Xenon Pharmaceuticals Inc (XENE) 2024 Q3 法說會逐字稿

Good afternoon and thank you for standing by at this time. I'd like to welcome everyone to Xenon Pharmaceuticals Inc., third-quarter 2024 earnings conference call. (Operator Instructions)

Thank you. I will now turn the conference over to Chad Fugere, Vice President of Investor Relations. Please go ahead, sir.

Good afternoon. Thank you for joining us on our call and webcast to discuss Xenons third-quarter 2024 financial and operating results. Joining me today are Ian Mortimer Xenon's President and Chief Executive Officer.

I'm just going to jump in for Chad. So Ian will begin with a summary of our recent progress across our business. Chris Kenny will provide an overview of our clinical stage programs and ongoing outreach to the medical community and I will close with a summary of our financial results and anticipated milestones. We will then open the call up for your questions. Please be advised that during this call, we will make a number of statements that are forward-looking including statements regarding the timing of and potential results from clinical trials, the potential efficacy safety profile, future development plans and current and anticipated indications, addressable market, regulatory success and commercial potential of our and our partner's product candidates. The efficacy of our clinical trial designs, our abilities to successfully develop and achieve milestones in our clinical development programs.

The timing and results of our interactions with regulators, our ability to successfully obtain regulatory approvals, anticipated timing of the top line data readout for our clinical trials of the Zu Kilner. And our expectation that we will have sufficient cash to fund operations into 2027. Today's press release, summarizing Xenon's third quarter, 2024 financial results and the accompanying quarterly report on form 10-Q will be made available under the investor section of our website at Xenon dash pharma dotcom and filed with the SEC and on SEDAR+. Now, I'd like to turn the call over to Ian.

Thank you, Sherry and good afternoon everyone and thanks for joining us on our call. Today, we have made significant progress over the past quarter. Consistent with our overall strategy of being at the forefront of discovery and development of ion channel therapeutics and our focus hasn't changed to maximize the full potential of our lead product is that you counter to build upon our leadership position in the KV seven space and to continue to mature our promising ion channel pipeline xenons leadership position in the KV seven field is unmatched as A Z two calendar represents the only highly potent and selective KV seven potassium channel opener in clinical development for multiple indications that is backed by long term efficacy and safety data in patients living with epilepsy and encouraging proof of concept data in patients with major depressive disorder.

Within our portfolio, we remain focused on three key areas.

Continuing the execution of our phase three is Zu Calendar epilepsy program. While raising the profile of the Zu Calendar with both physician and patient communities advancing our phase three is Zu Calendar MD D program with a focus on X nova two which is expected to initiate before the end of this year and expanding our pipeline both through the advancement of our portfolio of next generation ion channel modulators as well as further potential indication expansion of the Z two calendar.

As I said earlier, Xenons leadership in the KV seven landscape is unmatched. The Z two calendar represents the most advanced clinically validated potassium channel modulator in late stage clinical development.

Our substantial clinical experience with the Zu calendar includes robust long term efficacy and safety data with over 600 patient years of exposure in focal epilepsy patients.

Importantly, we have generated highly compelling double blind efficacy data from our exto study that we believe demonstrates the best placebo adjusted results ever seen in a clinical study in patients with focal onset seizures.

In our exto open label extension study, we are seeing patients experience the long term benefits of seizure freedom and improved quality of life as well as a favorable safety profile. We believe that a zu calendar represents a potentially best in class anti seizure medication that could be paradigm shifting in the treatment of epilepsy.

In addition to the impressive efficacy data generated to date is that to counter has other important attributes such as one once daily dosing without the need for titration, rapid onset of effect, novel mechanism of action and potential mood benefit.

The body of compelling clinical evidence that we have amassed to date continues to generate significant excitement from physicians and key opinion leaders as they see the potential of what is Zu counter could mean to the epilepsy community.

As we continue to educate key stakeholders around the benefits of the Zu calendar. Xenon will have an increased presence at the upcoming American epilepsy society meeting or a taking place. December 6th through the 10th in Los Angeles. We'll have new data presentations and updated results from our ongoing ex to open label extension study.

Patients in the Xol Ole have now been on drug for at least three years with some patients in the ooe having more than five years of exposure to A Z two counter.

We continue to see better efficacy in the open label extension. The longer patients are on drug and many patients are experiencing the long term benefits of seizure freedom and improved quality of life. And we're excited to present this new 36 month data at AES next month, we believe this long term data package will support our regulatory filings on the pathway towards commercialization and is a key differentiator when compared to other molecules in earlier stage clinical development.

Further, we are an incredibly fortunate position in that as that two calendars attributes enable significant potential across both epilepsy and neuropsychiatry including MD D and potential other indications.

Physicians who treat MD D are looking for medications with novel mechanisms and favorable product profiles such as as such as the ability to address anhedonia, demonstrate a rapid onset of effect or avoid adverse effects that are seen with standard of care agents such as sexual dysfunction or weight gain as we shared last quarter. Clinical site planning is well underway and we expect to initiate our phase three MD D program before the end of this year, 15 years beyond the Zu calendar to our broader pipeline.

