top line results from the XEN1101 Phase 2b extol 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 Doctor. Chris Kenny, our Chief Medical Officer, who will review the EXTOL efficacy and safety data in more detail. Then I will ask Chris Von Segern, 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 suggest 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 fifty two point eight percent reduction in monthly seizure frequency within the twenty five milligram dose group compared to eighteen point two percent 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 twenty milligram and twenty five milligram doses in the pairwise 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 twelve 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 Kenny 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 XTOL clinical trial. Before I dive into the details, and as a reminder, XTOL was designed as a randomized, double blind, placebo controlled, global, multicenter Phase 2b study to evaluate the efficacy, safety, and tolerability of XEN1101 administered as once daily adjunctive treatment in adult patients with focal epilepsy. The study results include a total of three twenty five randomized and treated subjects in the safety population, and three twenty five subjects in the modified intent to treat population for the efficacy analyses. Of the two eighty five subjects who completed the double blind period, ninety six point five percent 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 XTOL 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 one to three 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, a monotonic dose response with a p value of less than point zero zero one. Key secondary efficacy measures included a pairwise 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 slides. 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 fifty percent of subjects were on three background anti medications, with about nine percent and forty percent on one or two background anti seizure medications, respectively. Subjects in the XTOL study had failed a median of six previous anti seizure medications prior to study entry. And when we analyzed the literature, we've not been able to find another focal onset seizure study with half the subjects on three background anti seizure medications. And many studies actually excluded patients with three ASMs. In this context of a 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 percent reduction in monthly focal seizure frequency was fifty two point eight percent in the twenty five mg group, forty six point four percent in the twenty mg group, and thirty three point two percent in the ten mg group, compared to eighteen point two percent 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 anti seizure medications, and the number of concomitant anti seizure medications while on study. In addition, XEN1101 demonstrated a statistically significant reduction from baseline in monthly focal seizure frequency compared to placebo for all three XEN1101 doses in pairwise comparisons between each dose and placebo with two sided p values of less than 0.001 for twenty five mg versus placebo, a p value of less than 0.001 for 20 versus placebo, and a p value of 0.035 for ten mg versus placebo. These efficacy data strongly suggest that XEN1101 is highly active in the central nervous system. A key secondary endpoint of the study was a responder analysis, which compared 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 fifty four point five percent in the twenty five mg group, forty three point one percent in the twenty mg group, and twenty eight point three percent in the ten mg group, compared to just fourteen point nine percent in the placebo group. Statistical significance was achieved for all dose groups compared to placebo with two sided p values of p less than 0.001 for twenty five mg versus placebo, p less than 0.001 for twenty mg versus placebo, and a P value of point zero three seven for ten mg versus placebo. Additional secondary endpoints evaluated the Clinical Global Impression of Change and the Patient Global Impression of Change scale. These results show that forty six point four percent of clinicians rated their patients as having much improved or very much improved in the twenty five mg dose group with two sided p value less than point zero zero one. A similar result was seen with the patient global impression of change scores, with forty two point nine percent of subjects reporting much improved or very much improved in the twenty five mg group with a two sided p value less than point zero zero one. In addition, the XEN1101 twenty mg dose was statistically significant in patient global impression of change, while the XEN1101 twenty mg in clinical global impression of change and XEN1101 ten mg 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 antisizure medications. The incidence of treatment emergent adverse events was higher in the treatment groups as compared to the placebo group, with sixty two point three percent of patients in the placebo group, sixty seven point four percent of patients in the ten mg group, sixty eight point six percent of patients in the twenty mg group, and eighty five point one percent of patients in the twenty five mg 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 four arms of the study, with two point six percent of patients in the placebo group, four point three percent of patients in the ten mg group, three point nine percent of patients in the twenty mg group, and two point six percent of the patients in the twenty five mg 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 three point five percent of subjects in the placebo group, two point two percent of subjects in the ten mg group, thirteen point seven percent of subjects in the twenty mg group, and fifteen point eight percent of subjects in the twenty five mg 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 dizzy, twenty four point six percent somnolent, fifteen point six percent fatigue ten point nine percent, and headache ten point zero percent. The treatment emergent adverse event rates are in the range that are consistent with other antisthesia 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 two eleven 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 caused urinary retention to the extent that some patients required catheterization hospitalization. Therefore, overall we're not concerned with these urinary symptoms given the one percent 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 seventy subjects now treated more than twelve months in the open label extension. Overall, the safety and tolerability profile of XEN1101 is in line with other anti seizure medications, and what is expected given XEN1101 appears highly active in the central nervous system. The EXTOL 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 with 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 can play a very important role in treating focal epilepsy in the future. With these compelling top line results in hand, we're eager to work with FDA to plan for an expedited development path moving forward. I think this is a good segue to turn things over to Chris Von Seger, who is going to comment on the commercial potential for XEN1101 based on insights from key opinion leaders and prescribing physicians. Chris? Thank you, Chris. Briefly, by way of background, prior to the XTOL top line 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 anti seizure medications for