Good day. Thank you for standing by, and welcome to the Xenon Pharmaceuticals Reports First Quarter Results Call 2022. At this time, all participants are in a listen-only mode. After the speakers presentation there will be a question-and-answer session. [Operator Instructions]. I would now like to hand the conference over to your speaker today Ms. Sherry Aulin, Chief Financial Officer of Xenon Pharmaceuticals. The floor is yours.

Thank you. Good afternoon, everyone. Thank you for joining us on our call and webcast to discuss Xenon's first quarter 2022 financial and operating results. Joining me are Ian Mortimer, Xenon’s President and Chief Executive Officer; Dr. Chris Kenney, Xenon’s Chief Medical Officer; and Dr. Chris Von Seggern, Xenon’s Chief Commercial Officer. Please be advised that during this call, we will make a number of statements that are forward-looking, including statements regarding our and our collaborators' development plans; anticipated regulatory interactions and submissions; anticipated results and real time lines; the potential efficacy, safety profile, addressable market and commercial potential of our proprietary and partnered product candidates; the efficacy of our clinical trial designs and anticipated enrollment; the potential receipt of milestone payments and royalties from our collaborators; our expectation of having sufficient cash to fund operations into at least 2024; and the timing of potential release of future clinical data. Forward-looking statements are subject to numerous risks and uncertainties, many of which are beyond our control including the risks and uncertainties described from time to time in our SEC filings. Our results may differ materially from those projected on today's call. We undertake no obligation to publicly update any forward-looking statements. Today's press release summarizing Xenon's first quarter 2022 financial results and the accompanying quarterly report on Form 10-Q will be made available under the Investors section of our website at www.xenon-pharma.com and filed with the SEC and on SEDAR. Now I'd like to turn the call over to Ian.

Thanks, Sherry. Good afternoon, everyone. Thanks for joining our call. Today I will provide a high-level update on our proprietary pipeline programs and then I'll turn the call over to Chris Kenney, who will provide additional color around the new developments and next steps within our XEN1101 program, including the newly initiated XEN1101 Phase 2 clinical trial in major depressive disorder or MDD. Sherry will conclude our call by providing an update on our partner programs and briefly summarizing our financial results and anticipated key milestone events ahead. Chris Von Seggern is also on the call to provide his perspective during the Q&A session. Within our own proprietary pipeline, we continue to support our ongoing XEN496 Phase III EPIK pediatric clinical trial, which is a randomized double-blind placebo-controlled parallel group clinical trial evaluating the efficacy, safety and tolerability of XEN496 in approximately 40 pediatric patients, aged one month to less than six years with KCNQ2-DEE. Based on published physician case studies with ezogabine and its Kv7 mechanism of action, we believe that XEN496 has the potential to address an important unmet medical need. We continue to receive encouraging feedback from clinicians, caregivers and patient advocates on our XEN496 program including most recently at the Pediatric Academic Societies Conference in Denver. There is significant interest in the opportunity to provide a precision medicine which has the potential to positively impact the lives of these young patients. We continue to build momentum with new sites and jurisdictions coming on board and we expect to complete the XEN496 EPIK Phase 3 clinical trial in 2023. Turning now to our XEN1101 program. We have made significant progress advancing XEN1101 into a broad clinical development program, in both epilepsy and depression. Building on our topline Phase 2b X-TOLE results in adult focal epilepsy from last…

Thanks a lot, Ian. We've made a lot of progress driving forward multiple ongoing clinical trials and planning for XEN1101 Phase 3 initiation. Let me start by providing, further details about the Xenon-led XEN1101 MDD trial. As background, we've built a strong scientific rationale to support our exploration of XEN1101, as a treatment for symptoms of depression in anhedonia. Published preclinical studies suggest that increased activity of KCNQ type potassium channels reverses depressive phenotypes, following chronic social defeat stress. We conducted our own preclinical work with XEN1101, including data published at the 2021 Ascent Conference that demonstrated a potential benefit of XEN1101 in mood disorders. Further, the efficacious doses in plasma concentrations from the rodent depression and anhedonia and epilepsy-related MES studies overlap, suggesting that the exposure concentrations of XEN1101 and epilepsy patients may also provide appropriate drug exposure to have a beneficial impact on mood. In addition, a paper published in the American Journal of Psychiatry outlined statistically significant clinical results generated from a randomized placebo-controlled clinical trial that explore the targeting of KCNQ channels as a treatment for MDD and anhedonia using ezogabine. The results from our own X-TOLE Phase 2b epilepsy clinical trial showed an efficacy signal in focal onset seizures with all doses, including the low dose of 10 milligrams which had an excellent tolerability profile. So you will see within our MDD trial design, we intend to further study the 10-milligram dose alongside the 20-milligram dose. X-NOVA will enroll approximately 150 subjects who will be randomized on a 1:1:1 basis into three treatment arms; 10 milligrams, 20 milligrams and placebo. The primary objective is to assess the efficacy of 10 milligrams and 20-milligram doses of XEN1101 compared to placebo on improvement of depressive symptoms and subjects diagnosed with moderate to severe MDD, using the Montgomery-Åsberg…

