Q1 2025 Xenon Pharmaceuticals Inc Earnings Call
Thank you for standing by my name is Carly and I will be your conference operator today at this time I would like to welcome everyone to the Q1 'twenty 'twenty five xenon Pharmaceuticals 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. If you would like to ask a question. During this time simply press star followed by the number one on your telephone keypad.
Chad: You would like to draw your question Press Star one again. Thank you I would now like to turn the call over to Chad to year Jinan, Vice President of Investor Relations. Please go ahead.
Speaker Change: Good afternoon. Thank you for joining us on our call and webcast to discuss its first quarter 2025 financial and operating results. Joining me are in more of them.
Speaker Change: I'm, the President and Chief Executive Officer, Dr. Chris Kenny <unk>, Chief Medical Officer, and Sherri on Xenon as Chief Financial Officer.
Speaker Change: After completing their prepared remarks today, we'll open the call up for your questions.
Speaker Change: Please be advised that during this call we will make a number of statements that are forward looking.
Speaker Change: Statements regarding the timing of the potential results from clinical trials potential efficacy safety profile future development plans and current and anticipated indications addressable market regulatory success and commercial potential of our and our partners' product candidates.
Speaker Change: The efficacy of our clinical trial designs.
Speaker Change: Our ability to successfully develop and achieve milestones in our clinical development program, including the anticipated filing of biodiesel.
Speaker Change: The timing of the results of those filings and our interactions with regulators.
Speaker Change: Our ability to successfully obtain regulatory approvals and such.
Speaker Change: The timing of the topline data readout for our clinical trials that you're calmer and our expectation that we will have sufficient cash to fund operations into 2020.
Speaker Change: Today's press release summarizing our first quarter financial results.
Speaker Change: Company quarterly report on Form 10-Q will be made available under the investors section of our website.
Speaker Change: Dash pharma dot com and filed with the SEC and on SEDAR, plus now I would like to turn the call over to you.
Speaker Change: Thanks, Chad and good afternoon, everyone and thanks for joining our call today I'll begin with a brief review of highlights from the past quarter and our progress across our growing neuroscience focused pipeline, including progress on our phase III studies or is that your calendar in epilepsy are expanding colo clinical.
Speaker Change: <unk> work in psychiatry as well as our early stage programs that are entering first in human studies this year.
Speaker Change: After that I'll turn the call over to Chris who will share more details on our clinical development programs, including high level top line results from the completed investigator led Mdt's study.
Speaker Change: Along with an update on our recent engagement efforts to raise the profile of does that to caliber Sherri.
Jerry will close with a summary of our partnered program financial results and anticipated milestones.
Speaker Change: Starting with our is that your calendar phase III epilepsy program as.
Speaker Change: As you've heard from us consistently delivering data from our ex told two study remains our number one priority at <unk>.
Speaker Change: We are nearing the end of patient recruitment and ex told two which we expect will complete within the next few months with topline results anticipated early next year, while acknowledging the slight delay versus our prior guidance I want to emphasize that we are approaching the conclusion of the study and importantly progressing towards our goal of bringing this in.
Speaker Change: <unk>, new medicine to patients.
Speaker Change: From the outset to maximize study success, we have prioritized working with high quality experienced sites and monitoring key metrics rigorously throughout the study.
Speaker Change: As we approach the conclusion of this work we are very pleased that these metrics align consistently with our successful phase <unk> study.
Speaker Change: Bottom line, we continue to have high confidence in ex told to I'm sure the epilepsy community as excitement as we progress towards our phase III readout.
Speaker Change: It's this excitement that drives us and our scientific leadership and investment in the <unk> landscape.
As a reminder is that <unk> is the only <unk> seven opener and the only new ASM and development that is backed by long term efficacy and safety data from clinical studies of patients living with epilepsy now having amassed over 700 patient years of exposure in focal epilepsy patients.
Speaker Change: There remains a substantial need for new efficacious and well tolerated epilepsy therapies.
Speaker Change: Especially for those patients who continued to experience the debilitating impacts of focal seizures, even while taking multiple anti seizure medications and we believe that is that your calendar key attributes as seen to date demonstrate its potential to provide an important new option for the epilepsy community.
Speaker Change: We consistently hear positive feedback about the need for a new medicine to address continuing unmet needs in epilepsy treatments and there is excitement within the medical community about is that two calendar has potential to offer a novel mechanism without titration early onset of effect seizure freedom and mood.
Speaker Change: Benefits does that show calendar has the potential to be a best in class anti seizure medication that could offer significant and meaningful benefits into the future treatment of epilepsy.
Speaker Change: Shifting to broadening the use of is that your calendar beyond epilepsy inter neuropsychiatry enrollment is ongoing in our first phase III Mds study ex Nova to with our second MDT steady ex Nova three and our first phase III study in bipolar depression, both on track to initiate by midyear.