the treatment of adult focal FOS. Physicians emphasized 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 one of two commonly prescribed anti seizure medications, either levetiracetam or lamotrigine, early in treatment. These agents, used either as monotherapies or in combination with additional ASMs, are insufficient to address the seizure burden in approximately fifty percent 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 loss 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 thirty five percent reduction in the twenty five milligram treatment group, a comparable safety tolerability profile to existing ASMs, along with a 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 below: XEN1101 has demonstrated compelling efficacy in XTOL, and this efficacy is even more impressive given the history of the patients and 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 missed doses. The safety and tolerability profile to date 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 XTOL study suggest 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 Xtol Steering Committee members, the clinicians who participated in Xtol 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 and A session at 08:15 Eastern Time, but we'd be happy to follow-up with each of you throughout the rest of the day. Operator? And your first question will come from the line of Paul Matteis with Stifel. Great. Thanks so much and congrats Ian 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 SEEs? 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 Kenny 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 ten milligram and twenty milligram arm, smaller number of patients than in the twenty five milligram arm in placebo and we have the exact number of SAEs in twenty five milligrams in placebo. And there wasn't any trend there. It was 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, 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 this drug in our mind. All right. Thanks very much. And your next question comes from Andrew Tsai with Jefferies. Okay, great. Thanks. Big congrats on the data. Props to you on the execution, especially during COVID. So my question is about next steps for 11/2001. What do you plan to discuss specifically with the FDA? How quickly could we hear a resolution on next steps? And as a corollary, 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 FDA, given that you are looking for an expedited path forward? Thanks. 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 top line, 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 two 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 two registration studies, but obviously that will be a discussion with the agency. And even more broadly in terms of the development of eleven oh one 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 11O1 and the compelling data. Chris, anything to add to those comments? Well, 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. 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. But it's all dependent upon how the conversation goes with FDA. Thanks for the color. Congrats again. And your next question comes from the line of Mark Goodman with SVB Leerink. Hi, thanks for taking the question. This is Rudy on a call for Mark. Congrats on the data readout. You think the efficacy data looks pretty robust. So regarding baseline characteristics for the patients enrolled in the trial, how does compare with the patient study in the clinical trials of other products like teletomide and synobemate? 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 Sunovamate or other drugs that have been developed in our look at the literature, we believe this was a much more difficult to treat population. 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 fifty percent of the patients were on three background meds. And 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 this study, even more impressive. But Chris, I know you guys have looked at it in more detail, any comments to add? Well, you know, if you sort of compare this study to the Phase 2b study that was done with ezogabine, just as one example, one third of the ezogabine patients were on one ASM and about two thirds on two, and almost no patients on three. So it was really much less sort of, you know, treated in terms of the overall population. And then synovate, I don't think it's quite as dramatic, but you know, if you take a look at the number of ASMs and you look at the number of median seizures at baseline, I mean our population I think is more impaired from a disease severity perspective. And so, 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. Congrats again on the data. Okay, thank you. And your next question comes from Yatin Suneja with Guggenheim Partners. Hey, guys. 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 were there any meaningful difference between, let's say, you know, twenty and twenty five milligram versus the overall? So that's one question. And then anything on the mood factor that you saw or are you able to observe? And if And so, how were 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 I think we've touched upon that earlier in the Q and A, but we can address it again. So just to remind people, because we've had a lot of questions, we know that about thirty percent to fifty percent of patients with adult focal epilepsy have the comorbidity of depression. And we know that the potassium channel mechanism of eleven oh one has strong validation in depression with ezogabine both preclinically and also clinical studies that were run-in patients with depression and anhedonia. For the XTOL 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 eleven oh one. Chris, maybe you can just talk a bit about the AE profile overall. Yes, just a quick comment on mood. I mean, just for those of you who don't know, ezogabine, which has a similar mechanism of action, they completed a proof of concept in major depressive disorder and suggested there may be some activity. I mean, we're going to do the same with XEN1101. 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 events 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 events. 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 it doesn't change the overall risk benefit profile of this drug. Thank you. Your next question comes from Tim Lugo with William Blair. Thank you for the question and congratulations on just really incredible data. I know you settled in on twenty mg for the OLE portion of XTOL and whether XTOL was filable or not, I know there's probably going to be a lot of additional exploration. Can you just talk about where do you think the twenty five 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 you think twenty five 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 at Xenon, 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 ten milligrams be efficacious based on exposure and obviously it is. And then we also had separation clear separation between twenty milligrams and twenty five milligrams. So the team absolutely nailed the doses going into this 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 eleven oh one. 