Earnings Call: Q1 2020

May 21, 2020

Ladies and gentlemen, thank you for standing by, and welcome to the Q1 twenty twenty Xenon Pharmaceuticals Earnings Conference Call. At this time, all participants' lines are in a listen only mode. After the speakers presentation, there will be a question and answer Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today. Mr. Jody Rates, Thank you. Please go ahead, ma'am. Results. Joining me on today's call are Doctor. Simon Pimstone, Xenon's Chief Executive Officer and Ian Mortimer, Xenon's President and Chief Financial Officer. Following this introduction, Simon will give an overview of Xenon's clinical programs and then Ian will provide some high level financial commentary. After that, we will open up the call to your questions. Please be advised that during this call we will make a number of statements that are forward looking, including statements regarding the anticipated impact and timing of the COVID-nineteen pandemic on our business, research and clinical development plans and timelines and results of operations the timing of and results from clinical trials and preclinical development activities of proprietary and partnered product candidate, the potential efficacy, safety profile, future development plans, addressable market, regulatory success, and commercial potential of proprietary and partnered product candidate the anticipated timing of IND or IND equivalent submissions and the initiation of future clinical trials for proprietary and partner candidates. The efficacy of our clinical trial designs, our ability to successfully develop and achieve milestones in the XEN496, XEN1101 and XEN007 and other proprietary development programs. The timing and results of our interactions with regulators, the potential to advance certain of our product candidates directly into phase 2 or later stage clinical trials anticipated enrollment in our clinical trials and the timing thereof, the progress and potential of our ongoing development programs The potential receipt of milestone payments and royalties from our collaborators are expectation of having sufficient cash to fund operations into 2022 and the timing of potential publication or presentation of future clinical data. Forward looking statements are subject to numerous risks and uncertainties, many of which are beyond our control, including the risk 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. Today's press release summarizing the results of Xenon's first quarter of 2020 and the accompanying quarterly report on Form 10 Q will be made available under the Investors section of our website at www.xenonpharma.com and filed with the SEC and on SEDAR. Now, I would like to turn the call over to Simon. Thank you, Jody, and good afternoon, everyone, and thank you all for joining us today. At the end of March, we issued a statement outlining our response to the COVID-nineteen pandemic. Xenon continues to put the safety and well-being of people first including the clinicians and patients involved in our clinical trials as well as our employees and their families. We are fortunate that we have the cash runway to support our business objectives and to whether this unprecedented health and economic crisis. Despite the global impacts of the COVID-nineteen pandemic, I'm pleased to report exciting events from our pipeline of innovative epilepsy treatments over the next 12 months. Today, I'll provide a status update on each of our clinical stage products, as well as on our partnered programs. I'll start with XEN1101, which is a differentiated next generation Kv7 potassium channel modulator being developed for the treatment of adult focal epilepsy and potentially other neurological disorders. Patient enrollment for our XEN1101 Phase 2b clinical trial is currently underway in the United States, Canada and Europe. The trial is a randomized double blind placebo controlled multicenter study to evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive treatment in approximately 300 adult patients with focal epilepsy. The primary endpoint is the median percent change in monthly focal seizure frequency from baseline compared to the treatment period of active versus placebo. In order to assess safety tolerability and discontinuations in this ex toll trial, We continue to review blinded data from patients who have been treated. To date, XEN1101 has been well tolerated and the rate of discontinuations from the study are below what was modeled. In addition, more than 90% of subjects to date from the double blind portion of the trial enrolled over into the open label extension phase. Therefore, based on analysis of the blinded safe data to date, we have made a decision that we do not believe an interim analysis is required. As a reminder, this option would have allowed for resizing of lower dose groups or for other changes to the study, if tolerability was different than modeled, which is not the case here. In the context of the COVID 19 pandemic, and its impact on ongoing clinical studies, we are in close collaboration with each of the XEN1101 clinical sites in North America and Europe taking specific direction from their respective clinical guidelines as they relate to new patients screening and randomization. Our efforts remain focused on patients currently enrolled in the study, either in the double blind portion or in the open label extension portion of the study while making