Speaker Change: In addition, and as mentioned in today's press release, we now have the final results from the investigator sponsored study of is that through calendar and MDT, Chris will provide some details on these results in a moment, but briefly the results are consistent with our expectations and our prior ex Nova study, including.
Clear drug activity on both Mad dress and shops based on separation between us that two calendar and placebo at every time point. We believe these results reaffirm the already strong scientific rationale to pursue further development in this high unmet need patient population.
Speaker Change: Moving now to our early stage pipeline there is significant momentum across our preclinical programs with multiple regulatory filings expected. This year to support the initiation of first in human trials across a number of validated ion channel targets. This broadening and building out of our early stage pipeline.
Speaker Change: As a direct result of the successful leveraging of our extensive knowledge and expertise in developing potassium sodium channel therapeutics.
As our diverse pipeline of early stage drug candidates continues to mature I'm incredibly proud of the considerable progress we are making across multiple programs targeting high end channels that include <unk> 717, and NAV. One one today I'll give you an update on each of these promising programs.
Speaker Change: Recognizing the potential broad applicability of the cave seven mechanism or is that too calendar. We have identified multiple chemically diverse kv seven development candidates and believes that this mechanism may have utility in a broad range of therapeutic indications, including seizure disorders pain and nurse.
Speaker Change: Gastric disorders, such as MTBE and bpd.
Speaker Change: I am pleased to report that a clinical trial application was recently accepted for <unk> hundred 11 20.
Speaker Change: <unk> seven channel O'connor that we intend to study as a potential treatment for pain and a phase one study in healthy adult participants is now underway.
Speaker Change: As a reminder, there is good clinical evidence supporting the development of novel selective <unk> seven openers optimized for pain.
Speaker Change: We also have a number of other JV seven molecules and Chemistries that will follow <unk> hundred $11 20.
Speaker Change: We also continue to make substantial progress within our NAV one seven sodium channel program, where we believe we may have addressed the limitations of first generation drugs targeting that one seven a.
Speaker Change: A key part of <unk> heritage involves our pioneering work that contributed to the strong human genetic validation of NAV, one seven as a pain target and we believe NAV one seven could represent a new class of medicines, which address the unmet medical needs for effective alternatives to opioids, we have nominated multi.
Speaker Change: Support selective NAV, one seven development candidates to date and <unk>, enabling work is complete for our lead candidate <unk> hundred one for which we expect to initiate a phase one first in human study in the third quarter of this year.
Speaker Change: Work within our <unk>. One program also continues to progress our preclinical work to date suggest the targeting now one one could potentially address the underlying cause and symptoms of dry eye syndrome.
Speaker Change: Data shows that dosing with an orally available small molecule CNS penetrant in highly selective NAV, one one potentiate or suppress induced seizures and improved motor function supporting the potential for improvements and drive a patient motor function.
Speaker Change: Are there in these animal models chronic dosing suppressed spontaneous seizures protected against sudden unexpected death in epilepsy are stood up and increase long term potentiation of potential cellular karla of learning and memory. These.
Speaker Change: These preclinical data are incredibly exciting and we anticipate that will lead Nab won one candidate will enter IND, enabling studies this year.
Speaker Change: This summer we plan to host multiple R&D webinars to showcase various early stage programs that will include deeper dives into mechanism underlying human genetics preclinical results and other supporting data as well as an overview of disease prevalence and unmet medical needs within certain patient populations. This first webinar will take.
Speaker Change: Place in June and we will focus on our approach to treating pain with drug candidates targeting both NAV, one seven and <unk> seven.
Speaker Change: As the non continues to advance promising late and early stage programs. I believe we are entering a catalyst rich period for the company as we near most importantly, the first phase III topline readout or is that to your calendar and Sos. This represents a major inflection point for xenon signaling our evolution from a clinical stage.
Speaker Change: Our commercial organization and I look forward to keeping you updated on our progress as we await results I'll now turn the call over to Chris who will provide some additional details around our clinical development programs and importantly, the ISP results as well as our broader outreach to the HCP and patient communities Chris over to you.
Chris: Alright, and thanks a lot.
Chris: A reminder, our phase III epilepsy program includes our two X two studies and focal onset seizures or progress that's ex tool to an ex told three and our exact study in primary generalized tonic clonic seizures or PG Tcs as Ian noted we're nearing the end.
Chris: Patient recruitment and ex told you in the next few months. Despite the modest change to our top line guidance, we remain highly confident in the conduct and quality of the ex told two study as Ian mentioned, we continue to see investigator enthusiasm around it is that two calendar and a high rollover into the open label extension study.
Chris: Consistent with rates observed index tool.
Chris: In addition, as with all of our studies, we track a number of key metrics throughout this study as we near the end of the next tool to we believe that we are seeing strong consistency on all of these metrics when we compare to our successful phase two B X Tole study.