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. Yeah, well you can imagine things are moving pretty quickly with the data that we have in hand, everybody is sort of expressing their opinions about what we should do going forward. I think we're in a luxury problem, which is pretty much what Ian just said, is that 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 ten mg dose is pretty much identical to placebo, which is nice, and that the efficacy of the twenty five milligram group is, you know, the best in the totality of the data on twenty five 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, you know, dropouts because of adverse events, so 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 So luxury problem, any one of those doses could be moved or all of them. It's a great problem to have. And congratulations on this 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 oh sorry, Ian, go ahead. No, no, no. Keep going, Chris. Okay. Suicidality for sure was captured. It wasn't part of the top line, 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, you know, tease that apart as well as we can. You know, based upon the mechanism well, based upon AEs, we're seeing no worsening of depression or anxiety. And we're going to take a close look at the CSSR. Mean, drug is in development for major depressive disorder, so we actually have hypotheses that the reverse is true. And, you know, obviously suicidality is something that's in the label for all of these anti seizure medications, and there's recently I don't know you saw a publication recently within the past week or two, but there's a lot of pushback from the academic world that that's inappropriate. So you can be sure we're going be going to the table with FDA with all of that data and trying to make the argument that you can imagine. Great. Thank you for everything. And your next question comes from David Hoang with SMBC. Hey, good morning. Thanks for taking my question. Thank you everybody else congratulating you on the data. Was wondering in terms of the high dose twenty five milligram efficacy you're seeing there, can you remind us a little bit as to how that's compared to some of the other agents out there? I know agents such as it's appropriate to know the main target on some of the their efficacy endpoint, but maybe just help set that in context. Yes. Thanks, David. Sorry, you're cutting in and out a little bit, at least on my line. I think the question was try just put the eleven oh one efficacy into context with other ASMs. Is that the gist of it? Yes, you got it. Yes, you Okay, got great. Maybe I'll make a couple of comments and then Chris, Segern and the work that you and the commercial team have done in terms of looking at where eleven oh one would fit in. We'd love to hear your perspective on this. As many of you know, because we spent 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 MPC, 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 Kenny has 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 Sagern can 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 twenty five 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 anti seizure medications in clinical trials. So we feel that this product, again, as Angus 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. Thanks so much. And your next question comes from Sergey Belanger with Needham and Company. Hey, good morning. I'd like to also offer my congratulations on the solid data. I guess a question for Ian. I think you said you had over ninety percent of patients in the trial that were at least on two antiepileptic drugs. Can you just maybe comment on which one which were the most common of these AEDs? 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 the 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, 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 a 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 bolus. I'd just like to add on to that, if you don't mind, which is that, I mean, 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 subsequent study is to lean on the same sites that did a good job, right? Try not to reinvent the wheel. I do have a better answer to your question about the concomitant anti seizure medications, because I pulled up the table in the interim. So the top medications that were used procedures in this trial were lamotrigine, lacosamide, giviracetam, clobazam, levetiracetam, basically your sort of, usual suspects. Well, thank you. Thanks, Serge. Your next question comes from the line of Laura Chico with Wedbush Securities. Good morning, guys. Thanks very much for taking the question and 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 happens? Thank you. Thanks, Laura. So yes, we in the top line press release, 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. The second question was on Yes, sorry. Just on urinary retention. I don't think I missed it, just the doses at which that was occurring and just maybe quickly recap how elimination differs for eleven oh one versus ezagabine? Thanks. Yes. Thanks, Laura. I'll start and then Chris can add his perspective. So we saw two patients with urinary retention. They were in two different groups. We haven't disclosed the actual doses, but they were in two different groups. And as Chris mentioned in the prepared remarks, we've had we had two hundred patients on active drug in the study. So it's a less than one percent 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 route of elimination. We had always said that we thought that the risk for urinary symptoms with eleven oh one 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 eleven oh one 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 zogabine data, the frequency was a little bit higher. I mean, they had a larger safety database, but the frequency higher and the sequelae 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 were 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 weren't hospitalized. They didn't get catheterized. Manageable. But it did occur in two patients. Thanks guys. And your final question comes from Antonio Borovina with Bloom Burton. Hi. I just want to echo everyone and say congrats again on the data. My question is related to the pigmentation side effects. So you mentioned you didn't see any instances of that. I'm just wondering what measurements did you look at to come to the conclusion? And given the fact that now we only have seventy patients that have proceeded to the one year mark in the open label extension, do you believe this concern is largely at this point? Yeah, 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's 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 eleven oh one doesn't can't dimerize, it doesn't have the structure that allows it to dimerize. So our hypothesis going in is that we wouldn't have seen any pigmentation based on chemistry of eleven oh one 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 seventy patients that are out more than twelve 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 timeframe. 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. You know, just keep in mind that mechanisms of action don't dimerize. Chemicals do. And, you know, I'm not a chemist, but based upon what are saying that this drug really shouldn't dimerize. That said, you know, it obviously happened with ezogabine. It 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. Mean the beauty of this open label study is that it's going to be three years long. And then we'll have an open label extension for the Phase III work that's done as well. So 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, you know, ezogabine, which they didn't know what was going on, And, and they were looking for, you know, clinical signs, 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.