other necessary amendments in the study, including minimizing any in person patient visits and making provisions for adequate drug supplies to patients who have a possible to ensure the data integrity as well as new jurisdictions to support enhanced patient screening as soon as the individual clinical trial sites deem it safe to do so. We are seeing some clinical sites resume patient screening and patients entering baseline and being randomized. We believe this will continue to pick up over the coming months. Top line data is anticipated in the first half of twenty twenty one dependent upon feedback from the clinical sites and patient enrollment rates, which may be impacted by the COVID-nineteen pandemic. Given its unique mechanism of action, we also continue to explore potential indications for a phase 2 proof of concept trial with XEN1101 outside of epilepsy and we look forward to going into more detail as these plans develop over the coming months. Also within our portfolio of proprietary epilepsy products, XEN496 is a Kv7 potassium channel modulator that contains the active pharmaceutical ingredient ezogabine, also known as retigabine, that we have now reformulated and are developing as a treatment for a rare pediatric neurodevelopmental disorder called KCNQ2 developmental and epileptic encephalopathy or KCNQ2DE. A severe pediatric condition for which no medicine has been approved and which is characterized by multiple daily refractory seizures presenting within the 1st week of life. Most recent epidemiology sites the incidence at approximately 1 in 17,000 live births. There is a strong genetic rationale to suggest that XEN496 may be efficacious as a treatment for KCNQ2DE, which is further supported by non controlled clinical case reports and surveys as well as anecdotal parental and physician feedback. These data suggest ezogabine may be well tolerated and may reduce seizure burden with potential to improve development and cognition in this rare pediatric population. The FDA has granted orphan drug designation and in the first quarter, we were also granted fast track designation for the investigation of XEN496 for the treatment of seizures related to KCNQ2DE. Over the past few months, we have made considerable progress in our XEN496 program, which I'll outline for you. First, to support a planned Phase III clinical trial of XEN496 in patients with KCNQ2DE, we recently completed a pharmacokinetic or PK study testing our proprietary pediatric formulation in 24 healthy adult volunteers. Subjects were given a single 400 milligram dose of XEN496 in either the fed or the fasted states. While the study was not designed to determine by equivalents given ezogabine is not available to use as a comparator, The PK profile observed for XEN496 supports our Phase III plans and appears to be comparable to historical PK data for immediate releases Ogabine tablets, with XEN496 showing similar absorption and elimination curves. 2nd, and importantly, We recently received additional feedback from our second interaction with the FDA related to the Phase III program for XEN496. And we are confident we now have a clear path to initiate a single phase 3 study this year. Our proposed safety monitoring plans including long term follow-up to monitor potential side effects were acceptable to the FDA, who also indicated that it is acceptable to study XEN496 in infants and children up to six years old. Based on the entirety of the FDA's feedback, We anticipate initiating in to be the median It is anticipated that approximately 40 patients will be randomized in a blinded manner to either an active treatment group or placebo. After the initial screening, patients will enter a baseline period to assess the frequency of seizures followed by a titration and then a maintenance treatment period and then a post treatment follow-up period. It is expected that there will be an open label extension period after the double blind portion of the trial and we've named the Global Steering Committee as well as a principal investigator for the study, Doctor. John Miller chap, with site selection also well underway. In addition, our clinical development team is planning for regulatory submissions outside of the U S to support the broader clinical development of XEN496 We expect to submit our Phase III protocol around midyear as previously guided and initiate the XEN496 Phase III clinical trial this year in 2020. We believe this is the 1st study of its kind ever in KCNQ2DE, The first time a monogenic epilepsy trial will include infants as young as 1 month of age, and the first precision medicine treatment in a monogenic epilepsy in using a drug with foresee any hurdles to initiating the phase 3 trial in 2020 other than the potential impact of COVID-nineteen. We therefore find ourselves at an exciting juncture, and we are eager and highly motivated to bring significant innovation to a severe and heart to treat neurological disorder where high medical needs still exists. We are presenting 3 e poster presentations related this XEN496 program using the virtual platform hosted by the American Academy of Neurology, which is in lieu of its annual conference. First poster summarizes the recent results from our PK study, examining the PK and food effect of XEN496. The second poster summarizes our online survey of caregivers of patients with KCNQDE and the 3rd poster examines literature and survey results to