Xenon Pharmaceuticals Q3 2024 Earnings Call Transcript

Quartr
Provided by Quartr
November 12, 2024

There are 12 speakers on the call.

Operator

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. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question and answer session.

Operator

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

Speaker 1

Good afternoon. Thank you for joining us on our call and webcast to discuss Xenon's Q3 2024 financial and operating results. Joining me today are Ian Mortimer, Xenon's President and Chief Executive Officer Doctor. Chris

Speaker 2

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 and current and anticipated indications, addressable market regulatory success and commercial potential of our and our partners' product candidates, the efficacy of our clinical trial designs, our ability 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 AZETUKELINER and our expectation that we will have sufficient cash to fund operations into 2027.

Speaker 2

Today's press release summarizing Xenon's Q3 2024 financial results and the accompanying quarterly report on Form 10 Q will be made available under the Investors section of our website at xenon pharma dot com and filed with the SEC and on SEDAR Plus. Now I'd like to turn the call over to Ian.

Speaker 3

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, Isatucalner, to build upon our leadership position in the Kv7 space and to continue to mature our promising ion channel pipeline. Xenon's leadership position in the KV7 field is unmatched as Ozethu calendar represents the only highly potent and selective KV7 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 3 key areas.

Speaker 3

Continuing the execution of our Phase 3 AZETU Calendar epilepsy program, while raising the profile of AZETU Calendar with both physician and patient communities, advancing our Phase 3 AZETU Calendar MDD program with a focus on XNOVA-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 AZETTU calendar. As I said earlier, Xenon's leadership in the KV7 landscape is unmatched. AZETTU Calendar represents the most advanced clinically validated potassium channel modulator in late stage clinical development. Our substantial clinical experience with AZETTU 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 XTOL study that we believe demonstrates the best placebo adjusted results ever seen in a clinical study in patients with focal onset seizures.

Speaker 3

In our XTOL 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 ezetu 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, ezetuCalendar has other important attributes, such as 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 AZETU KALINAR could mean to the epilepsy community. As we continue to educate key stakeholders around the benefits of AZETU KALINAR, Xenon will have an increased presence at the upcoming American Epilepsy Society meeting or AES taking place December 6 through 10 in Los Angeles.

Speaker 3

We'll have new data presentations and updated results from our ongoing XTOL open label extension study. Patients in the XTOL OLE have now been on drug for at least 3 years with some patients in the OLE having more than 5 years of exposure to AZETTU calendar. 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.

Speaker 3

Further, we are in an incredibly fortunate position in that EZETU Calendar's attributes enable significant potential across both epilepsy and neuropsychiatry, including MDD and potential other indications. Physicians who treat MDD are looking for medications with novel mechanisms and favorable product profiles 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 3 MDD program before the end of this year. Shifting gears beyond ezetocalinir to our broader pipeline. Our discovery team has applied its many years of experience in ion channels to advance multiple KV7 product candidates that are chemically diverse from ezetocalinir 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.

Speaker 3

Today, we have multiple KV7 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 topic of our early stage pipeline, we continue to make meaningful progress within our NAV1.7 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 nav1.7. Conversely, individuals who experienced non precipitated spontaneous severe pain correlated with nav1.7 gain of function mutation.

Speaker 3

This identification of nav1.7 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 NAV1.7 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 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 NAV1.7 inhibitors within our portfolio of next generation modulators. Currently IND enabling work is underway with a lead NaV1.7 development candidate in support of our goal of filing an IND or equivalent in 2025, enabling us to generate important de risking proof of concept data. In addition to NAV1.7 and KV7, we are also advancing potentiators of NAV1.1 with the aim of addressing the underlying etiology of Dravet syndrome and delivering a disease modifying therapy.

Speaker 3

In support of our hypothesis that a precision medicine therapy for Dravet syndrome should restore NaV1.1 activity specifically without impacting other neuronal functions or proteins. We look forward to presenting some of our preclinical NaV1.1 data including protection against spontaneous seizures and SUDEP as well as strengthening long term potentiation at the upcoming AES meeting. These data support an incredibly compelling profile for a small molecule NaV1.1 potentiator 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, Doctor.