Thanks, Chris. Before I make a few comments on our Q1 financials, I'm pleased to report progress from our partnered programs with Neurocrine Biosciences and Pacira Biosciences. Of note, we received a milestone payment from Neurocrine Biosciences in connection with successfully reaching a collaborative milestone within the quarter. Both collaborators have clinical studies underway. Pacira is conducting a Phase 1b proof-of-concept trial that's evaluating the safety and tolerability of PCRX301 administered as a single dose in patients undergoing bunionectomy. And Neurocrine now has two separate Phase 2 clinical trials underway evaluating NBI-921352 in adult patients with focal onset seizures and pediatric patients with SCN8A-related epilepsy. And Neurocrine has guided that they expect to have data from the focal epilepsy study in 2023. We look forward to keeping you updated as these partners programs reach important milestones. Next, I'll briefly touch on the highlights from this quarter's financial statements. Please refer to our news release and 10-Q report filed today for more detailed information from Xenon's financial statements. Cash and cash equivalents and marketable securities as of March 31, 2022 were $537.9 million compared to $551.8 million as of December 31, 2021. Based on current assumptions which include fully supporting the planned XEN1101 clinical development program, XEN496 and preclinical and discovery programs we anticipate having sufficient cash to fund operations into at least 2024 excluding any revenue generated from existing partnerships or potential new partnering arrangements. Looking ahead there are a number of key objectives and milestone opportunities within the Xenon pipeline. So following our end of Phase 2 meeting in the second quarter and receipt of final FDA minutes we anticipate being in a position to share our final Phase 3 plans for XEN1101. In parallel, we'll continue to evaluate and plan for an XEN1101 program in another epilepsy indication and expect to be in a position to outline our plans in the coming months. We'll provide continued support for both X-NOVA and the ongoing investigator-led study examining XEN1101 in MDD and with the ongoing advancement of our EPIK Phase 3 clinical trial in pediatric patients with KCNQ2-DEE, our team is driving towards study completion in 2023. In summary, we intend to continue to build on the positive momentum and excitement generated since the release of our top-line Phase 2b X-TOLE results last fall. We're grateful for the online support of our shareholders and Ian and I have had the pleasure of conducting in-person meetings at recent conferences with some of you on the call. With a strong balance sheet and prudent management of capital, we believe Xenon is well positioned to support our business objectives across our proprietary programs and we look forward to reporting our progress in the coming quarters. I'll now ask the operator to open the line for any questions.

[Operator Instructions] Your first question comes from the line of Andrew Tsai from Jefferies. Your line is now open.

Hi, very good. Thanks and good afternoon. Thank you for taking my question. My first one is on 1101. Clearly, the base case for you guys for your Phase 3 program is to do two studies regardless. Although you will see if the FDA is willing to consider X-TOLE as a pivotal study. So, my question is are there precedents out there where the FDA kind of explicitly told the sponsor we'll consider your Phase 2 as a pivotal study. So, in other words could we expect that level of detailed confirmation from the FDA? Thanks.