Chris: We continue to be excited by the prospect of this first phase III <unk> study outcome and we believe the finish line is in sight as we look forward to completing patient recruitment in the next few months.
Chris: As we're getting closer to top line data, we continue our ongoing educational and scientific outreach efforts to raise the profile of the <unk> calendar amongst healthcare providers. Our team recently presented three Apple FC related posters at the American Academy of Neurology.
Chris: And that took place in early April building upon more than 700, plus patient years of data. We're excited to share our 36 month as their two calendar data from our ongoing X Tole open label extension study and F O S, which shows sustained monthly reduction in seizure frequency impressed.
Chris: Seizure freedom rates and a consistent safety profile, suggesting long term efficacy and tolerability of <unk> two calendar.
Chris: We also presented an exploratory analysis from our X tole study showing reduced seizure frequency rates across for focal seizure subtypes. These promising data support our conviction that is there are two calendar may offer hope for people will continue to seek new efficacious and well tolerated therapies.
Chris: To address the debilitating impacts of uncontrolled seizures.
Chris: And also provided another time the opportunity for us to connect directly with a broad range of health care providers and patient advocacy groups discussions at the conference were wide ranging and gave us the opportunity to present, the science and the data to date and highlight the mental health burdens associated with epilepsy.
Chris: And engage in meaningful discussions around the under detected and Undertreated depressive symptoms associated with epilepsy.
Chris: One of our poster presentations focused on patient reported survey data that we collected which further illustrates the substantial burden of illness for people living with epilepsy.
Chris: With reduced quality of life high seizure frequency.
Chris: As well as other comorbidities, such as anxiety and depression further underscoring the need for new treatments to help people living with epilepsy.
Chris: We also highlighted executive calendars potential neuropsychiatric disorders, such as MTV.
And bipolar depression based on scientific rationale and unmet medical needs before I dive into an update on our company sponsored clinical programs and neuropsychiatric indications I wanted to provide additional details and context from a recently completed investigator sponsored study of <unk> calendar.
Chris: MDT that was led by Doctor James Morrow at the Icahn School of Medicine Mount Sinai.
Chris: As a reminder, this study was designed as a 60 patient placebo controlled trial with a functional primary endpoint to evaluate the effect of the 20 milligram daily dose of the debt to calendar on brain measures a reward as measured by the change in activation within the bilateral eventual striatum.
Chris: From baseline to end of treatment at week eight as assessed by functional MRI.
Chris: And also to evaluate secondary endpoints that include an assessment of modules and shops chefs through an eight week period.
Chris: Despite being a small study the results provide additional evidence supporting the potential of the JV mechanism and is there do calendar to have anti depressants and anti hedonic effects, which is a significant unmet need in treating patients with depression.
Chris: Highlights of the ISP results include the following.
Chris: Compared to <unk> and what we expect in our phase III program, given our entry criteria. The investigator initiated trial enrolled a less impaired population as indicated by lower baseline modules and shop scores.
Chris: For both module and shops, two calendar numerically outperformed placebo at every time point measured.
Chris: As expected given the small sample size the improvements were not significant.
Chris: Looking specifically at modules compared to subjects in the placebo group subjects and use that to calendar group saw both early and larger improvements in module scores.
Chris: The separation was approximately two points at the first time point measured to confirming early onset of effect.
Chris: And peaked at a greater than four point delta between active and placebo at week six.
Chris: As a reminder, we six was the end of the study for ex Nova and is the M. Four Rfps Mbd studies, therefore, confirming and actually slightly outperforming our phase II <unk> data.
Chris: For the ISP. The study went out to eight weeks and the separation between active and placebo was less pronounced at week eight compared to week six due to a significant improvement in placebo between weeks six eight when looking at the individual patient data this effect could potentially be explained by three.
Chris: <unk>, whose module scores fluctuated considerably between week six and week eight all in the context of a small sample size.
Chris: Subjects in their two calendar group also saw earlier and greater improvements on shops measure of anhedonia, which is a core symptom of MD.
Chris: Again, we see the same pattern with early separation between exactly calendar in the placebo group in this separation continued throughout the study consistent with the separation as seen in our ex Nova study, including a greater than three point delta between active and placebo at week six.
Chris: On the safety side is that your calendar was generally well tolerated with an AE profile generally consistent with prior studies and the known mechanism. In addition, there were no reports of weight gain or sexual dysfunction, which are common adverse events with standard of care agents.
Chris: The most common adverse events include dizziness, and coordination and confusion.
As we look at the <unk> of the data most of these aes were mild or moderate in severity with only one serious adverse events deemed unrelated to exact to calendar and a low rate of treatment discontinuation due to adverse events that was comparable to placebo.
Chris: So in summary, as edgy calendar demonstrated consistent and numerically greater improvement on module shops at all time points measured importantly, the greater than four point and three separation between <unk> calendar and placebo on modules and chaps, respectively at week six.