Our discovery team has applied its many years of experience in ion channels to advance multiple KV seven product candidates that are chemically diverse from A Zu calendar so that we can leverage the targets pipeline and a mechanism potential. Providing us with numerous clinical development opportunities across a broad range of therapeutic indications including seizure disorders, pain and neuropsych conditions and ultimately extending the reach of this differentiated mechanism to even more patients in need of better therapeutic options.

Today, we have multiple KV seven candidates in our pipeline and IND enabling work is currently underway to support our goal of filing an IND or equivalent for the first of these candidates in 2025. Staying on the top of the topic of our early stage pipeline, we continue to make meaningful progress within our NAV 1.7 sodium channel program as well.

We are proud of Xenon's pioneering work to identifying promising genetic targets associated with rare phenotypes. It was through these efforts that the connection was made between individuals who had the inability to perceive pain and the complete loss of function mutations in the gene encoding for NAV 1.7. Conversely, individuals who experience non precipitated, spontaneous severe pain, correlated with NAV 1.7 gain a function mutation.

This identification of NAV 1.7 as an important pain related target also offered the possibility of a new class of pain medications that are not burdened by the liabilities of opioids. Importantly, we believe that NAV 1.7 has by far the strongest genetic validation amongst pain targets. And we continue to pursue the development of novel non opioid based pain medications.

And while and and while the development of ion channel therapeutics is certainly a complex challenge, we are applying all of the knowledge gained from the past molecules to advance novel selective NAV 1.7 inhibitors within our portfolio of next generation modulators. Currently I&D enabling work is underway with a lead NAV 1.7 development candidate in support of our goal of filing an I MD or equivalent in 2025 enabling us to generate important derisking proof of concept data.

In addition to NAV 1.7 and KV seven, we are also advancing potentiators of NAV 1.1 with the aim of addressing the underlying etiology of Dravet syndrome and delivering a disease modifying therapy in support of our hypothesis that a precision medicine therapy for Dravet syndrome should restore NAV 1.1 activity specifically without impacting other neuronal functions or proteins.

We look forward to presenting some of our pre clinical NAV 1.1 data including protection against spontaneous seizures and suit up as well as strengthening long term potentiation at the upcoming a meeting.

These data support an incredibly compelling profile for a small molecule NAV 1.1 potentiator when, when compared to other drugs available and in development to treat Dravet Syndrome.

Finally, as I continue to reiterate, it's an exciting time for xenon due to the advancement of our clinical programs and our progress towards commercialization in August of this year. Dr Matthew Rsim joined our senior executive team as Chief Operating Officer based in Boston, overseeing our R&D operations and providing strategic and operational leadership for our pipeline of small molecule programs and preparation for the anticipated commercial launch of the Z two calendar. Matt's extensive operational pharmaceutical development and manufacturing expertise are important as we expand our phase three programs plan for regulatory submissions and commercialization as well as progressing our broad portfolio of early stage assets. Matt has already made a positive impact and we look forward to his continued leadership with that. I'll now turn the call over to Chris Kenny to provide a brief overview of our clinical stage programs and our own ongoing outreach with healthcare providers at key medical Congresses. Chris over to you.

Okay, thanks a lot, Ian. I'm pleased to report that our late stage clinical development programs for Zu Counter are progressing as planned. Our phase three epilepsy program includes XOL two and XOL three in focal onset seizures and exact in primary generalized tonic clonic seizures. Importantly, the first top line focal onset seizure data readout from X two is anticipated in the second half of 2025. In support of an anticipated NDA filing, we plan to submit the results from XOL two along with the existing data package from XOL and additional safety data from other clinical trials.

In parallel with the significant progress made across our phase three of the two counter programs. Our medical affairs team continues to engage with the broader medical community to highlight the robust scientific evidence generated to date. We're in an enviable position. As not only can we showcase the positive results from our completed ex tool trial. But we have our ongoing seven year open label extension study, providing further long term data from patients living with epilepsy, which we believe is a key differentiator from other molecules. Currently in development to give you a sense of some of these interactions. In September, we attended the European epilepsy Congress which attracted more than 3,600 delegates from around the globe. Zenon had a strong presence presenting three posters and hosting a scientific exhibit. We successfully engage with key opinion leaders prescribing clinicians and principal investigators from our study sites. Many of our discussions centered around the X Tole data which we believe demonstrate the best placebo adjusted clinical efficacy in the most refractory patient population trial as well as a favorable tolerability profile in adult patients with focal onset seizures. Furthermore, we continue to receive strong feedback from the epilepsy community on the long term efficacy data from our ex to open label extension study which shows increased seizure reductions with patients on a zu counter out to 30 months experiencing a greater than 90% reduction in median monthly seizure frequency. Additionally, approximately one in four patients on a Zu counter for at least two years in the exto open label trial have been seizure free for a full year or longer giving both us and the epilepsy community tremendous confidence in the Zu Counter's potential to address the significant need for new anti seizure medications.

These data are particularly impressive given that the literature concludes the likelihood of achieving seizure control. Once a patient has failed, three anti seizure medications is less than 5%. And we believe that future open label extension data updates including our upcoming 36 month data set at AES will continue to strengthen our leadership position.

Physicians regularly treating epilepsy. Patients are impressed by the A zu calendar data gathered to date noting that it sets an incredibly high bar not just for other KV seven drugs in earlier stage clinical development but other anti seizure medications within the current treatment landscape. This is especially true when considering some of the Zu calendar is potentially differentiating attributes such as its positive impact on mood.