Thanks Andrew for the question. Happy to address it. So, our -- we've been really consistent with our messaging and communication with investors. We believe the X-TOLE data were very robust and we're going to ask the FDA as part of the end of Phase 2 meeting on whether X-TOLE can be one of the two registration studies. Regardless we've been clear that we're going to run two Phase 3 clinical trials regardless of the outcome. You asked about -- so I -- we are going to try to get clarity and obviously, what we can receive in terms of clarity from the FDA once we're in the receipt of minutes then we'll be in a position to communicate that publicly. In terms of precedent, obviously, we don't have the opportunity to read regulatory minutes from other companies, but we have seen other companies and disclosure that is consistent with being able to communicate on whether their Phase 2 study has been a registration or has been seen as a registration study from an efficacy point of view. Obviously, when we think about the broader clinical development of any program and the NDA it's a much broader package than just looking at efficacy results.

Makes sense. Thank you. And my follow-up is on the MDD program that you started up. Can you kind of talk about the powering assumptions whether both doses need to work for the study to succeed? And how have you tailored your MDD study to succeed in terms of the trial design? Any differences here for the X-NOVA study versus ezogabine's prior placebo-controlled study for instance? Thank you guys again.

Sure. Chris Kenney do you want to walk through both kind of the our company-sponsored design and some of the things that we're doing a little bit differently as well as the powering question?

Sure. Happy to do so Ian. So I mean I think the first thing just to kind of take a step back I mean you have with ezogabine you have a drug that demonstrated improvement in focal onset seizures. And now we've done the same with a similar mechanism using XEN1101. And when we think about the differences in the potencies and we think about it there's a significant difference there but we think that there's overlap in terms of the doses that we use and the doses that they use that was effective in FOS. And same thing with MDD that we're currently using doses that were quite similar when you take into account differences in potency with what ezogabine used in the small proof-of-concept study that was positive in MDD that was alluded to earlier. And the difference there is that they were able to demonstrate statistical significance in a study with about half the number of patients per treatment arm. So in the context of that we think that there's a reasonable chance that if XEN1101 is effective in MDD that we'll see it. I mean do you want me to go further in terms of that, or do you want me to leave it there and then go back to the study design?

Yes. Why don't we go -- yes, let's go through a little bit of the study design. And obviously, there's always questions around, trying to manage the placebo rate. So we can talk a little bit about that and then we can get specific -- more specific on the powering calculations and I'm happy to walk through those as well.

Okay. So in terms of like planning for success with this study say a few different things. I mean first of all, very careful to keep the number of sites limited and then to make sure that the quality of the site is as good as it can possibly be. Can sometimes see differences in terms of placebo effect in different regions and what we can tell you is that the sites that have been chosen are all US-based. Obviously, you need to pick a good CRO and so we went through a rigorous process to choose that. We're doing -- we're working with CT&I to complete eligibility review of patients, so that once a site determines that a particular patient is eligible for the study, that patient is then reviewed in remotely for eligibility based upon everything that the site has provided an independent assessment of the confirmation of the diagnosis of MDD and then also an assessment of the extent of the MDD. That group which is composed of psychiatrists and psychologists from mass general will also be involved with training the raters and then keeping an eye on the surveillance over a period of time. So I think, we're -- so there's a lot of different things that we're doing and hopes of planning for success with that trial. And then obviously, having the number of patients per arm twice -- twofold higher than the pack that was positive with ezogabine should help with that as well.

Thanks, Chris. Let’s go -- operator, if we can go to the next question.

Your next question comes from the line of Paul Matteis from Stifel. Your line is now open.

Thanks so much for taking my question. I had a couple if you don't mind. On XEN1101 in epilepsy, as it relates to FDA and EMA feedback, is your expectation that the EMA will prefer a responder analysis as the registrational endpoint, or is FDA may prefer median seizure reduction and any other discrepancies that you may anticipate? And then on the additional seizure indication, I was just curious -- again, I don't want to speculate on what you might pursue, but if you're going to do generalized seizures or something like that, can you just sort of point to what other seizure populations out there are there that would materially change the way this drug is used in the real world? I guess asked another way, if you have a label for both procedures, do you need a broader indication to really kind of broaden the prescribing within the refractory population? And then just lastly in MDD, I was just curious how you're handling concomitant antidepressant use or prior antidepressant use intrusion refractory here? Thanks so much.