Chris: Demonstrates meaningful drug activity and reflects the length of the double blind period in our phase III MTV program.
Chris: In addition, we believe the benefit risk profile of ejection calendar is reinforced as there is nothing unexpected or concerning in the adverse event profile seen in this study given the study design and small numbers.
Chris: The lead investigator Dr. James Merle has submitted an abstract to present these data at the American Society.
Chris: Clinical psychopharmacology.
Chris: Or <unk> later, this month and intend to submit for peer reviewed publication at a later date.
Speaker Change: Turning to xenon as efforts to expand the debt you Calvin argues in neuropsychiatry I wanted to first highlight that ex Nova to the first of three planned phase III clinical trials evaluating <unk> calendar in patients with Mds continues to enroll patients after initiating late last year and the next.
Speaker Change: The second study <unk> three is on track to initiate by mid year.
Speaker Change: We continue to engage with physicians, who treat patients with Mds to educate them about our ongoing clinical studies and the potentially differentiated profile of <unk> calendar versus standard of care agents.
Speaker Change: Of note physicians are interested in is that your calendars novel selective TV seven mechanism of action and its potential benefit on and had done yet.
Speaker Change: <unk> of onset as well as potentially favorable tolerability profile with data to date supporting no notable adverse effects on sexual function or weight gain.
Speaker Change: We also plan to run two identical clinical studies evaluating <unk> calendar and a mixed population of bipolar one and bipolar depression with the first study on track to initiate by mid year. After recently, receiving IND clearance from FDA.
Speaker Change: We look forward to providing more details around our apd.
Speaker Change: Registrational program once our first trial is initiated.
Speaker Change: In summary, as we drive towards the phase III readout, we believe that as that two calendar provides the promise of a new anti seizure medication to people living with the burdens of seizures and looking beyond epilepsy could address the needs of people living with neuropsychiatric disorders, such as MTV and bipolar depression.
Speaker Change: I'd like to now turn the call over to Sherri, who will begin by providing some additional detail around our partnered program before summarizing our financial results.
Sherri: Thanks, Chris now looking briefly at our financial results, we recognized revenue of $7 5 million during the first quarter related to a milestone payment in connection with our collaboration with Neurocrine secured by the initiation of a phase one study at <unk> 91, 355 <unk>.
Sherri: Active inhibitor of NAV, one two and now <unk> in development for the potential treatment of certain types of epilepsy.
Sherri: Cash and cash equivalents in marketable securities totaled 691 1 million as of March 31, 2025, compared to $754 4 million as of December 31, 2024.
Sherri: Just on current operating plans, including the completion of because that two calendar phase III epilepsy studies and supporting late stage clinical development or is that too calendar in MTBE and bpd, we anticipate having sufficient cash to fund operations into 2027.
Sherri: Given our proven track record of strong fiscal management <unk> is in a fortunate position of having a strong balance sheet to support multiple registrational programs for that to counter and the continued maturation of our early stage pipeline I would refer you to our news release and 10-Q report filed today for further details around.
Sherri: Our financial results.
Sherri: We're entering a transformational period for xenon as we evolve from clinical to commercial stage company. We believe that positive topline results from our phase III epilepsy program will enable an NDA submission to the FDA, but if all of the bad thing is that to counter towards commercialization.
Sherri: In addition, other late stage neuropsychiatric programs will be well underway by year end with two ex Nova trials and MDT expect it to be recruiting patients in our Registrational study in PPD also initiated by midyear.
Sherri: Our deep pipeline also contains multiple promising early stage therapeutic candidates across a number of ion channel targets supporting our goal to be a fully integrated premier neuroscience focused company on behalf of everyone on the xenon team were incredibly excited and denounce evolution and remain focused on taking important steps forward.
Sherri: To bring us closer to delivering at that key calendar to people living with epilepsy with that I will pause and open the call for your questions operator greater.
Speaker Change: At this time I would like to remind everyone in order to ask a question Press Star then the number one on your telephone keypad well pause for just a moment to compile the Q&A roster.
Speaker Change: Your first question comes from Paul Matteis with Stifel.
Speaker Change: We're taking a question.
Speaker Change: We were just wondering.
Speaker Change: Yes.
Speaker Change: The topline data epilepsy data in early 2026, how quickly could you file assuming thats positive and then just a second question you guys talked about tracking some key metrics could you provide any color on what those are.
Speaker Change: Yeah, just like kind of what those metrics are and how they compare to the STB. Thank you.
Speaker Change: Sure, Yes happy to address both of those questions. So on the top line data to NDA filing. So we haven't provided specific guidance, but I think many people have heard from us in the past and we will be able to refine this over time, but it's approximately six months from topline data to filing.
Speaker Change: Important to note is that it.
Speaker Change: As the clinical data that's on their critical path. So we know just how.
Speaker Change: Our broad and NDA filing is as it relates to the non clinical sections CMC clinical pharmacology all of the data.