Our outreach to the medical community is not limited to epilepsy. We're also engaging with prescribing physicians in the MD D space with our phase three MD D program. The first of three planned phase three clinical trials examining a Zu counter and major depressive disorder is anticipated to initiate before year end. At the end of October, we attended the site congress in Boston, giving us another key opportunity to interact with physicians in the MDD space and present our phase two X Nova data discuss the potential use of A Z two counter as a treatment for MDD and outline our near term plans to initiate a phase three program in Major depressive disorder. We continue to emphasize A Z two. Calender's potentially differentiated profile versus standard of care agents in MD D. As physicians continue to have a particular interest in A Z two Kars novel selective KB seven mechanism of action and its potential benefit on anhedonia, rapid onset of effect as well as its potentially favorable tolerability profile. With no notable adverse effects on sexual function or weight gain.

We have the benefit of being able to reference not just the ex nova data for efficacy but also the long term tolerability data gathered from our ongoing ex to open label extension study. We're excited to be advancing another late stage clinical development program for Zu Calendar with the hope of addressing the needs of patients diagnosed with MDD who are still struggling to find effective treatments. We also continue to support the investigator led MDD study conducted by Dr James Murrow of Mount Sinai School of Medicine and Dr Sanjay Matthew at the Baylor College of Medicine. This 60 patient placebo controlled phase two trial has a functional primary endpoint with the objective of evaluating the effect of A Z two counter on brain measures of reward as measured by the change in activation within the bilateral ventral striatum from baseline to end of treatment at week eight as assessed by functional MRI.

Also, the study is evaluating secondary end points that include mods and shaps. Patient enrollment was recently completed and results anticipated in the first half of 2025. Now, looking ahead, we're incredibly excited to expand our presence at A E AES this year as part of our ongoing outreach to the medical community as the premier epilepsy conference A is an important venue for us as we continue to strengthen our profile and reputation as a leader in epilepsy. Laying the foundational framework for a successful future potential launch in epilepsy. We have scheduled numerous meetings with physicians, key opinion leaders, academic leaders and patient advocacy groups. I'm extremely proud that we have five accepted abstracts at this medical meeting and look forward to presenting these posters including an update to our ex to open label extension study. We have expanded our presence in the exhibit hall and are eager to welcome all visitors to the Xenon booth who are interested in learning more about a Zu Counter and our broader pipeline. I'll now turn the call over to Sherri who will provide an overview of our third quarter financial results and upcoming upcoming milestones. Sherry.

Thanks Chris looking briefly at our third quarter financial results. As of September 30 2024 we had cash and cash equivalents and marketable securities of 803.3 million compared to 930.9 million as of December 31 2023. Based on current operating plans including the completion of the is that two counter phase three epilepsy studies and fully supporting late stage clinical development of the Z two counter and MD D. We anticipate having sufficient cash to fund operations into 2027. I refer you to our news release and 10-Q report. For further details around our financial results.

We anticipate that 2025 will be a pivotal and transformational year for Xenon with several important milestones on the horizon. First and foremost, we're driving towards the highly significant data read out from X to two expected in the second half of 2025. Importantly, positive results from XOL two will enable the submission of our ND A. With the goal of advancing is that two counter towards commercialization in the MD D program, we're anticipating results from the investigator sponsored phase two proof of concept study of the Z two calendar and MD D in the first half of 2025. In addition, our company sponsored broad phase three MD D program will be well underway with the initiation of ex Nova two anticipated before this year end.

As we continue to advance our early stage pre clinical pipeline, we anticipate filing multiple in DS or equivalent in 2025 with the goal of initiating first in human trials across multiple targets while also exploring other potential indications for Z to counter that may be well suited for late stage clinical development.

With this in mind, we have built a foundation of strong thoughtful fiscal management which positions us to execute on our plan strategies to advance that to counter through late stage clinical development in both epilepsy and MD D. While at the same time supporting a robust pipeline of next generation ion channel therapeutic candidates to summarize some of the key takeaways from today's call. We believe strongly in the Z two Kars compelling clinical profile, which is built on its unique mechanism of action and supported by the meaningful body of clinical data we've generated. Thus far, we're excited to engage with key patient and physician communities to raise further awareness about the potential of a that two counter in the future treatment of epilepsy at the upcoming Aes meeting where we will also present the latest data from our ongoing text to Ole study. For those of you on the call attending AES. We look forward to connecting with you in Los Angeles and looking slightly further out, we look forward to connecting at the upcoming JP Morgan conference which will give us an opportunity to kick off the year and outline our key goals for 2025 in more detail. I hope you share our excitement as we continue to execute our clinical development plans and anticipate these key events next year. Thank you for your attention today and we look forward to sharing more in the coming months. I'll now ask the operator to open the line for any questions.

(Operator Instructions) Paul Mattys, Stifel.

Hi.

There. This is Julie Im for Paul. Thanks so much for taking our question and congrats on the progress. Just wondering if you could provide a little bit of color again, on, on enrollment dynamics and, and whether things are tracking according your expectations, any other details or, or learnings perhaps since you know, our last quarterly update. And then secondly, quickly, just on the MD D investigator sponsored study, I'm just curious on how you perceive that study. Either reading on to or not reading on to your phase three pivotal program and thus confidence and execution of your own study. Thank you.