Speaker 3

Matthew Ronshime joined our senior executive team as Chief Operating Officer based in Boston, overseeing our R and D operations and providing strategic and operational leadership for our pipeline of small molecule programs and preparation for the anticipated commercial launch of AZETTU KALINAR. MAT's extensive operational pharmaceutical development and manufacturing expertise are important as we expand our Phase 3 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 ongoing outreach with healthcare providers at key medical congresses. Chris, over to you.

Speaker 4

Okay. Thanks a lot, Ian. I'm pleased to report that our late stage clinical development programs for zetucalynor are progressing as planned. Our Phase III epilepsy program includes XTOL-two and XTOL-three in focal onset seizures and exact and primary generalized tonic clonic seizures. Importantly, the first top line focal onset seizure data readout from XTOL-two is anticipated in the second half of twenty twenty five.

Speaker 4

In support of an anticipated NDA filing, we plan to submit the results from XTOL-two along with the existing data package from XTOL and additional safety data from other clinical trials. In parallel with the significant progress made across our Phase III AZETU KALNA programs, our medical affairs team continues to engage with the broader medical community to highlight the robust scientific evidence generated to date. We are in an enviable position as not only can we showcase the positive results from our completed X TOLL trial, but we have our ongoing 7 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. Xenon had a strong presence, presenting 3 posters and hosting a scientific exhibit.

Speaker 4

We successfully engaged with key opinion leaders, prescribing clinicians and principal investigators from our study sites. Many of our discussions centered around the XTOL data, which we believe demonstrate the best placebo adjusted clinical efficacy in the most refractory patient population trialed 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 XTOL open label extension study, which shows increased seizure reductions with patients on AZETU calendar out to 30 months experiencing a greater than 90% reduction in median monthly seizure frequency. Additionally, approximately 1 in 4 patients on AZETO calendar for at least 2 years in the XTOL open label trial have been seizure free for a full year or longer, giving both us and the epilepsy community tremendous confidence in AZEDU Calendar'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 3 anti seizure medications is less than 5%.

Speaker 4

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 AZETU 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 AZETUKALINAR's 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 MDD space.

Speaker 4

With our Phase III MDD program, the first of 3 planned Phase III clinical trials examining ezetuCalinir in 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 2 ex Nova data, discuss the potential use of AZETU calendar as a treatment for MDD and outline our near term plans to initiate a Phase 3 program in major depressive disorder. We continue to emphasize AZETTU calendar's potentially differentiated profile versus standard of care agents in MDD as physicians continue to have a particular interest in AZETTU Calendar's novel, selective, Kb7 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 XTOL open label extension study. We're excited to be advancing another late stage clinical development program for AZETTU Calendar with the hope of addressing the needs of patients diagnosed with MDD who are still struggling to find effective treatments.

Speaker 4

We also continue to support the investigator led MDD study conducted by Doctor. James Murrow of Mount Sinai School of Medicine and Doctor. Sanjay Mathieu at the Baylor College of Medicine. This 60 patient placebo controlled Phase 2 trial has a functional primary endpoint with the objective of evaluating the effect of AZETU Calendar 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 8 as assessed by functional MRI. Also, the study is evaluating secondary endpoints that include MADRS and SHAPS.

Speaker 4

Patient enrollment was recently completed and results anticipated in the first half of twenty twenty five. Now looking ahead, we're incredibly excited to expand our presence at AES this year as part of our ongoing outreach to the medical community. As the premier epilepsy conference, AES 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 5 accepted abstracts at this medical meeting and look forward to presenting these posters, including an update to our XTOL open label extension study.

Speaker 4

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 AZETU Calendar and our broader pipeline. I'll now turn the call over to Sherry, who will provide an overview of our Q3 financial results and upcoming milestones. Sherri?

Speaker 2

Thanks, Chris. Looking briefly at our Q3 financial results, as of September 30, 2024, we had cash and cash equivalents and marketable securities of $803,300,000 compared to $930,900,000 as of December 31, 2023. Based on current operating plans, including the completion of the AZETTU Kelner Phase 3 epilepsy studies and fully supporting late stage clinical development of AZETTU Kelner and MDD, we anticipate having sufficient cash to fund operations into 2027. I'd 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.