Speaker Change: All of that is in really good shape and we are already writing certain sections of the NDA now and we'll continue to do that through the remainder of this year.
Speaker Change: On the metrics question, so theres a lot of things that we track in all of our clinical studies to really make sure that we believe we have.
Speaker Change: We're working with the highest quality sites, we're making sure we're getting the right patients and they conduct is there, but just to give you a bit of an idea in epilepsy, we have patient screening period, and we have a baseline period. Then the patients are randomized that goes through a double blind period, and then if they complete the double blind period, they have an ability to roll.
Speaker Change: Over into open label extension, so as we think about that Theres lots of things that we can kind of measure along the way so in that kind of screening.
Speaker Change: I'll give you some examples kind of in that screening and baseline period, we can look at the patient baseline characteristics of the demographics, what their baseline seizure burden is we can measure even before they get randomized what their compliance is going to be like two a diary. We can also look strong.
Speaker Change: The double blind at a number of things and then we can look at rollover rates into the open label extension as well. So there's a number of things that we kind of track.
Speaker Change: Along the way just to make sure that we're comfortable in terms of the way. The study is being conducted.
Speaker Change: Great. Thank you so much.
Speaker Change: Yep Yep.
Ken: Your next question comes from Ken <unk> with J P. Morgan.
Speaker Change: Okay.
Speaker Change: Hi, Ian and team good afternoon, guys and thanks, so much for taking our question.
Speaker Change: Following up here can you provide any quantification on how many patients you still need to recruit for external to any numbers you can put around that for us.
Speaker Change: What are you specifically focused on to ensure you meet this guidance or is it really just par for the course here we noticed on clinical trials that got that it seems like some additional trial sites have recently been added and finally can you talk to what the screen failure rate is coming out to be and is that similar to what you saw in <unk>.
Speaker Change: Thanks, so much.
Speaker Change: Sure I'm happy.
Speaker Change: Peter.
Speaker Change: <unk> My perspective crest, Steve can add to this as well.
Speaker Change: So yes, I think as you saw in the press release and with our prepared remarks is we're going to close so we feel we're in the next couple of months will be done.
Speaker Change: <unk> to predict exactly.
Speaker Change: Theres always we've talked about in previous calls.
Speaker Change: These ebbs and flows in a clinical trial like epilepsy, just Kevin.
Speaker Change: The number of clinical sites that we use overall and the number of patients that are screened or randomized from any given site is a reasonably small number that you do see some variability month to month and screening and randomization, but I think we feel good that we're.
Speaker Change: We're getting close to the end, we can see the finish line.
Speaker Change: We'll get there over the next couple of months.
Speaker Change: In terms of kind of new sites, yes, I mean look.
Speaker Change: Vast majority of the size thresholds who've been ups and tie up and running for some time, obviously in the early parts of a clinical trial. If we look back in a couple of years ago as the study was getting up and running.
Speaker Change: Those sites come online at different rates for a whole bunch of different reasons. Some of it's jurisdictional based and some of it is just the individual site as we work through contracting and site visits.
Speaker Change: A couple of sites that have come in late and the only reason there is because for whatever reason maybe they now have the resources ready to participate in a clinical trial or there was something else that prevented them from starting earlier, but I think it's a very very small number so I wouldn't.
Speaker Change: I wouldn't focus too much on that I think we should all be focused on is that we're getting close to the end here.
Chris: Chris any anything to add.
Chris: I think you covered it thanks.
Chris: Thanks for the question Hugh I guess, the one piece that you asked about was the screen failure rate. So.
Chris: <unk> already provided you with a number of metrics that we felt in the phase III program to to ensure that the quality and the conduct of ex told two is heading in the direction that we want and screen failure rate is one of them and so we haven't seen I think as you know the inclusion exclusion criteria are really quite similar between.
The two studies and in fact, there is sort of.
Chris: Pretty standard recipe that's used for Sos studies so it's.
Chris: Basically a very similar study to the phase two so we're seeing so not surprisingly based upon that we're seeing screen failure rates that are very similar.
Chris: Thank you.
Your next question comes from Brian Abrahams with RBC capital markets.
Brian Abrahams: Hey, good evening, thanks for taking my questions.
Chris: Really two from me I guess first.
Do you have any sense as to the reasons behind the slight timeline slippage.
Chris: For <unk> two.
Are there kind of implications on kind of competitive dynamics, there and any learnings.
Chris: That you can apply to Japan.
Patient finding in the commercial setting and then secondly on the Mount Sinai study it seems like in a more mild population I don't think they had a ham D entry criteria there.
Chris: There were fairly robust effects as good or even better than what you saw in your study.
Chris: Any thoughts on how that might impact I guess your phase III plan in.
Chris: In terms of your entry criteria or any modifications there or to the powering of your phase III and MPD, given what youre seeing coming out of Mount Sinai.