Thanks very much for the question. So I'm happy to take the first one and, and maybe start on the second one. And Chris Kenny, you can provide your perspective on the, on the Ist and MD D as well. Yeah, obviously, we get a lot of questions on just how we're doing in the phase three epilepsy program. We're really comfortable where we are. I'm not sure anything's changed in the last quarter to your very specific question. You know, I would always remind people that I think we have more experience kind of in the contemporary clinical trial environment of executing large focal epilepsy studies. So we're very comfortable on where we are. You know, obviously, we always get the best information we can. And, and currently the guidance ForEx tool too is to have top line data in the second half of next year. So I don't think there's anything specific that, that you haven't heard from us and seen from us that, that I need to add to that answer in terms of MD D. Yeah, I'll give maybe a perspective on the read through to what we're thinking about. And then Chris can just remind the group, you know, what we expect to see from that study because the end points, Chris mentioned in his prepared remarks, but they are slightly different than, than what we would look like we would look at on the sponsor side. We've always said that, you know, these are two really important KOLS in, in terms of the group at Mount Sinai and at Baylor with Doctor Murrow and Doctor Matthew, and they have done a lot of the early and pioneering work around this mechanism in, in major depression. And so we're very happy to support them in terms of drug supply and collaborate with them, their key collaborators with us that said, you know, it's a small ist at two medical centers. And it's not something that we're reading through to our own MD D program. You know, we've committed to running three phase three clinical trials in major depression with the 20 mg dose of of is that your calendar? And as we mentioned, the first of those studies, ex Nova two, we've made really nice progress and that'll be up and running shortly. So I really no read through in terms of what that study may show. We look looks like we'll have top line data from that study in the first half of 2025. Chris, do you want to add your perspective?

Sure. Just as a reminder, the investigator initiated trial is has enrolled 60 patients, one in one arm and placebo and one arm in active. And as a reminder, our Ex Nova study had like 168 patients. And as we go forward into phase three, our phase three program, phase three studies are going to have 450 patients. So I'm I'm just trying to make the point that the investigator initiated trial is relatively small in size 3,030 patients per treatment arm. And and so it's underpowered from the standpoint of the clinical outcomes like Mori and shop shops, what it is powered for is to show improvements in FMRI based upon the FMRI work that was done with the Zyga in moderate to severe depression. And so it will be interesting. I think two things will be interesting from that study. One is, you know, is there a read out on FMRI, which is, it's a bit academic, but it'd still be quite interesting to, you know, to understand why this mechanism is helpful in major depressive disorder. The hypothesis is that it helps out with the reward circuit. So that'll be interesting. But to Ian's point, it's not going to gate our phase three plans. And the other thing that, you know, I think this study will be interesting is, you know, we saw great tolerability in the in, in our phase two study. And so it'll be nice to confirm that in or confirm or refute that in the you know, in when we see those results next year.

That's all I have. Thanks.

Thank you, operator. We can go to the next question.

Tessa Romero, JPMorgan.

Hi team. This is Caroline Pocher on for Tessa Romero with JP Morgan. Thanks for taking our questions. So, first from us, when can we expect to learn more about the clinical profile of the lead nav 1.7 candidate, including the level of receptor occupancy and potentially its signing site? And then if I could just sneak another one in. Based on your prepared remarks, it sounds like a proof of concept study is in the cards for next year. Could you just frame what such a study could look like for NAV, 1.7? Thank you.

Great, thanks very much. I'm happy to, to take that one. Yeah, we've, we've been, we've, I think a lot of the overall properties you've, you've, you've hit a couple of receptor occupancy and binding site. I mean, it's even broader than that in terms of just the selectivity profile, the bio distribution. There's a number of things that we track that I think we've learned a ton from the field. We haven't provided a lot of that information publicly and I don't think you're going to hear a lot from us. I think that's really important learnings that we've made that were incorporated into our program that we're not sharing broadly. You know, but needless to say, you know, we believe we have the right profile of molecules to really run the correct human experiment to see whether selective NAV 1.7 sodium channel inhibition with, you know, high receptor occupancy can provide analgesia. So I, I think we're, we're very comfortable that we have the right profile to test the hypothesis in humans which what we're really excited about in terms of the clinical development plan. So the initial study will be a standard you know, first in human study, Sad Mad. And then when we talk about proof of concept, not fully designed yet, but probably is no surprise. We're really thinking about running a proof of concept study in Bunionectomy. So we're starting to bring all of that planning together. But first step would be to get through G LP toxicology and and file an IND and, and get into the first in human studies.

Andrew Tsai, Jefferies.

Hey, good afternoon. Thanks for the updates. Thanks for taking my question. Maybe a brief question is just for the ongoing XOL studies X to two and three. What are you assuming for the placebo rate on cesar reduction? Is it similar to what you saw in the phase two B? And how are you controlling for placebo risk if there is one? Thanks.