evaluate the use of diaries versus video, electroencephalography or video EEG for counting seizures in patients with KCNQ2DE. All three of these posters have been added to the Xenon websites as well as the AAN virtual platform. So I encourage you to review them. Turning now to XEN007 with the active ingredient for narrowzine. This is a CNS acting calcium channel modulator that modulates CAB 2.1 as well as T type calcium channels. As a reminder, physician led proof of concept study is now ongoing. Examine the potential clinical efficacy, safety and tolerability of XEN007 as an adjunctive treatment in pediatric patients diagnosed with treatment resistant childhood, absence epilepsy. It is anticipated that the study will enroll approximately 20 patients with CAE an open label manner, patients who have failed standard of care because of lack of efficacy or because of adverse events. Results from this phase 2 study are expected in 2020 dependent ultimately upon patient enrollment rates given the ongoing COVID-nineteen pandemic. Depending on our analysis of the final results from the study, CAE, of course, may represent a potential orphan indication for future development of XEN007. Before turning to our partner programs, I should also note that our early stage drug discovery efforts continue to build upon our robust pipeline of early stage preclinical candidates, encompassing our work related to a number of sodium and potassium channel targets. We look forward to highlighting this exciting and novel preclinical work as it matures. We have an ongoing collaboration with Neurocrine Bioscience to develop treatments for epilepsy. Neurocrine has an exclusive license to XEN901, now known as NBI 921352, a clinical stage selective NaV1.6 sodium channel inhibitor with potential in SCNHA developmental and epileptic encephalopathy or SCN8A DEE and other forms of epilepsy. Neurocrine Biosciences has indicated that it in participate filing an IND application with the FDA in mid-twenty 20 in order to start a Phase 2 clinical trial in SCN8A DEE patients in the second half of this year. This important milestone would trigger a $25,000,000 milestone payment to Xenon upon the FDA acceptance of an IND for NBI 921352 with 55% of that amount in the form of an equity investment in Xenon. Prior to our collaboration with Neurocrine, the Xenon Clinical team conducted a survey of caregivers of SCN8A DEE patients These data have been summarized in an e poster that will also be presented on the virtual AAN platform and posted on the Xenon website. In addition, we are presenting 2 other posters relating to XEN901 or NBI 921352 One summarizes the relative bioavailability, pharmacokinetic and food effect assessment of 2 immediate release formulations, including both pediatric granules and adult tablets of XEN901. The other summarizes a study of 18 healthy adult subjects and provides an assessment of the potential pharmacokinetic and pharmacodynamic interactions between XEN901 and phenetoin, a non selective sodium channel blocker with the attention of providing useful safety information regarding the co administration of XEN901 with drugs for future clinical trials. With XEN90101 and beyond 921,352. Moving now to our partnership with Flexion Therapeutics. Who acquired the global rights to develop and commercialize XEN402 and have 1.7 inhibitor. Flexion's preclinical product candidate known as FX 301 consists of XEN40 2 formulated for extended release from a thermosensitive hydrogel. The initial development of APeX301 is intended to support administration as a peripheral nerve block for control of postoperative pain. In April of this year, Flexion presented new animal data in an e poster presentation on the American Society of Regional Anesthesia And Acute pain website that showed FX301 provided sustained post operative analgesic effect with no impairment in motor function compared to liposomal bupivacaine and placebo. In addition, high local concentrations of XEN402, the active ingredient in FX301 were measured at the site of administration for the duration of the study, which is consistent with the creation of a depot providing controlled drug release. The start of a GLP tox study with FX-three zero one triggered a $500,000 milestone payment to us in April. Flexion anticipates initiating human clinical trials 2021, and we look forward to updating you on this exciting partnered program. I'm so proud of the Xenon team as we support one another and adapt to find ways to stay focused on our work through the COVID-nineteen public health crisis. Xenon has what we believe to be the most exciting epilepsy pipeline currently in development and we continue to strive to bring novel much needed new therapies to patients in need. We're also showing great community leadership during the COVID-nineteen pandemic leading numerous initiatives that we believe could assist businesses transitioning employees back and managing the workplace in the face of what will likely be near to medium term future that includes COVID positive employees or close contacts in our workplace. At this point, I'll ask Ian to recap our financial position and to provide some closing commentary before opening up the call to your questions. Ian? Thanks, Simon, and good afternoon everyone. The specific details within our financial statements are covered in today's press release and in our 10 Q filing, but I will provide an overview and