Speaker 2

1st and foremost, we're driving towards the highly significant data readout from EXHIL-two expected in the second half of twenty twenty five. Importantly, positive results from EXTL-two will enable the submission of our NDA with the goal of advancing ezetu Kelner towards commercialization. In the MDD program, we're anticipating results from the investigator sponsored Phase 2 proof of concept study of AZETU Kelner in MDD in the first half of twenty twenty five. In addition, our company sponsored broad Phase 3 MDD program will be well underway with the initiation of XNOVA II anticipated before this year end. As we continue to advance our early stage preclinical pipeline, we anticipate filing multiple INDs or equivalent in 2025 with the goal of initiating 1st in human trials across multiple targets, while also exploring other potential indications for AZETTU Kelner that may be well suited for late stage clinical development.

Speaker 2

With this in mind, we have built a foundation of strong thoughtful fiscal management, which positions us to execute on our planned strategies to advance AZETTU KELNER through late stage clinical development in both epilepsy and MDD, 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 AZETTU Kelner's 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 the vec2 calendar in the future treatment of epilepsy at the upcoming AES meeting, where we will also present the latest data from our ongoing ex Toll 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 JPMorgan conference, which will give us an opportunity to kick off the year and outline our key goals for 2025 in more detail.

Speaker 2

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

Thank you. We will now begin the question and answer session. Your first question comes from the line of Paul Matteis with Stifel. Your line is open.

Speaker 1

Hi there. This is Julian on 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 enrollment dynamics and whether things are tracking according to your expectations. Any other details or learnings perhaps since our last quarterly update?

Speaker 1

And then secondly, quickly, just on the NDD investigator sponsored study, just curious on how you perceive that study either reading on to or not reading on to your Phase 3 pivotal program and thus confidence in execution of your own study? Thank you.

Speaker 3

Thanks very much for the question. So I'm happy to take the first one and maybe start on the second one. And Chris Kenny, you can provide your perspective on the IST and MDD as well. Yes, obviously we get a lot of questions on just how we're doing in the Phase 3 epilepsy program. We're really comfortable where we are.

Speaker 3

I'm not sure anything's changed in the last quarter to your very specific question. 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. Obviously, we always get the best information we can and currently the guidance for XTOL2 is to have top line data in the second half of next year. So I don't think there's anything specific that you haven't heard from us and seen from us that I need to add to that answer.

Speaker 3

In terms of MDD, yes, I'll give maybe a perspective on the read through to what we're thinking about and then Chris can just remind the group, what we expected to see from that study because the endpoints, Chris mentioned in his prepared remarks, but they are slightly different than what we would look like we would look at on the sponsor side. We've always said that these are 2 really important KOLs in terms of the group at Mount Sinai and at Baylor with Doctor. Murrow and Doctor. Matthew. And they had done a lot of the early and pioneering work around this mechanism in major depression.

Speaker 3

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, it's a small IST at 2 medical centers, and it's not something that we're reading through to our own MDD program. We've committed to running 3 Phase 3 clinical trials in major depression, with the 20 milligram dose of ezetrocalendar and as we mentioned the first of those studies ex Nova 2 we've made really nice progress and that'll be up and running shortly. So 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 twenty twenty five.

Speaker 3

Chris, do you want to add your perspective?

Speaker 4

Sure. Just as a reminder, the investigator initiated trial has enrolled 60 patients, one arm in placebo and one arm in active. And as a reminder, our exnova study had like 168 patients. And as we go forward into Phase 3, our Phase 3 studies are going to have 4 50 patients. So I'm just trying to make the point that the investigator initiated trial is relatively small in size, 30 patients per treatment arm.

Speaker 4

And so it's underpowered from the standpoint of the clinical outcomes like MADRS and SHAPS. What it is powered for is to show improvements in fMRI based upon the fMRI work that was done with ezogabine in moderate to severe depression. And so it will be interesting I think 2 things will be interesting from that study. One is, is there a readout on fMRI, which is it's a bit academic, but it still be quite interesting to understand why this mechanism is helpful in major depressive disorder. The hypothesis is that it helps out with the reward circuit.

Speaker 4

So that will be interesting. But to Ian's point, it's not going to gate our Phase III plans. And the other thing that I think this study will be interesting is we saw great tolerability in the in our Phase 2 study. And so it will be nice to confirm that in or confirm or refute that in the when we see those results next year. That's all I have.

Speaker 4

Thanks.

Speaker 3

Thank you. Operator, we can go to the next question.

Operator

Next question comes from the line of Tessa Romero with JPMorgan. Your line is open.