Thanks Andrew. Chris, maybe I'll, I'll start because I might take the question in a little bit of a of a different direction. Andrew just to give you a, provide a little bit of context and perspective, I think would be helpful. And then Chris, maybe you can just weigh in on controlling the placebo rate in, in epilepsy studies in terms of jurisdiction and quality of sites that we're, we're working with. But Andrew in terms of our modeling because I think the question really comes down to what are we comfortable with in terms of the study design and the powering and the statistical analysis. So, what we've done is we've looked at all of the data we generated in the X Tole study, obviously, that was a large forearm study, three active doses and placebo. And that's really forms the basis of our statistical model on powering. So we've used the actual CBO rates, which if you recall from our ex to study. But just as a reminder that was kind of in the high 10s in terms of the placebo rate and, and that's kind of what we expected going into the phase two study. So I think it was really, you know, well executed. And, and what we would expect and then we can take those actual data in terms of the placebo rate, the active rate, the standard deviation into our model for phase three. And as I think, what we said previously is that the high dose of 25 mg, we have more than 99% power and we have around 90% power for the lower dose of 15 mg. And so in terms of the sizing of the studies, we really went off that lower dose because we have considerable power at the high dose. Chris maybe just you can comment on the execution of phase three in terms of placebo rate.

Yeah, I mean, one of the luxuries of, of epilepsy compared to other areas of neurology or psychiatry is is the translatability of the data going from phase two to phase three.

So, but that said there are several things that we're doing to try to mitigate the risk of a, of an increasing placebo effect and it largely has to do with geography. So there are known geographical regions where the placebo effect in epilepsy is higher relative to others. And the other thing that we've used is to target experienced sites, not just experienced sites based upon other drugs, but actually sites that have had experience working with the Z two counter. And then we've also been fairly picky about the sites that in general that we allow into the study in terms of their experience with, with epilepsy. So you could, you know, potentially open up a study like this to many other sites. And we, we've been quite choosy and, and most all of our sites have, you know, dedicated expertise within epilepsy. So those are the main ways in which we're, we're working on mitigating the placebo effect going from phase two to phase three.

Awesome. And I'll Chris, I'll, I'll add and Andrew, I'll, I'll add one more, which I think is really interesting is is the use of electronic diaries. And, you know, when we were initiating the Expo study, that was a real conversation internally because it was where it seemed to be a transition between companies using and sponsors using paper diaries or electronic diaries. And obviously, we can't run the experiment twice. But I, I think we do have a feeling internally that the electronic diary and the technology that we used in phase two that we're and we're using electronic diaries in phase three as well. Has helped on, on that side because we're continuously reminding patients to enter in their seizure data. And we can track that real time in the cloud to make sure that there's not missing data. I think that's also beneficial.

Brian Abrahams, RBC Capital Markets.

Hi there. Thanks for taking my question and congrats on the continued progress. As we head into Aes, I'm wondering if you could talk a little bit more about what some of the highest focus elements of the 36 month data will be relative to prior cuts, your level of continued of confidence in the continued safety profile. And then some of the key aspects that you're going to be highlighting and seeking input on there as you ramp up your presence and engagement. Thanks.

Thanks Brian. Actually, yeah, really important questions. I I think this Aes is, is really the most important medical Congress in, in Apple C and, and it's a huge amount of planning for our team going into it. We're going to have an incredible presence there and we're really excited about showcasing all of the work we're doing across the portfolio. So maybe I'll start and and, and both Chris Kenny and Chris Von SERN to, to provide their perspective as well because both of their teams are going to have a really large presence there, both as we continue on our medical communications side as well as the preparation on the commercial side of the business. But all, all my perspective initially on the 36 month data. So the nice thing is Brian, you, you've seen the ole data cuts from us before. So you're going to see consistency there. You're going to be, you're going to see you know, all of the patients have gone through 36 months. We have a cut of those data where we can show what the population looks like in terms of the seizure reduction. And as we've mentioned, we can, we've seen you know, improve seizure reduction over time for those that stay on drug just as a reminder. The second thing we'll see is just what the seizure freedom rate is. And that number, you know, continues to go up because patients are on the drug for longer. And so for that 12 month seizure freedom rate, which is really kind of the focus of the clinical and medical community. Is that more patients have the opportunity to have that 12 months of seizure freedom. So we're excited to be able to communicate that I don't want to lose the point that Chris Kenny made in prepared remarks. You shouldn't, you know, if we look at the literature that this patient population, given the number of drugs that they have failed, and kind of the refractory nature of them, we really shouldn't be seeing seizure freedom or the literature would suggest it should be less than 5% but we've seen considerably higher seizure freedom in our in our 24 month cut of the data last year and we'll be updating it for 36 months this year. And on the safety side, you know, one of the things again that gives us a lot of confidence is we've seen a real consistency in the safety profile. So we will provide a safety update. But the types of adverse events that we're seeing in the double blind period is consistent with what we're seeing an open label extension as well. So as we mentioned, now that we have patients over five years of dosing and we have over 600 patient years of exposure. We're really, we're really understanding the adverse event and safety profile over all of the molecule and have real comfort and confidence around that. But Chris Kenny, why don't you start with your perspective? And then Chris Von Seger and I know this is a big meeting for your team as well.