Brian Abrahams: Thanks, Brian.
Brian Abrahams: Chris I can take the first one just on on the timeline and any competitive dynamics and commercial staff and then do you want to address.
Brian Abrahams: Just any learnings from the ISP and any read through into into the phase III <unk> program.
Brian Abrahams: So Brian on your first question, Yes look we view this as a pretty minor delay we will get there in the next couple of months and we should see data early next year I think.
Brian Abrahams: As I mentioned on the last question when we kind of take a big step back we do see some variability just kind of month to month. So I don't think we read too much into this on the competitive side, we're not seeing a change there. So we're not seeing.
Brian Abrahams: The competitive dynamics change at the individual site level.
Brian Abrahams: Given the at least in our experience.
Brian Abrahams: Most clinical sites and maybe I should say most investigators folks are focused on one <unk> study at a time on the on the therapeutic side, they're generally not running multiple sometimes you'd get a handful.
Brian Abrahams: Different pis at an institution different pis may focus on different things, but for the most part.
Experience and feedback we've had from our clinical investigators there as they are focused on kind of one study at a time and given that we've been in this phase III program.
Brian Abrahams: Longer than our competitors have in terms of their clinical programs right now and I don't think thats, having any impact.
Brian Abrahams: I will just comment a little bit on the commercial setting because I think that's a really I think thats an important question when we look at clinical development and the inclusion exclusion criteria.
Brian Abrahams: Including the baseline seizure burden that's necessary to do the statistical analysis and the powering in a clinical study that is a very different population than what we think about in the commercial setting.
Brian Abrahams: All of the work we've done commercially from primary market research to feedback from physicians at Aes in all of the medical Congresses is there still this 30% to 50% of patients that are not getting good seizure control and are really looking for new therapies and as we've said a number of times, if we look at the profile and the atrophy.
Brian Abrahams: Or is that through calendar.
Brian Abrahams: We get this really warm reception and excitement about is that your calendar coming to market. It will be the first time, we have a novel mechanism in quite some time, if we look at the placebo adjusted efficacy from X Tole, we look at the long term open label data.
Brian Abrahams: No titration, the easy to use easy to use attributes and potentially the benefit on mood as well is that we see early onset and thats kind of a package that I think we haven't really seen in the treatment of epilepsy and so.
Brian Abrahams: I think the commercial excitement continues to be there and I would actually say the profile or is that your calendar coming off of Aes in Los Angeles, a few months ago and all of our outreach is the profile of the molecule just continues to grow in the medical community.
Chris: But Chris I'll, let you handle the second one in terms of the ISG.
Chris: Yes sure thanks, Ian so.
Chris: Thanks, Brian for the question.
Chris: Just going to say kind of one O make one overarching comment and then I'll answer your question directly.
Chris: I'm, just I'd like to zoom out for a second and just to acknowledge that.
Chris: In depression, having one study after the other be positive for any drug is challenging and what we're sitting on now is the second study in major depressive disorder using two calendar that suggests that this drug may have activity on depression and have tonia.
Speaker Change: Our Airbus now James Rose study the investigator initiated trial, but then don't forget that there were there actually there was another controlled trial with the Zagunis showed similar results and there was an open label as well. So we actually have four studies that are suggested two different drugs with the same mechanism of action is showing that this <unk>.
Chris: Mechanism shows promise.
Chris: And just on a high level, it's really I think it's.
Chris: Just reassuring I mean, we don't know how the phase III program is going to pan out, but it's reassuring.
Speaker Change: To be more specific about your question they use different criteria to to get patients into their study the major enrichment criteria that the Doctor Moreau.
Speaker Change: And Dr. Matthew views was the clinical global impression of change rather than the Ham D or any other depression scale.
Speaker Change: <unk>.
Speaker Change: And I should just say this.
Speaker Change: Sure. He has been very consistent all along this study does not gate, we werent waiting for this data to change anything and so.
Speaker Change: The punch line is that we have no intention of changing anything in the phase III program, but I would attribute the.
Speaker Change: The really robust data more to the fact that it's two two sites to investigators that the data is very controlled.
Speaker Change: <unk> get more complex as you kind of blow out to a phase III program with 40 or so sites.
Speaker Change: So anyway, I mean, it's pretty impressive we got a separation of active and placebo four points at week six the phase III program is powered at two to two five points. So I think I think we're in pretty good shape.
Brian Abrahams: And again, thanks for the question Brian.
Brian Abrahams: Thanks, Chris and thanks Ian.
Speaker Change: Thank you.
Speaker Change: Your next question comes from Brian <unk> with Baird.
Brian Abrahams: Hey, good afternoon, guys. Thank you for taking the question I guess also to follow up on the ISP studies, while maybe you can just kind of walk through the details around that.
Speaker Change: The MRI <unk>.
Brian Abrahams: Primary endpoint.
Brian Abrahams: <unk> expectations, we're here original way.