Speaker 5

Hi, team. This is Caroline Pocha on for Tessa Romero with JPMorgan. Thanks for taking our questions. So first from us, when can we expect to learn more about the clinical profile of the lead nav1.7 candidate, including the level of receptor occupancy and potentially its finding site? And then if I could just sneak another one in.

Speaker 5

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 NAV1.7? Thank you.

Speaker 3

Great. Thanks very much. I'm happy to take that one. Yes, we've been I think a lot of the overall properties you've hit a couple receptor occupancy and binding site. I mean, it's even broader than that in terms of just the selectivity profile, the bio distribution.

Speaker 3

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 we're incorporating into our program that we're not sharing broadly. But needless to say, we believe we have the right profile of molecules to really run the correct human experiment to see whether selective NAV1.7 sodium channel inhibition with high receptor occupancy can provide analgesia. So I think we're very comfortable that we have the right profile to test the hypothesis in humans, which we're really excited about.

Speaker 3

In terms of the clinical development plan, so the initial study will be a standard 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 GLP toxicology and file an IND and get into the first in human studies.

Operator

Next question comes from the line of Andrew Tsai with Jefferies. Your line is open.

Speaker 6

Hey, good afternoon. Thanks for the updates. Thanks for taking my question. Maybe a brief question is just for the ongoing XTOL studies, XTOL 2 and 3. What are you assuming for the placebo rate on seizure reduction?

Speaker 6

Is it similar to what you saw in the Phase 2b? And how are you controlling for placebo risk if there is 1? Thanks.

Speaker 3

Thanks, Andrew. Chris, maybe I'll start because I might take the question in a little bit of a different direction, Andrew, just to give you provide a little bit of context and perspective, I think it would be helpful. And then Chris, maybe you can just weigh in on controlling the placebo rate in epilepsy studies in terms of jurisdiction and quality of sites that 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 XTOL study, obviously that was a large forearm study, 3 active doses and placebo and that's really forms the basis of our statistical model on powering.

Speaker 3

So we've used the actual placebo rates, which if you recall from our XTOL study, but just as a reminder, that was kind of in the high teens, in terms of the placebo rate. And that's kind of what we expected going into the Phase 2 study. So I think it was really well executed 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 3. And as I think what we said previously is that the high dose of 25 milligrams, we have more than 99% power and we have around 90% power for the lower dose of 15 milligrams.

Speaker 3

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 3 in terms of placebo rate.

Speaker 4

Yes. I mean, one of the luxuries of epilepsy compared to other areas of neurology or psychiatry is the translatability of the data going from Phase II to Phase III. So but that said, there are several things that we're doing to try to mitigate the risk 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.

Speaker 4

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 AZETU calendar. 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 epilepsy. So you could potentially open up a study like this to many other sites and we've been quite choosy and most all of our sites have dedicated expertise within epilepsy. So those are the main ways in which we're working on mitigating the placebo effect going from Phase 2 to Phase 3.

Speaker 3

Awesome. And Chris, I'll add and Andrew, I'll add one more, which I think is really interesting is the use of electronic diaries. And when we were initiating the EXPOL 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 paper diaries or electronic diaries. And obviously we can't run the experiment twice, but I think we do have a feeling internally that the electronic diary, and the technology that we used in Phase 2 that we're and we're using electronic diaries in Phase 3 as well, has helped, on that side because we're continuously reminding patients to enter in their seizure data.

Speaker 3

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.

Operator

Next question comes from the line of Brian Abrahams with RBC Capital Markets. Your line is open.

Speaker 6

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 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.

Speaker 3

Thanks, Brian. Yes, really important questions. I think this AES is really the most important medical Congress in epilepsy and it's a huge amount of planning for our team going into it. We're going to have an incredible presence there. We're really excited about showcasing all of the work we're doing across the portfolio.

Speaker 3

So maybe I'll start and both Chris Kenny and Chris von Seggern 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 communication side as well as the preparation on the commercial side of the business. But my perspective initially on the 36 month data. So the nice thing is Brian, you've seen the OLE data cuts from us before. So you're going to see consistency there. You're going to see all of the patients have gone through 36 months.

Speaker 3

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've seen improved 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 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.

Speaker 3

I don't want to lose the point that Chris Kenny made in his prepared remarks. You shouldn't 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 24 month cut of the data last year and we'll be updating it for 36 months this year. And on the safety side, 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 in open label extension as well.