conclude with a summary of our upcoming milestones. In the first quarter, we reported total revenue of $7,100,000 related to the recognition of $5,800,000 of deferred revenue, as well as $1,200,000 There was no revenue recognized for the same period in 2019. R and D expenses for the quarter were $11,800,000, This compares to $9,100,000 for the same period in 2019. The increase of $2,700,000 was primarily attributable to increase spending on Xenon's clinical development product candidates, XEN1101 and XEN496. And to a lesser extent increased spending on preclinical, discovery and other internal program expenses. This was partially offset by decreased spending on MBI 921352 as clinical development costs are now borne by Neurocrine. G and A expenses for the quarter were $3,300,000, compared to $2,600,000 for the same period in 2019. And this increase primarily is attributable to increased stock based compensation expense, salaries and benefits, insurance premiums and business development expenses, partially offset by a decrease in legal fees for intellectual property protection. This gives us a net loss for the quarter The change primarily attributable to revenue recognized during the first quarter of 2020 and partially offset by an increase in R&D And G And A expenses as compared to the same period in 2019. Cash and cash equivalents and marketable securities as of March 31, 2020 were $229,700,000, and this compares to $141,400,000 as of December 31, 2019. I should also mention that subsequent to quarter end, we paid our outstanding loan with Silicon Valley Bank, the $15,500,000 in debt was put in place in 20172018 and provided a meaningful bridge enabling our current epilepsy pipeline to mature. It is now prudent to repay the loan as the repayment today is accretive from a cash flow perspective given our current cash runway. Based on current assumptions, which include fully supporting the planned clinical development of XEN1101, XEN496, and XEN007, we anticipate having cash sufficient cash to fund operations into 2022, excluding any revenue generating from existing partnerships potential new partnering arrangements. Importantly, we believe we have the cash runway to support our business objectives that we have outlined today. And we continue to make prudent business and spending decisions to manage through these unprecedented times. And I'd also like to echo Simon's comments and commend the Xenon team for their diligent efforts and their flexibility that have enabled us to stay on track for important clinical milestones over the next 12 to 18 months. Briefly, we expect top line data in the first half of twenty twenty one, from the XEN1101 Phase 2b Xtol study currently underway in adult focal epilepsy and continue to explore other potential indications for this novel Kv7 potassium channel modulator. We expect to initiate in 2020 Phase III clinical trial to examine XEN496 efficacy in KCNQ2DE, We expect results from the physician led Phase 2 open label study in treatment resistant childhood absence epilepsy with XEN007. And we expect a $25,000,000 milestone payment upon the FDA acceptance of an IND that our partner Neurocrine intends to file in mid-twenty 20 to start a phase 2 clinical trial for MBI-nine twenty one-three fifty two in SCN8A DE pediatric patients. And we expect Flexion to continue the development of FX-three zero one, supporting the initiation of human clinical trials in 2021. And Xenon's eligible for various regulatory and development milestone payments up to $9,000,000 through the initiation of a phase 2 proof of concept clinical trial. With these important milestone opportunities ahead, we look forward to updating you on our progress. At this point, operator, And our first question comes from Paul Matteis with Stifel. Your line is now open. Great. Congrats on the progress and thanks for taking my questions. I have a few, if you don't mind. 1 on 1101 Simon, I was wondering if you could clarify some of the numbers you put around retention rates in the study. So where exactly is your discontinuation rate tracking? And when you say 90% have rolled over to the OLE, is that 90% of patients who finished the double blind portion or 90% of total? And then just separate on 496, two quick questions. One, can you just clarify the seizure type you're using for the primary endpoint and your confidence that that's an easily countable seizure across patient age? And 2, how are you thinking about the statistical hurdle for success for that study? Do you need a P value of 0.05 and if so, are you powered for it? Thanks so much. Yes. I'll work backwards. So yes, in the current draft protocol, we're not going to go into all the details today. Paul, the plan is as we launch that study, would be to have a call and update on sort of the details of the study specifically, but just at a higher level This is going to be a P value driven study. We are powered based on what we think are reasonable assumptions And of course, building into that is studies that others have done in rare pediatric monogenic epilepsies as well as what we know and K01 steering committee input into the protocol about the disease itself and natural history. So I think we've made we've given a ton of thought to the assumptions that go in. And I think have been reasonably conservative and believe that an end of about 40, as I said, divided at this point between active and placebo arms, would suffice