Okay. Great. Thanks Paul. Why don't I -- I'll -- Chris, maybe I'll tackle the first one and then Chris Von Seggern why don't you talk a little bit about the market opportunity and other seizure disorders outside of focal and how we think about kind of the market there. And then Chris Kenney, we can get to the content question on MDD. So your first question Paul is just around regulators in the US versus Europe. Yes, I think you described it well that European or US regulators FDA, we expect we'll focus on MPC. That was the primary endpoint in the X-TOLE study and would be the primary endpoint in the Phase III program. And European regulators will focus on the responder analysis or RFD and that's the key. That was the first secondary endpoint in X-TOLE and we can do that analysis and look at that under the statistical analysis plan. And, obviously, given the robustness of the data with 1101 as you just see massive consistency between those two endpoints, regardless of which one you do we see very strong statistical significance, which is to be expected with a very active drug based on those two statistical analysis. So Chris Von Seggern, kind of, expanding the market opportunity outside of focal.

Yeah, absolutely. So as we said previously, focal onset is the biggest component of the epilepsy opportunity, representing approximately 60% of the patients who are treated and managed. But that leaves a fairly sizable segment of the marketplace that has either we would generally consider a generalized form of epilepsy or -- within that bucket. That side of the equation is much more fragmented with different conditions contributing to the different manifestations that would fall into a broader generalized bucket but they are broadly treated similarly although not the same. And there are products that have indications that sit on either side of the FOS versus the primary generalized marketplace. As a result, we do think expansion of the clinical label is important for two reasons; first, having clinical data in unique patient populations that will be important given that not all products are broad spectrum and we want to be able to be in a position where we can have data specifically supporting use in adjacent patient population, as well as that we do believe this is a promotionally sensitive market, and being able to communicate that data through commercial and medical needs will be important in order to establish positioning for a product even in light of having a potential broad-spectrum outcome. So both of those reasons necessitate exploration of at least generating data and pursuing labeling should the data be positive is something we feel quite strongly about.

Thanks Chris. Chris Kenney on the MDD question.

Yeah, hey Paul. So with regard to the medication, so patients entering the study will not be allowed to be taking an antidepressant. And in terms of eligibility it's okay to have failed one antidepressant in the current depressive episode but no more than one. And then any failure of greater than three antidepressants at any point in time will be exclusionary as well.

All right. Thank you all very much.

Thanks Paul.

Your next question comes from the line of Brian Abrahams from RBC Capital Markets. Please go ahead.

Hi, good afternoon. Thanks for taking my questions. It sounds like you mentioned your confidence is continuing to grow on 1101 as the data continue to evolve. So I'm actually curious if you could talk maybe a little bit more about the emerging data. I know the specifics around the open-label extension update that are going to be presented later this year. But maybe if you could just remind us how far along patients are at this point on dosing? And maybe qualitatively what you're seeing out of that that helps shape your confidence? And then secondarily you did mention we were going to see updated cuts from X-TOLE later this year. And I'm just curious if you could maybe talk broadly about how some of those analyses such as the time to efficacy could further help differentiate 1101's profile? Thanks.

Thanks Brian. Chris, I'll make a few comments. And then, I'll pass it over to you. Maybe assuming a little bit of color on the open-label extension and I don't know if we -- Chris, I don't know, if we know -- if you know off top of your head just kind of -- I know we have patients that are out quite some exposure now, but maybe we can just give a little bit of information if it's -- if you have it at your fingertips on how many patients we're seeing kind of out 12 to 24 months. On the -- yeah, Brian, I think one of the things that's really strong about the data set overall is regardless of how we cut the data it's remarkably consistent and very intuitive. A lot of these subgroup analyses in patients with less severe disease but data looks even more impressive which is what you would expect, but it's nice to see that consistency. We're interested in this time course to efficacy, because of the no titration. So although this is a novel mechanism, and we would say likely best-in-category efficacy that we've seen so far, continuing to look at other ways where we could differentiate against, what are number of other anti-seizure medicines that are available. So what we've been doing is we've been looking at cuts of the data on efficacy at -- this was an eight-week study. So on a weekly basis and we can start to look at where efficacy shows up. And again, without the drug being titrated, the hypothesis is there's an opportunity to see that earlier than you may see some of the other drugs. So that's something that we're interested in, among other things. And then, I'll pass it to Chris maybe just to give a bit of color on OLE data, because we're just starting to dig into some of that data. We have focused on the OLE safety data initially as part of preparation for our end of Phase 2 meeting, but now we're starting to think about the efficacy cuts that we would like to share later this year as well. Chris?