Speaker 3

So as we mentioned, now that we have patients over 5 years of dosing and we have over 600 patient years of exposure, we're really understanding the adverse event and safety profile overall 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, I know this is a big meeting for your team as well.

Speaker 4

Yes, it's our Super Bowl. We have a lot going on at AES above and beyond the open label extension poster. But that's what, Brian, you focused 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 1 year and 2 year, but out to 3 years.

Speaker 4

And I think what we're seeing is that patients who once they reach 2 years, they really tend to stay in the study for a long time. 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?

Speaker 7

Yes. Then beyond just the data platform itself, which we're really excited about, AES referenced that's a phenomenal opportunity for us to engage with potential future prescribers in this marketplace. And we think about AES as a high concentration of epileptologists and broader neurologists 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 its Etsy calendar, the profile and how it could potentially fit into a marketplace. So 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 physicians in the space.

Operator

Next question comes from the line of Brian Skorney with Baird. Your line is open.

Speaker 1

Hi, this is Luke on for Brian. Thanks for taking the question. On FOS, can you share your current thinking on bringing AZETYALINAR into development for pediatric patients? And is this something that could commence ahead of XTOL-two data? And is there anything unique from XTOL-two in how you would conduct a study in these patients?

Speaker 1

Thanks.

Speaker 3

Thanks, Luke. Yes, 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 EMA. So we know exactly what we need to do to bring the molecule into younger patients.

Speaker 3

So just as a reminder, in FOS, XTOL2 and XTOL3 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 FDA feedback. So that study is looking at 12 and above. But we have an agreed upon plan and essentially you go through younger cohorts of patients over time.

Speaker 3

There's nothing specific in the X TOLL-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 toxicology, 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 you'll start to see some clinical development over the next couple of years in younger FLX patients.

Speaker 3

And then as I mentioned on the primary generalized side, we're already down to age 12.

Speaker 4

Yes. 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. 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 make dose adjustments. But that's it. Otherwise, Egan covered everything.

Speaker 4

Thanks.

Speaker 3

Thanks,

Operator

Frank. Next question comes from the line of Jason Gerberry with Bank of America. Your line is open.

Speaker 1

Hey, guys. Thanks for taking my question. Mine just is a patent question actually. So, specifically your food effect patent, my understanding is the strength of these patents tends to be, can you get some sort of incorporation in the product labeling around the food effects such that 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 3 study protocol and getting label language around a recommendation for dosing close to meal time, which I think is sort of key to that bioavailability argument with that patent and just wanted to understand kind of how you're thinking about that and the strength of that patent?

Speaker 1

Thanks.

Speaker 3

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

Speaker 2

Yes, 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 patent, but more broadly in our patent portfolio, which takes us out to 20,39,40 absent extension of term. But on the Food Effect point specifically, so we do have a food effect with this molecule, which is unique to AZETU Kelner. So it's not something that is seen broadly with the mechanism. So it wasn't, for example, seen with azogabine, and we understand it's not seen with other KB modulators in development, not something that was therefore predicted by us.

Speaker 2

But yes, we have been dosing AZETTU Kelner with food in proximity with the evening meal through our Phase 2 study, x toll as well as in Phase 3 development, both in our epilepsy program as well as in MDD. 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 not doing so would potentially have implications on both or either of efficacy and tolerability.

Operator

Next question comes from the line of Sara Shram with William Blair. Your line is open.

Speaker 8

Hi. Yes, 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 bunionectomy studies earlier, but is there kind of anything specific to nab1.7 that would be more well suited to one pain setting or the other?

Speaker 8

And relatedly, given your expertise in ion channel chemistry, would you ever look to develop a NaV1.8 inhibitor? Or do you see that space is increasingly crowded here? Thanks.

Speaker 3

Thanks, Sarah. Yes, happy to answer those questions. So a priority the target of NAV 1.7 does not lend itself just to acute or chronic nociceptive or neuropathic. So as we sit today and with the caveat that it's still early days, this is still a preclinical asset. I think we want to do a proof of concept study like bunionectomy to show target engagement and that we can get an analgesic effect.

Speaker 3

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, NAT1.7 versus 1.8, that's a question we often get. We like 1.7 as a target, a number of reasons. We think the genetics are stronger.

Speaker 3

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 we can capitalize on. 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 NAV1a program just to address that question head on. We've really focused on NAV1.7 because I think it is a target where we're uniquely suited to be able to run the human clinical experiment.