to meet a P value. So that's the first question. The second question on seizure type, Yeah, I think we're looking at tonic and focal tonic seizures as your endpoint. And this would be captured by a diary, just as it's done has been done in other pediatric epilepsies. You may recall there was some discussion early on whether video EEG would be required. We'll be looking at video EEG as part of screening, but it's not requirement based on the interaction we've had for measurement for the endpoint, which we think is a big one for us and we think makes sense. We feel very confident that the caregivers can determine these focal tonic seizures which would be counted in diary form. And then your first question was on 1101. Yeah, the 90% rollover is of those that complete the double blind period because those are the individuals that roll over. So, we can't say to the state that 90% of those randomized drug rolled over because not everyone has completed the double blind. So, the portion of subjects that have completed the double blind have rolled over. And as I said, it's over 90% of those within those that, that have entered the randomization phase of the study, the dropout to date, and again, patients are at different segments of the study from a few weeks to many weeks to beyond. So those rates differ, Paul, but to date, the dropout rate has been lower than what we've modeled. And so that's all we can say point in time. Ian? Yes. I was just going to go back to Paul, one of your earlier questions, and just point you and others on the call. We had a nice poster. It's actually in slide presentation for the virtual AAN meeting on the video EE the types of seizures. And we've actually collaborated with academics and with the advocacy group to ensure that caregivers can be trained and that you can correlate that back to EEG to the video EEG. So we feel very comfortable that the caregivers do that. That was our presentation to the FDA via a white paper. We presented that data at AAN in this virtual format And that will be the subject of a future publication as well. So some really nice work to feel comfortable, in using caregivers to look at the seizure numbers in the upcoming 496 study. That's great. Thanks for the detailed answers. Appreciate it. Thanks, Paul. Thank you. And our next question comes from Tim Lugo with William Blair. Your line is now open. Hey, this is Laughlin on for Tim. Thanks for taking the questions. I was just wondering how the screen failure rate in the EXHOL study of SYM1101 has sort of compared to your expectations going in and if that's been a factor in the delay or if that's all? Yes. Tim, the screen failure rates are about what we have modeled. So pretty standard. Again, we're not giving percentages and numbers for all our rates of this and that, but it's what we had modeled, we had expected. So we're not seeing, again, this is, let's say, pre COVID. We haven't seen screen failure as a major impediment. What happens post COVID? I can't say whether that's going to change from a percentage standpoint. I don't know. We're hopeful based on what we're seeing, particularly in Europe, that sites are starting to kind of emerge from COVID again and we'll see what the next month or 2 holds in that regard, but I don't expect screen failure rates are going to go up. But I certainly, we haven't seen a higher failure rates than modeled or anticipated. Okay, great. And just sort of follow-up on that, with the potential introduction of de novo may in the adult partial onset epilepsy field. Would you expect patients enrolling to be failing that moving forward once that's on the market? I think that's going to be a very small, impact if any, by the time that gets out, remember again, coming out of COVID, this is not a a drug that is easy to initiate, it requires, but by this, I mean, the synovomide drug, it does require a very, very careful dose titration. Because of this dress here synophilic syndrome, which can be quite severe in some patients. And so I think we really have to be a pretty back to normal clinical environments. I think before a drug like that is going to be easily rolled out at specialty centers. This is not a drug that's going to be used by your average neurologist. It's going to be at epilepsy centers. Still most specialty centers are doing virtual consults. Most virtual consults are not starting patients on drug that have difficult titration strategy. So, Tamara, I don't think this is going to have a major impact on trial recruitment What impact that has from a commercial standpoint over the next number of years? We could talk about it at length, but wasn't the purpose of your question, but I think that should that suffices in terms of how I see Cinnober made risk over the next 6 to 12 months. Great. Thank you. And if I could squeeze in 1 more on the 496 trial, have you outlined what the sort of standard of care is in the control for that trial? Yes. It's going to be, we believe just a local center decision on standardized treatment. Now, again, centers, they aren't standardized guidelines for patients, but centers, I would say in general, would likely be using sodium channel blocking drugs. So these kids often, present very young. As you know, they put often on Velcro H or FeNO Bob and then our transition generally onto drug like lamotrigine, lecosamide, oxcarbazepine, carbamazepine. Those are generally your agents used. And so While I