Yeah, it's our Super Bowl. We have a lot going on at Aes above and beyond the, the open label extension poster. But that's what Brian, you focused. The, the question on that. I think Ian covered it pretty thoroughly. The only thing that I'll add is that we'll also have retention rates out for a longer period of time, not just at one year in year, but up to three years. And I think what we're seeing is that patients who, you know, once they reach two years, they really tend to stay in the study for, for a long time. And and just to build on what Ian said about seizure freedom, just the longer that study goes, the longer we're able to look at seizure freedom over longer periods of time. I think you'll be impressed with the data. Chris?

Yeah and beyond just the data platform itself, which we're really excited about AES reference. That's a phenomenal opportunity for us to engage with potential future prescribers in this, in in this marketplace. And, and we think about AES is a high concentration of epileptologists and broader neurologist with a focus on epilepsy. And our team is going on mass in order to have the opportunity to interact with as many potential both key opinion leaders as well as potential future prescribers in this marketplace as possible to hear feedback on it two calendar, the profile and how it could potentially fit into a marketplace. So this this meeting represents as Chris has already mentioned our Super Bowl for not just data but the opportunity to interact with a number of leading positions in the space.

Brian Skorney, Baird.

Hi, this is Luke on for Brian. Thanks for taking the question. On F OS. Can you share your current thinking on bringing a Z two calendar into development for pediatric patients? And is this something that could commence ahead of XOL two data? And is there anything unique from Xol two and how you would conduct a study in these patients? Thanks.

Thanks, Luke. Yeah, good questions. We haven't actually talked about the pediatric development probably for a few quarters now. So a nice reminder. So yes, we have agreed upon pediatric plans with both FDA as well as E MA. So we know exactly what we need to do to bring the molecule into younger patients. So just as a reminder in F OS, XL two and L three are, are, are focused on adults actually in our primary generalized tonic clonic seizure study, we're going down to 12 year olds. So that was based on some D A feedback. So that study is looking at 12 and above. But we have an agreed upon plan and, and essentially you go through younger cohorts of patients over time. There's nothing specific in the X tool two data that we're looking for that necessarily informs there, a lot of the work we're doing is really the pediatric formulation, juvenile, talk to the the other work that we need to do to get into younger patients. So a lot of that work is happening in parallel. And then over time, you'll see kind of these age groups of cohorts as we step down, all the way into very very young patients over time. So the pediatric plan is ongoing kind of in parallel in the background. And and you'll start to see some clinical development over the next couple of years in younger F OS patients. And then, as I mentioned on the primary generalized side, we're already down to age 12.

Yeah, the, the only thing I'll add to that is that you asked a question about Luca, you asked about the unique take on the pediatric. And the, the only other thing that we need to take into account is that of course, those patients are lighter in weight. So we have to, to make dose adjustments, but that, that's it. Otherwise I covered everything. Thanks.

Jason Gerberry, Bank of America.

Hey, guys, thanks for taking my question. Mine just is a patent question actually. So, specifically your food effect patent. You know, my understanding is the strength of these patents tends to be, you know, can you get some sort of incorporation in the product labeling around the food effect. Such the generics wouldn't be able to eventually one day carve it out in their own insert. So just wanted to get your confidence when you think about the phase three study protocol. You know, and getting that label language around a recommendation for dosing close to meal time, which I think is sort of a key to that bioavailability argument with that patent and, and just wanted to understand kind of how you're thinking about that and the strength of that patent. Thanks.

Thanks. Yeah, thanks, Jason II. I think you framed it really well. Sherry can go into the details on, on our approach.

Yeah, I won't, I won't get into too much detail on this. Jason, as I'm sure you can appreciate there's some sensitivities around this, but look overall we're very comfortable in this food effect pattern, but more broadly in our patent portfolio, which takes us out to 2039 40 absent extension of term. But on the food effect point specifically, so we, we do have a food effect with this molecule which is unique to that two calendar. So it's not something that is seen broadly with the mechanism. So it wasn't for example, seen with the ZO be.

And we understand it's not seen with other KB modulators and development. Not something that was therefore predicted by us But yes, we have been dosing is that two calendar with food, in proximity with the evening meal through our phase two study X tool as well as in phase three development, both in our epilepsy program as well as in MD D. So we do reasonably expect that that will be on label at the end of the day.

Given that's how the drug has been dosed. And you know, not doing so, would potentially have implications on both or either of efficacy and, and you know, tolerability.

Sarah Schram, William Blair.

Hi. Yeah, congrats on another great quarter and thanks for taking my questions. So, given what we know about other sodium channel targeting therapeutics in the clinic to treat pain. Would you expect to pursue both acute and chronic pain indications or do you anticipate a little bit more of a narrow focus? I know you mentioned Bunnik studies earlier, but is there kind of anything specific to NAV 1.7 that would be more well suited to, you know, one pain setting or the other and relatedly give your expertise in ion channel chemistry. Would you ever look to develop a NAV 1.8 inhibitor or do you see that space is increasingly crowded here?