Operator

Next question comes from the line of Paul Choi with Goldman Sachs. Your line is open.

Speaker 9

Hi. Thanks for taking our questions. Clinicaltrials dot gov is currently showing that the XTOL-three study will reach primary completion just 4 months after XTOL-two. So presumably the top line results should be available roughly or concurrently with your planned NDA filing for azetaculina following XTOLL-two. So can you maybe just update us on your latest thinking of how XTOLL-three might figure as part of your data strategy for your filing will be primarily included in the NDA or is it primarily for the European filing?

Speaker 9

Just your latest thoughts there would be great. Thank you.

Speaker 3

Yes. Thanks, Paul. I'm happy to start. Chris, if you've got comments, please add in. Yes.

Speaker 3

I mean, we said for some time that we've prioritized XTool II over XTool III, and that's being pulled through a couple of different ways. 1, XTool II was just initiated before XTool III 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 ex Toll II. And we did have a bias in jurisdiction as well where these studies get up and running generally quicker in the U. S.

Speaker 3

Than they do in some other jurisdictions. And so we've biased a number of those sites into XTOOL-two. So and the priority and the focus on XTOOL-two is really because that's on the critical path, as you mentioned the filing the NDA and commercialization in the U. S. In terms of XTOOL-three, yes, we think it's important for filing in jurisdictions outside of the U.

Speaker 3

S. So you're absolutely right there. And it's really important for our overall safety database. So obviously we think about safety in terms of the requirements under ICH, but also just exposures in the labeled population. So I think we're going to have a huge we've talked a lot this afternoon about our long term exposure.

Speaker 3

We're going to have lots of long term exposure, but I think we're going to have a lot of unique exposures as well both with XTOL, XTOL2, XTOL3 and Exact and all of the open label work. So, I think that kind of provides the perspective in terms of how the interplay between the two studies. Chris, Kenny, anything that I missed?

Speaker 4

No, you didn't miss it, but I just think it's really worth emphasizing that we are positioning the XTOL study as our first pivotal trial in focal onset seizures. Once we get the second trial, presumably ex Toll 2, we will submit the NDA. So there will be no holdup waiting for ex Toll 3 to submit the NDA. I just want to be I just want to make sure that's absolutely clear.

Speaker 3

Thanks, Paul.

Operator

Next question comes from the line of Danielle Brill with Raymond James. Your line is open.

Speaker 5

Hi, guys. Thanks so much for the question. Chris, you commented during the prepared remarks that in XTOL, AZETTU Calendar demonstrated the best placebo controlled efficacy to date. If the effect size happens to diminish in XTOL2 relative to XTOL, what impact might that have, if any, on its value proposition? Thanks so much.

Operator

You want

Speaker 4

me to go in?

Speaker 3

Chris, do you want me to start and then you carry on? Yes. Okay, cool. Thanks, Danielle. Yes, I mean the message really is that I think we've set an incredibly high bar here, right?

Speaker 3

So, in terms of our review of the literature with all the caveats across trial comparisons, we believe is that you counter has the best, efficacy on a placebo adjusted basis. So looking at 25 milligrams, the MPC primary endpoint in X TOLL minus the placebo rate, 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 XTOL and XTOL2, that doesn't change, right?

Speaker 3

No one is going to those data are completed. That double blind is unblinded. We have those data already. So 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. And so to your very specific question, Danielle, if the X TOLL 2 data aren't quite as robust as XTOLL, I still think we have the XTOLL data and XTOLL2 we believe 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.

Speaker 3

So we actually don't anchor too much on exactly what the efficacy readout is going to be in XTOOL-two and what the implications may be. And I think Chris Kenny should provide his perspective, but first one second as well because ultimately, I think you're asking a commercial question, if we see something different in XTOLL 2 than in XTOLL. So Chris Kenny, maybe you want to add and then Chris von Seggern.

Speaker 4

I'll just say one thing quickly. I mean, we really emphasize the XTOLL data because it's what we have and because we think it's quite compelling. It's not that we're looking at X Toll 2 or 3 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 it's really we're just making that emphasis because it's the actual data that we have in hand.

Speaker 4

But I mean, ultimately what we need is for the trial to be positive and then we can submit the NDA. Chris?