don't think it'll be specified, I think we'll definitely see an aggregation of drugs probably within the sodium channel blocking class. As your baseline use. Our next question comes from yatin Suneja with Guggenheim. Your line is now open. Hey, guys. This is Eddie on for Gautam. Thanks for taking the question. Just a couple on the 496. You had previously guided that you thought you need about 20 to 30 patients and your age group was 1 month to two years old. And now you're saying that you're there are about 40 patients needed and you're going to go up to six years old. So can you give us any other details on what the regulator saw or what your meeting, minutes said about where those requirements changed? And does that change your estimated time for enrollment or site number And then as a follow-up, what's the current gating factor for initiating this trial? Like what are you still waiting on from the regulator? Right. So we aren't waiting on anything from the regulators other than we have to submit the final protocol. So that's sort of the gating item. As I said, we expect to submit in and around the middle of the year. So we don't see anything gaining between now and then in terms of drug supply, but we have to finish everything up, finish the protocol up and submit the I and submit the protocol So we expect that to happen in the pre near term. In terms of some of the other questions, the age adjustment was put forward by us, not by the FDA that was with the recognition that the age at which you study your patient is important in many, many ways. One is There's a label impact. Number 2, it may give us benefits of the drug outside of the traditional high seizure burden when it comes to some of the other endpoints we're going to be looking at obviously a secondary endpoints in development. And remember, independent of the age, kids can only get into the study if they meet the inclusion criteria, which is a certain seizure frequency at baseline. So The fact that they're up to six years of age, they will still have to meet the certain number of weekly seizures to be allowed into the study. So I don't I think the age going beyond 6 is only a benefit to us from a label perspective. There's no downside. Your other question was the patient number. Yeah, And that really just came down to the ultimate design that we've landed on and we'll be going forward on. It's just a matter of numbers of patients in one group versus another time of patients in placebo and crossing over versus not crossing over. So it really just came down to the fact that we think the cleanest design will be a parallel placebo controlled study And based on the assumptions we've built into it, we feel that number is going to be about right for the statistical significance. We don't think it's going to impact enrollment in a meaningful way. Yes, you are right, we will probably need more sites to keep timelines as aggressive as we would have with 24 to 30 subjects. So another 10 or 15 subjects as we will need for the study will require some more sites We really have had an unbelievable response from sites in terms of participating. This is a really unique study and I actually think will be a pretty high profile study given its kind of precision medicine nature. And so, I don't think our challenge is identifying sites to participate. And as I mentioned in my remarks, we are going to look to submit in Europe and conduct the study both in the U. S. And in Europe. So site number again shouldn't be a limitation, but we may land up certainly needing more sites open to recruit for 40 than we would have at 24. But it's not going to hold us back or add another year in terms of timeline. I appreciate the details. Thanks guys. Okay. Thank you. Our next question comes from Laura Chico with Wedbush Securities. Your line is now open. I guess, one question on 1101. I think I heard you say that you were starting to have some sites reopen. I was just curious if you could kind of put a percentage number on that or frame it a little bit more relative to the overall sites. Are the majority now reopening And if not, do you have a better estimate as to when the remaining sites will open? And then on 496, Is there any additional color you might be able to provide in terms of, the titration scheme and how long the maintenance period might last Sure. Yes. So on 1101, sites are starting to reopen. I it's not the majority of sites at this point. And this isn't just our trial. I think this is the majority of trials out there. I think the next few months is obviously going to be very important to see, how that how that builds. As I mentioned in my remarks, we are looking to open up other jurisdictions as well as new sites in existing jurisdictions. And we purposefully looks at other jurisdictions that we think we'll be opening sooner. So, the answer is not the majority, but they are starting to open. And I think over the next few months, we expect there'll be more meaningful recruitment in the study for sure. But just too early, Laura, to give you kind of an estimate in terms of impacts. We still think this should allow us and we've built in a bit of cushion to hit up guidance that we've provided, which is top line first half of 2021. So, that's that question. The 496 in terms of titration, yes, there will be a titration. We've talked about that previously, it'll be a few weeks. And patients will get to a maximum dose or a