Thanks, sir. Yeah, happy to answer those questions. So a priority, the target of nav 1.7 does not lend itself just to acute or chronic, no deceptive or, or neuropathic. So, as we sit today and, and with the caveat that it's still early days, this is still a pre clinical asset. I think we want to do a proof of concept study like bunionectomy to show, you know, target engagement and that we can get an analgesic effect. But as we think about the mid and later stage clinical development, nothing's off the table right now. So I think we would be looking at all of those things because as I mentioned, kind of going into this, we're not guided one way or another based on the genetics or based on the target. In terms of you know, that 1.7 versus 1.8 that's a question we often get, you know, we like 1.7 as a target, a number of reasons, we think the genetics are stronger. I think you mentioned it's a less competitive space. I think it's been harder chemistries. And I think we have a real leadership position there that, that, that we can capitalize on. You know, we have some other ideas on where we may want to go, which we haven't really talked about publicly, but we don't have a formal NAV one, a program just to address that, that question head on. We've really focused on NAV 1.7. Because I think it is a target where we're uniquely suited to be able to run the human clinical experiment.

Paul Choi, Goldman Sachs.

Hi, thanks for taking our questions. Clinical trials.gov is currently showing that the XOL three study will reach primary completion just four months after XOL two. So presumably the, the top line results should be available roughly or concurrently with your plan ND A filing for. Is that the call following exto two? So can you maybe just update us on your latest thinking of how exto three might figure as part of your, your data strategy for your filing will be primarily included in the ND A or is it primarily for the European filing? Just your latest thoughts there would would be great. Thank you.

Yeah, thanks Paul. I'm happy to start first. If you've got comments, please, please add in. Yeah, I mean, we said for for some time that we've prioritized X tool two over X to three. And that's being pulled through a couple of different ways. One, X to two was just initiated before X tool three in terms of those first clinical sites up and running. We also prioritized a number of the sites that had experience with the molecule into X tool two and we did have a a bias in jurisdiction as well where you know, these studies get up and running generally quicker in the US than they do in some other jurisdictions. And so we've biased a number of those sites into X tool too. So, and the, and the, and the priority and the focus on X tool too is really because that's on the critical path. As you've mentioned, the filing, the ND A and, and commercialization in the US, in terms of next to three. Yes, we think it's important for filing in jurisdictions outside of the US. So you're absolutely right there. And it's really important for our overall safety database. So, you know, obviously we think about safety in terms of the requirements under, under IC H but also just exposures in, in the labeled population. So, you know, I think we're going to have a huge, we've talked a lot this afternoon about our long term exposure. We're going to have lots of long term exposure, but I think we're going to have, you know, a lot of unique exposures as well, both with X to X to two X to three, and exact and all of the open label work. So, you know, I think that kind of provides the perspective in, in terms of how the interplay between the two studies. Chris Kenny, anything that I missed.

No, you didn't miss it, but I just think it's really worth emphasizing that we are positioning the X Tole study as our first pivotal trial in focal onset seizures. Once we get the second trial, presumably ex toll two, we will submit the ND A so that there will be no hold up waiting ForEx toll three to, to submit the NDA. I just want to be, I just want to make sure that's absolutely clear.

That's simple.

Daniel Brill, Raymond James.

Hi guys. Thanks so much for the question. Chris, you commented during the prepared remarks that an X tool is that two calendar demonstrated the best placebo controlled efficacy to date. If the effect size happens, diminish an X tool to relative to X tool, what impact might that have if any on its value proposition? Thanks so much.

You want me to go in.

Chris, do you want me to start and then you carry on?

Okay, cool. Thanks, Danielle. Yeah, I mean the the message really is that I think we set an incredibly high bar here, right? So in terms of our review of the literature with all the caveats of cross trial comparisons we believe is that your calendar has the best efficacy on a on, on a placebo adjusted basis. So looking at 25 mg, the M PC primary end point in X toll minus the placebo rate has has the highest number that we can see in the literature. And just as a reminder in the most severe or refractory population, ever trialed, at least based on our review of the literature. So I know we're doing cross trial comparisons, but I think it's a very impressive efficacy outcome and has set a very, very high bar. Because as we've just talked about in the last question because we're filing on XOL and X tool two that doesn't change. Right. We, you know, no one is going to those data are completed that double blind is unblinded, we have those data already. So, you know, the nice thing about epilepsy is we see this reproducibility and consistency study to study, but there's always going to be differences and I think there's always going to be a different rate. You know, and so to your very specific question, Daniel, if the X tool two data aren't quite as robust as X tool, I still think we have the X tool data and X tool two we believe are, are going to be confirmatory that this is an efficacious agent and an important molecule and there's all of the other attributes as well. So we actually don't anchor too much on exactly what the efficacy readout is going to be. Inex tool two and what the implications may be.

And I think Chris Kenny should provide his perspective, but Chris Von Seger as well because ultimately, you know, I think you're asking a commercial question. If we see something different in in next tool too than in next tool. So Chris Kenny, maybe you want to add and then Chris Fons.

I'll just say one thing quickly. I mean, we're, we really emphasize the ex toll data because it's what we have and because we think it's quite compelling, it's, it's not that we're looking at ex to two or three and saying, I think the data is going to be better or worse or the same. It's sort of hard to predict these things. So so it's really, we're just making that emphasis because it's, it's the actual data that we have in hand. But I mean, ultimately, what we need is for the trial to be positive and then we can submit the ND A Chris.