Brian Abrahams: Process on making that the primary wells in.
Brian Abrahams: What we've seen versus other active MVD drugs that are approved on similar neuroendocrine neuro imaging endpoints.
Speaker Change: Thanks, Bryan Chris do you want to address yes, Hi, My question.
Speaker Change: Yes, sure happy to Ian Thanks, Thanks for the question.
Speaker Change: I mean this is the.
Speaker Change: Yes.
Speaker Change: These were two academic <unk> Doctor Moreau, Dr. Matthew who were following up on a study that they had done where the primary endpoint was met MRI with a dog in that study had 46 patients so less than 30 per arm and and yet the results for MRI.
Speaker Change: We're somewhat promising there were not significant in that is all getting trial, but they did appear to be.
Speaker Change: Promising and so what they did is they they powered the study larger pointed out 46 up to 60 and powered the study for MRI to see if there was a difference and there wasn't so I would I would position.
Speaker Change: <unk> I mean, all along we've been really interested in what the clinical skill show, but in defense of the approach. It really does ask you very interesting mechanistic question about.
Speaker Change: How is it that this mechanism actually improves depression in there was the hypothesis behind it about the reward circuit, which I'll I'll spare all of you.
Speaker Change: The details of.
Speaker Change: But ultimately you know as a clinician and as a company we were really interested in the clinical skills and they showed consistency improvements in <unk>.
Speaker Change: Separation between active and placebo for module and shops on the order of what we saw with extra over so overall, yes. The primary endpoint of <unk> was negative and so don't want to Dodge that but.
Clinical scale showing.
Speaker Change: Evidence of efficacy similar to what we're planning on doing in phase III as I think a pretty good outcome for us.
Speaker Change: Great. Thank you.
Marc Goodman: Your next question comes from Marc Goodman with Leerink partners.
Speaker Change: Hi, Good afternoon. Thank you for taking my question the plasma onto Mike.
Marc Goodman: Have a question about the NAV one wanted Judy syndrome.
Speaker Change: Do you think the competitive landscape in the multiple ongoing trials in <unk> syndrome first I would like to know how would you like to what's your plan to assess the efficacy of this asset and also since this is the precise approach are you going to plan to assess behavior and cognition trial as well. Thank you that's it for us.
Speaker Change: Yes. Thank you for the question, yes, you've seen.
Speaker Change: In our prepared remarks and for those that had the opportunity to attend the American Epilepsy Society meeting last December I think we are generating some really compelling preclinical data.
Speaker Change: And it really gets to the heart of your question both on the seizure reduction, but the potential for disease modification as well so.
Yes, we would agree that there are a number of drugs that are used and have been developed.
Speaker Change: To treat dry eye syndrome, but there's been very few that have gotten really gotten to the underlying genetic cause of the disease and so we think so.
Speaker Change: Our knowledge, we're the only company that's developing an oral small molecule that can potentiate. The channel that can have an impact not only in these genetic animals. These animals that actually have.
Speaker Change: A 50% loss of function is now $1, one which is the human.
Speaker Change: It really is the human disease.
Speaker Change: Is that we can protect these animals from from Caesars spontaneous seizures from from suite App and then we can have this impact on long term potentiation. So thats the real potential here. So it is a little bit early.
Speaker Change: Kind of map out the entire development plan for <unk> one.
Speaker Change: But given our approach we would want to look at in clinical development, both seizure reduction as well as some of those endpoints that you were referring to in terms of disease modification and we really think that a lot of the.
Speaker Change: Pediatric and genetically defined epilepsy, that's where the field needs to go we need to continue to provide better drugs.
Speaker Change: For these patients both in terms of seizure reduction, but importantly disease modification and that's really what we hope to address with an Apple and one program.
Speaker Change: Okay.
Speaker Change: Thank you.
Your next question comes from Myles Minter with William Blair.
Myles Minter: Hi, everyone and thanks for taking the question just on the powering I think you've said it.
Myles Minter: <unk>, 99% powered at 25, mcdyess, 90% at 15 million eggs for that 360 patient target enrollment.
Myles Minter: So I think if you look at phase two we got our phase III placebo doesn't really change in FRS studies, but the drug effect comes down and I think it was about 7% on a on that.
Speaker Change: Asia frequency. So just wondering given your comments that you powered the study based on what you saw in <unk>, which was better than we expected.
Speaker Change: Do you assume some sort of effect size that <unk> got in our phase three and.
Speaker Change: And if you do.
Speaker Change: So there's an opportunity to maybe increase enrollment beyond that 360 patient number just wondering how you're thinking about that thanks.
Chris: Okay. Thanks miles, Chris can I pass this one to you in terms of modeling for the primary endpoint in the <unk> program.
Speaker Change: Yes.
Speaker Change: Actually.
Brian Abrahams: Happy to cover this one so youre correct miles the study is powered with <unk>.