Yeah. Sure. Yeah, I mean, I think that the main point is that as we look into the data, the double-blind data regardless of how we cut it the signal persists. And so that's part of the story in terms of being reassured. The other part will be messaged clearly in the second half of this year regarding interrogating the open-label data. And we're just getting our hands around it. It's a moving target right, because it's an ongoing study and every day patients have one more day of exposure. But -- and the other thing is that the number -- not all patients have finished up the first year, because they wrapped up in the summer last year. The last patients who enrolled wrapped in the summer. But roughly speaking, we're closing in on having a couple of hundred patients up to a year and then about 50% over two years. So it's a fairly robust data set. And we're taking a look at that data and obviously having it vetted by key opinion leaders who are respected and then, being sure that we go out with a balanced story about what we're seeing.

Great. Thanks Chris.

[Operator Instructions] Your next question comes from the line of Marc Goodman from SVB Securities. Your line is now open.

Hi. Thanks for taking my questions. It's Rudy on the line for Marc. Just a quick follow-up question for the X-NOVA study, for 1101, can you provide more color on the powering of the study? Like, what are your expectations for the magnitude of effect in matters for both placebo and 1101? And secondly, given the enrollment criteria it seems like we are targeting monotherapy instead of adjunctive use. Maybe can you provide more color here on the clinical setting for 1101? Thanks.

Yes. Chris, do you want me to do powering, or do you want to do the powering in the monotherapy?

I'm happy to make it start it off and then maybe you can add color to it afterwards. So I sort of alluded to the fact that we're going to have about twice the number of patients that were in the ezogabine proof-of-concept study. So from like a go in deep perspective you got – you're shooting for an effect size around 0.5. But in terms of the separation between active and placebo, where the powering assumptions assume that there would be about a 5-point separation between active and placebo and that that would give us an 80% power to detect a change for each one of the doses compared to placebo. So that's the powering. And then in terms of the monotherapy you're – yes I mean you have it right. So these patients will not be on an additional antidepressant and so we're looking for a signal in patients who are not being treated with another antidepressive at the same time.

Got it. That’s very helpful. Thank you.

[Operator Instructions] Your next question comes from the line of Yatin Suneja from Guggenheim. Please go ahead.

Hey, guys. Just a couple of questions from me on the MDD side. Can you just talk about the dose selection there using a 10-milligram dose there? It's just curious how did you come up with the lower dose? And then did you mention the effect size that you are looking at 0.5. Can you just talk about how did you derive at that 0.5? The effect size and fight for delta and your pausing assumptions?

Yes. So Ian do you want me to go?

Yes. Why don't you start and I'm happy to add.

Yes. So the 10-milligram dose in the focal onset seizure study demonstrated efficacy and tolerability and a safety signal that was made it difficult to extinguish the 10-milligram group from placebo. So really good tolerability and evidence of efficacy. And so we want to take that forward into MDD and see if the same would be true within MDD. And then as far as the powering I think it's probably better to just focus on this is an MDD study. We're expecting a fairly pronounced placebo effect as has been the case historically despite efforts to keep it minimized. And then the separation between active and placebo we're assuming it's five points and a standard deviation that's about twofold higher than that. And that's a little bit less than what we've seen with the ezogabine proof-of-concept study completed in two sites. We're going to be going to more sites. So that signal may become less robust as we do that. So that's the powering background.

Got it. And do you have any clarity on when you make the data from investigator-initiated MDD study?

So yes, it's still early days. The Mount Sinai study started in Q4 of last year and we're not giving specific guidance on it. And I will mention just because it's publicly available on clinicaltrials.gov. They say that it's going to be early '24 when that study completes. So our expectation has always been that our company-sponsored study, although it has started after the MST we'll read out before the IST because we expect data from our study in 2023.

Next question is from the line of David Hoang from SMBC. Please go ahead.

Hi. Thanks for taking the question. So, I had one and then a follow-up. So, first in terms of 1101 in MDD, if we think about how it might be positioned and adopted in the real-world setting, do you think about the low-hanging fruit as epilepsy patients with comorbid MDD, or is this really more of something for the broad all-comer MDD population that could be conceivably used in anyone who had maybe failed an SSRI?

Chris Von Seggern, do you want to talk about the opportunity?