maximum tolerated dose. We haven't disclosed at this point what the maintenance period is. But it's going to be fairly standard. Going to be fairly standard. This isn't a 2 week maintenance phase. So this is going to be, a couple of months and likely to have a few weeks of titration to get there. Laura, maybe just I can add a little bit to Simon as well. On 1101, we didn't, just to be clear, we didn't close any sites, right? We were we made the decision that we really wanted to be guided by the individual clinicians at those sites when they were comfortable. And that enabled us to continue all of the patients on study to get drug and and make adjustments there. So we even had some patients that went longer in baseline before they were randomized until physicians were comfortable randomizing. So Again, we've never shut anything down, and need to reopen. It's really more, and we're talking clinicians every day that are getting comfortable doing a randomization visit. And so we're seeing that come online as Simon mentioned. On 496 on the titration. So ezogabine was titrated as a drug. So again, this isn't specific to to the trial design or to the patient population, it's really specific to the drug. We don't have titration in 1101 based on the drug. It kind of self titrates, but for 496 based on the active ingredient being a zagrebine, you do titrate that drug up to a certain level and we'll be doing PK draws and then And then after that, they would draw into the maintenance phase. Thank you. Our next question comes from Maury Raycroft with Jefferies. Hi, everyone. Thanks for taking my questions. For the decision not to do the 1101 interim, Just wondering if you could say if that means there were no notable differences in tolerability across the different doses And can you talk more about what specific blinded data you had access to for that? So because it's blinded, we don't know about tolerability differences across doses, Maurice. So that that I can't answer. But if you look at the overall tolerability, the overall AEs in the cohort, We're very comfortable with what we're seeing, very happy with what we're seeing to date. Obviously, still got to finish study, but so far, we're comfortable. So we don't have specific rates to disclose or to discuss at this point. But I'd say that the incidence of AEs, are lower than what we had expected at this point in the study. Was that another part of the question? Yes, I think so. So it's basically it was based on just the AEs that you seeing across the group and then also the dropout rate in terms of the 2? Yes, not so much the AEs, but remember, the whole reason to have built in the option to do an interim was to know whether if we had high dropout rates, because if tolerability was poor, and high dropout rates for various reasons, we may need to upsize to ensure we get sufficient numbers to hit our statistical significance. And And so we built a certain dropout model into the statistical plan. We're well below that in terms of numbers of people that be dropped out of the double blind portion of the study. So what that means is that we should have a at least equivalent, if not higher power than what was initially models to observe the effect we've projected based on the numbers we'll get. So with fewer people dropping out, our power goes up determine. That just means the chances of this happening, randomly, or should I say the chances of seeing a significant effect is is higher, with higher numbers. And so we're, we feel very confident based on what we've seen such that we don't think there is a need to do an interim, for this point in the study. Got it. Okay. That's helpful. For the 496 Phase III, just wondering if you could say how many sites you think you're going to need for this study or are you going to provide a range? I don't know. It's going to be probably north of 20, but I can't tell you exactly how many at this point. I think it's probably looking at around 1 to 2 patients per site is the initial expectation, over the course of the study. But we already know some sites have more patients than that. We just we haven't done, obviously, prescreening, and that needs to all happen to see available patients, whether they what proportion fit the criteria. It's just a bit premature at this point to know exactly. But we'll be aggressive on on sites initiation, to make sure that we can recruit as quickly as possible. Got it. Okay. And then last quick question. For the phase 3 with 496, can you say how long the running period is going to be and what the frequency seizures per week is at baseline? We haven't disclosed that. Our plan is to give this kind of detail over the near term once we submit the protocol and we're ready to go. We'd like to hold off those types of details until the study is essentially final in its protocol and we can disclose all elements of it together. Understood. Okay. Thanks for taking my questions. Not at all. Thank you. Our next question comes from David Martin with Bloom Burton. Your line is now open. Good afternoon. Thanks for taking the questions. The first question is the pediatric formulation of 496 You had thought at one point that maybe it would eliminate the bluing and possibly the urinary rent retention. I think the bluing is in part, stability in the vial and part of it, how it acts in the body. So I'm wondering now you're through the phase 1. Have you seen a reduction in the blue