Yeah. And then if we, if we think about the positioning of zu counter in a potential future commercial environment, clearly, why, what we said in the past is that physicians are, are looking for new medicines to address continued seizures in this patient population and efficacy is that is an important value attribute. But when we think about efficacy there multiple dimensions beyond just the, the top line data, we, we're going to share the updated open label data which are going to show continued durable response and impressive seizure freedom data over time. That's the totality of the efficacy story. In addition to potential rapidity of onset is demonstrated by week one and then there are a whole host of other ease of use attributes that consistently are identified by physicians as a reason to turn to is at to counter for a patient who's continuing to suffer firm residual seizures. So, while efficacy is important, the totality of the data package associated with this molecule, we consistently hear time and time again is compelling. And therefore we believe it will will offer a really important treatment alternative to patients in this marketplace.

Marc Goodman, Leerink Partners.

Ian, can you just talk about the strategy for MD D program just in total with respect to, when are we going to get the second trial started? And the third trial started and how you're thinking about that, how to stagger it and you know, just in the same light as the way you talk about the epilepsy program just so we have an update. Thanks.

Yeah. Thanks, Mark. Yeah, very consistent with with the epilepsy program. So essentially, we want to run the phase three studies in MD D in parallel, but they just never practically start at the same time. So we're not gating you know, X Nova three on an outcome next Nova two. But there will be a natural stagger. It's usually kind of in, you know, a couple of quarters between, you know, we're right now focused on X Nova two and getting that up and running and then there'll be a bit of a natural delay before X Nova three is run. But both of those studies and then X Nova four, those studies will be run essentially in peril. Well, you know, as you know, the, the MD D studies are a little quicker to enroll in our epilepsy studies. And so, you know, maybe I'll kind of zoom out a little bit. And if we think about over the next couple of years, 2025 2026 2027 there's going to be a huge amount of clinical data coming from Zenon with the Z two calendar kind of across the entire portfolio.

Joseph Thome, TD Cowen.

Hi there. Good afternoon. And thank you for taking my question. Maybe as we think about the KV seven development candidates that you have in the early pipeline. How are those differentiated from? Is that the calendar? Do they have different selectivity, different PK or sort of what will you be looking for for those, those assets? And then related to an earlier question, would all of these have, I guess a new IP portfolio around it? Can you, can you talk a little bit about that as well? Thank you.

Yeah, thanks Joe. Yes, to answer your last question first. Yes, these are all this is all, these are all novel structures and novel Marcuse. So yes, all, all, all different intellectual property when compared to a static calendar, you know, one of the interesting things and discussions we have internally when we think about the KV seven molecules and, and, and maybe franchise is there's nothing specific in the profile of a Z two calendar that we're trying to change or improve on. So, you know, as you can understand these things are multi factorial, right, we're looking at a whole bunch of different properties on these molecules, but we haven't really zeroed in on any one specific thing, you know, you mentioned PK or selectivity. There's nothing one thing that we're really focused in on because I think the profile you know, as, as, as as Chris and Chris just mentioned is so compelling of is that to counter that said we absolutely have chemical diversity. And so these all these are novel. But we do have chemical diversity and in terms of really what some of those properties are going to be. I mean, I think we're really excited about the properties pre clinically, but I think the proofs really as we transition those into the clinic and we start to learn about the PK in a human and also making sure, you know, one of the nice things about epilepsy and I know we're going to go broader than epilepsy for our KV portfolio. But we also know kind of the exposure levels that we're looking for in a human because the translatability in terms of some of the pre clinical work. We know that we're in the, we'll be in the right range. We also know with the zu calendar at a certain exposure in the plasma, we're seeing an anti seizure effect, we're also seeing an anti depressant effect. And so we know we can look at that translatability from animals into humans as well. So yeah, it's a, it's a real exciting time for the early stage portfolio, you know, in addition to KV, with, with the 17 program and the 11 program, but I think you're going to see multiple molecules on KV seven, you know, mature and head into human clinical development over the next couple of years. And some of them will look, we expect will look more like a Z two calendar. And some I think will probably have some different properties which we'll learn about in the development.

Laura Chico, Wedbush Securities.

Hello. Thank you for taking our question. This is Dylan on for Laura Chico. We're just wondering. So how should we think about the cadence of readouts for the ion channel portfolio? And should we be looking for data in the 2025 time frame?

So, thanks for the question, Dylan, we haven't got to that level of granularity yet, I think from the prepared remarks and what you've seen in our press release and in our Q the KV seven molecules and the 1.7 molecules are a little bit ahead of where we are with NAV 1.1. So what we said is we're, you know, we're in IND enabling studies for, for KV seven and for and for NAV 1.7 so those molecules are going to transition you know, if everything goes well in the remaining non clinical studies, those will transition into human clinical development. Next year, I think, depending and we'll give updates during 2025 as those transition. And depending on the timing of that transition is when, you know, we'll have a better idea of when we're going to see some human PK data as well as our sad mad data. And then we can start talking about some of the properties of those molecules like we talked about on the last question, you know, the earlier question in terms of exposure as it relates to receptor occupancy in terms of our NAV 1.7 program. So I think we're going to learn a lot in those first in human studies. And then, and then we move into the proof of concept studies thereafter. So stay tuned for further updates in 2025.

No further questions at this time, I will turn the call back over to Sherry Aulin for closing remarks.

Great. Thanks everyone for joining us today. If we didn't manage to get to your question during the allotted time. We'll reach out directly to connect operator. We can now end the call.

And this concludes this conference call. You may now disconnect.