Yeah. No absolutely. So first let's start with MDD, that indication while it does have numerous available agents as you've mentioned an overwhelming number of patients will be treated with an SSRI or SNRI, but many of those patients will fail first or second-line therapy. And just like in the FOS space, there is a sizable percentage of patients that require an alternative mechanism. In this situation predominantly, monotherapy to address their depression symptoms and we do believe that there is an opportunity for a novel – for an agent with a novel mechanism of action that has a good safety tolerability profile to fit in nicely despite the competitive dynamic that sits in that space. Your second question, though, relates to the fact that within the FOS patient population, there is a sizable percentage of patients that have comorbid depression. It's one of the most common comorbidities within the epilepsy space and there certainly is the opportunity to differentiate with appropriate data in that segment of the patient population where you can imagine that you can be a go-to agent with compelling antidepressive effects as well as best-in-class efficacy as we've seen with XEN1101.

That's helpful. Thanks. And then just quickly, if I may. In terms of the IST study, which will read out after your company-sponsored study are there any key learnings that you expect to glean from that study that may not be apparent in the company-sponsored study?

I don't think so. I mean Chris mentioned in his prepared remarks, and if you look at the ezogabine publication from a year ago from the study, so it was the same group out of Mount Sinai and Baylor that ran the ezogabine study that was published last year. And then, they're the same ones running the RIST, or the IST with 1101. They're interested in a functional endpoint a functional MRI at primary because they're interested based on some of the preclinical data and where the expression is the increased expression of Kv7.3 in the brain. And so that's going to be an endpoint that we're not replicating. So that will be new information from their study, but then when they get into their secondary endpoints in terms of the clinical scales of depression and anhedonia that will be consistent with our study. So I'm not sure that, we learn a lot David from their study that would be a read through in terms of our future development.

Okay. Thanks a lot. Appreciate.

[Operator Instructions] You have your next question coming from the line of Laura Chico with Wedbush. Please go ahead.

Hey, good afternoon. Thank you for taking the question. I just have two. One we saw a recent report looking at correlation of seizure frequency and quality of life in patients. Interestingly, there's third quarter better correlation being qualitatively life and days of un-interested due to seizers. When you looking a the recent 11/01 data, I am wondering, if there is a similar type of relationship that exit in the focal epilepsy setting. So, not necessarily seizure freedom days, but days that were uninterrupted due to seizures. And then secondarily, I guess, with respect to the study in MDD, the X-NOVA trial, could you just elaborate a little bit more fully in terms of how you're going to be assessing patients remotely, kind of what steps you're taking to kind of control placebo response? Thank you.

Chris Kenney, both of those, can you address?

Well, I don't know if I can address the placebo response any better than I already did. So I'll just go through it again quickly. And basically, it has to do with choosing good sites U.S. focused, making sure that the sites were trained properly by CT&I, ensuring that we choose a good COO, assessing the eligibility criteria for entrance into this study using a different scale that's being used to assess the primary end points, so specifically HAM-D versus moderate. And then using this group of CT&I, who are mass general attending in psychology or psychiatry performing this remote assessment of patient eligibility ensuring that the HAM-D score is appropriate for recruitment into the study, and then keeping using those same folks to train the sites and to surveil them over a period of time to ensure that there isn't anything apparent going on with the data. So don't think, I can add anything more to that. And what was the other one? I apologize.

There is question -- go ahead, Laura.

Well, I remember it was the seizure free. Yes. So we've taken a look at seizure freedom. Some of that has been released previously in press releases. We've also looked at seizure-free days. That data hasn't been released, although, it sort of shows what you might expect it would show. We haven't tried to correlate that seizure freedom or seizure-free days with quality of life.

Okay. And if I could maybe sneak in a quick one. I'm sorry if I missed this on 1101 and the MDD study. Have you disclosed kind of expectations around a screening failure rate? Thanks very much.

We have not. Sorry, just to answer that last question, operator. So, no, Laura, we haven't given any guidance on where we expect the screen failure rate may be. That's something that I think we can track over time and then give more information on.

Okay. Thank you. That ends our question-and-answer session. I'll turn the call back over to Sherry Aulin for closing remarks.

Thank you everyone for joining our call and webcast to discuss our first quarter 2022 results. Operator, you may now end the call.

Ladies and gentlemen, that concludes this conference call. Thank you all for participating. You may now disconnect.