way? No, remember, Dave, the pigmentation for ezogabine was seen very late. In fact, it wasn't observed actually in the clinical studies of the drug, which included, fairly long term Phase III studies in adults. So it started to get reported post launch in post market work and as it was used, commercially. So we don't expect to see pigmentation changes in a phase 1 setting, like this Of course, we've submitted as part of the meeting we've just had with the FDA. We submitted our monitoring plans, which they're in agreement with so we are going to monitor for this over time. The formulation itself I don't think I've said before that we don't expect urinary effects based on the formulation, but we do know ezogabine does have a degree of urinary retention. And, but in all reported cases that was well managed and there's no bladder toxicity that has been reported in a patient. In terms of the pigmentation itself, we'll monitor for it. I don't believe given this appears to be cosmetic that, as I've said before, even if we do observe it, There has not been a case to the best of our knowledge. There has not been a case described of visual toxicity associated with this retinal pigmentation. So even if we were to observe it, which it hasn't yet been observed in any patient used off label, right? This is, of course, in the earlier days of Patiga, drug was used in a number of these patients not described. And in some patients for a number of years, it's been used. That just may be a cumulative effect. So I don't think we'll likely see anything Dave one way or the other in a shorter term study. But even if we were to see pigmentation, the nature of this disease, I believe, is such that I don't think This is going to impact the commercial opportunity of this drug. It appears to be just a cosmetic finding at this point. Okay. Second question also on XEN496. Is it going to be, the drug added to standard of care versus standard of care alone or is it the drug alone versus standard of care? No, no, drug on top of. So these are again, going to be refractory patients who have a certain seizure count over and above what they're currently on. All of these kids will have been started on something. And depending on the age at which they get recruited into the trial. They may have been on one drug, 2 drugs or 10 drugs before. But usually these drugs, these kids have spectrum of drugs on, at baseline, they generally are on 2 to 3 drugs in the 1st month or so of their life. So we do expect, this will be on top of probably 1 to 2 or 2 to 3 other agents. And the standard of care arm, if they move on to another drug because they're failing what they're on, will that be counted as a failure? Will you no longer be counting their seizure rate? In the placebo group that's on top of standard of care? Yes, yes. Your question is So right now, the way the study is designed is they are not crossing over to the active arm? No, no, I mean, in the, placebo group, placebo on top of standard of care, if they're failing and the physician says, will I have to move them on to the next drug, not to 496, but to another drug. How will those patients be treated? Will they be failures? And the trial at that point? Or will you continue to, to measure their seizure rate? Very standard in these studies and similar to 1101, they have to be on stable background standard of care, right? And that can change from individual to individual site to site. So they'll be on a background set of antiepileptic they'll still be having a baseline number of seizures, which will meet the entry criteria. And then in study, they'll be blinded as we c bar active. If they are breaking through and having a significant number of seizures, there's always an ability to rescue. And if they, if they rescue you, then obviously that's going to impact, and that all of their seizures are going to be taken into consideration. Obviously, if that's in the placebo as the drug arm, it's going to have an impact on the outcome of the study. But there'll always be an ability for patients in a study to rescue Okay. Last question, I know in the 1101 trial that you're blinded as to which arm the dropouts are coming from. But do you know the cause of the dropouts, if it's a tolerability issue or if it's something else? And are you seeing low tolerability rates and that's why you're comfortable? We're seeing good tolerability. So low dropout rates for tolerability is, I guess, what you're asking. Yes. And dropouts are generally in a study for a whole host of reasons. Patients move cities just decide they don't want to be in it. Their whole host of reasons. And we're seeing the dropouts that we've seen across all of those reasons. So there's nothing that looks consistently drug related for the majority of dropouts. So that's probably about what I can say there. We don't see anything that stands out as a drug related cause for dropouts. But yeah, there'll always be some patients who for tolerability reasons will step out of a study and others for a host of other reasons. And we've said we've seen it across the, across the, all of these, possibilities. Okay, great. Thank you. Thank you. Ladies and gentlemen, this concludes our question and answer I would now like to turn the call back over to Jody Rates for any closing remarks. Thank you. Thanks for joining us today. Operator, we will now end the call. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.