Speaker 7

Yes. And then if we think about the positioning of XepTcalar in a potential future commercial environment, clearly what we've said in the past is that physicians are looking for new medicines to address continued seizures in this patient population and efficacy is an important value attribute. But when we think about efficacy, there are multiple dimensions beyond just the top line data. 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 as demonstrated by week 1 efficacy.

Speaker 7

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 his epsilonir for a patient who's continuing to suffer from residual seizures. So while efficacy is important, the totality of the data package associated

Speaker 3

with this molecule, we consistently hear time

Speaker 7

and time again as compelling. And therefore, we believe it will offer a really important treatment alternative to patients in this marketplace.

Operator

Next question comes from the line of Mark Goodman with Leerink Partners. Your line is open.

Speaker 10

Ian, can you just talk about the strategy for MDD program just in total with respect to when are we going to get the 2nd trial started and the 3rd trial started and how you're thinking about that, how to stagger it and just in the same light as the way you talk about the epilepsy program, just we have an update? Thanks.

Speaker 3

Yes. Thanks, Mark. Yes, very consistent with the epilepsy program. So essentially we want to run the Phase 3 studies in MDD in parallel, but they just never practically start at the same time.

Speaker 9

So we're not

Speaker 3

gating XNOVA 3 on an outcome on XNOVA 2, but there will be a natural stagger. It's usually kind of in a couple of quarters between and we're right now focused on XNOVA II and getting that up and running and then there'll be a bit of a natural delay before XNOVA III is run. But both of those studies and then XNOVA IV, those studies will be run essentially in parallel. As you know, the MDD studies are a little quicker to enroll than our epilepsy studies. And so maybe I'll kind of zoom out a little bit.

Speaker 3

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 Xenon with the Zetu calendar kind of across the entire portfolio.

Operator

Next question comes from the line of Joseph Thome with TD Cowen. Your line is open.

Speaker 11

Hi there. Good afternoon and thank you for taking my question. Maybe as we think about the KV7 development candidates that you have in the early pipeline, how are those differentiated from Azatakeloner? Do they have different selectivity, different PK or sort of what will you be looking for, for those assets? And then related to an earlier question, would all of these have, I guess, a new IP portfolio around it?

Speaker 11

Can you talk a little bit about that as well? Thank you.

Speaker 3

Yes. Thanks, Joe. Yes, to answer your last question first, yes, these are all these are all novel structures, novel markets. So yes, all different intellectual property, when compared to a Zeta calendar. One of the interesting things and discussions we have internally when we think about the KV7 molecules and maybe franchise is there's nothing specific in the profile of AZET-two calendar that we're trying to change or improve on.

Speaker 3

So as you can understand these things are multifactorial, 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 mentioned PK or selectivity. There's nothing one thing that we're really focused in on because I think the profile, as Chris and Chris just mentioned, is so compelling of AZET2 calendar. That said, we absolutely have chemical diversity.

Speaker 3

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 proof is really as we transition those into the clinic and we start to learn about the PK in a human and also making sure 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 preclinical work, we know that we're in the we'll be in the right range. We also know with AZETTU KALINAR at a certain exposure in the plasma, we're seeing an anti seizure effect. We're also seeing an antidepressant effect. And so we know, we can look at that translatability from animals into humans as well.

Speaker 3

So yes, it's a real exciting time for the early stage portfolio. In addition to KV with the 1.7 program and the 1.1 program. But I think you're going to see multiple molecules on KV7 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 Azatutylcalnar and some I think will probably have some different properties, which we'll learn about in the development.

Operator

And our last question comes from the line of Flora Chico with Wedbush Securities. Your line is open.

Speaker 1

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 timeframe?

Speaker 3

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 Kv7 molecules and the 1.7 molecules are a little bit ahead of where we are with NAV1.1. So what we said is we're in IND enabling studies for KV7 and for NaV1.7. So those molecules are going to transition.

Speaker 3

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 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, an earlier question in terms of exposure as it relates to receptor occupancy, in terms of our NAV1.7 program. So I think we're going to learn a lot, in those first in human studies, and then we'd move into the proof of concept studies thereafter. So stay tuned for further updates in 2025.

Operator

There are no further questions at this time. I will turn the call back over to Sherry Olin for closing remarks.

Speaker 2

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.

Operator

And this concludes today's conference call. You may now disconnect.

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Earnings Conference Call
Xenon Pharmaceuticals Q3 2024
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