Brian Abrahams: Greater than 99% for the 25 milligram.
Speaker Change: Actually powered higher than 90% on the 15 milligram arm.
Brian Abrahams: So.
Brian Abrahams: And then it's powered for multiple key secondary endpoints as well as we're interested in week.
Brian Abrahams: Week, one endpoints and patient global impression of change and so forth trying to get them into the label. So.
Brian Abrahams: We think that we're covered from a from a powering perspective, I do hear what youre, saying that conventionally.
Brian Abrahams: These studies can be over enrolled.
Brian Abrahams: <unk>, but I would say that the study is powered appropriately right now.
Brian Abrahams: And then in general is fairly good consistency transitioning from phase II to phase III in epilepsy.
Brian Abrahams: And the phase two data was was robust.
Brian Abrahams: So I think we're in good shape from a from a powering standpoint and enrollment perspective.
Speaker Change: Do you want to add to that.
Chris: I know, Chris you cover that thank you.
Chris: Your next question comes from Laura Chico with Wedbush.
Chris: Alright, thanks very much for taking the question. This is Dylan on for Laura Chico.
Speaker Change: Just to clarify how long do you envision towards three enrollment taking relative to AG. So too. We're just trying to understand the separation of the readout timing.
Chris: Okay.
Chris: Thanks, John Yes, we havent given for the other two epilepsy studies or the depression program, we havent given specific guidance to topline data.
Chris: So if we go back and just to remind everyone. When we transition from phase <unk> study into phase III, we focused on export to and that was based on that being on the critical path to filing the NDA and the regulatory interaction that we had had at that time and so <unk>.
Chris: Two was up and running first and we also prioritized into X tole too.
Chris: The majority of sites that we had worked with an X tole, both from the individual site level as well as a number of the countries that we prioritized and so there is a delay Jack's all three because it did get up and running later, we haven't given specific guidance on that but it will be later than <unk>.
Chris: I think later this year, we'll be in a position to give guidance on <unk>.
Chris: Thank you.
Chris: Okay.
Chris: Your next question comes from Paul Choi with Goldman Sachs.
Chris: Hi, This is Daniel on for Paul.
Speaker Change: Interested about your.
Speaker Change: Trial design for the Bpd.
Speaker Change: Do you plan to stratify, the bvd type one and type two between in order to increase the detection.
Speaker Change: Signal to noise ratio. Thank you.
Speaker Change: Alright, thanks for the question so.
Speaker Change: I'll give a high level comment and then Chris I think you can address specifically bipolar one and bipolar two in terms of the patient population that we're including it in the phase III program.
Speaker Change: We'll provide.
Speaker Change: When the bipolar rent.
Speaker Change: Registration program gets up and running in the next couple of months, we've said mid year. The first phase III will be up and running well.
Speaker Change: We'll give more detailed information on the phase III design, so standby for kind of the more granular detail.
Speaker Change: John.
Speaker Change: On the endpoints and powering assumptions and sample size, but we can address your specific question on bipolar one and bipolar two and including both of those in the Phase III program Chris.
Chris: Yeah sure. So thanks for the question. So the bipolar there'll be two studies in bipolar depression there'll be a mixture of both studies will be a mixture of type one and type two as you know based upon the question that you're asking so.
Chris: You were specifically asking about stratification. So we as I said in my prepared remarks, we intend to share a lot more information about those studies.
Chris: In the near future and just suffice it to say that if you have a primary endpoint and you think that it can be affected by something in the study like a mixture of patients and stratification is a pretty good question to be thinking of.
Chris: I think on its theoretical level. There is there is a reason to think that there could be a little bit of a difference in the response between type one and type two and there's probably going to be not 50, 50 mixture of one and two it will be lopsided and so I think.
Chris: I think youre, making a good point about stratification something that we're definitely seriously considering and we're going to share all of that.
Chris: Your next question comes from Andrew Tsai with Jefferies.
Andrew Tsai: Thanks for the update my best wishes to Sherry I believe.
Speaker Change: That's your last earnings call at Xenon.
Speaker Change: For <unk> two is the general guidance still to revise the data timing guidance to a specific time point over time, such as a specific month or by chance could you plan to press release or announce when you do in fact complete enrollment and then secondly, we know back and ex told there was a stronger efficacy.
Speaker Change: <unk> for patients who are on fewer aed's at baseline.
Speaker Change: Any color on the enrolled phase three <unk>, two and three base patient type in terms of the number of Pryor and concomitant.
Speaker Change: AED there on a baseline thank you.
Andrew Tsai: Thanks, Andrew Yeah, I can address those.
Speaker Change: So yes, as we do with all of our clinical studies as we get closer to the end you can expect us narrowing and refining that guidance. Just so everyone has a really good idea of when the topline data are going to be available.
Speaker Change: Generally we've just updated enrollment in our quarters.
Speaker Change: But as we get closer to the top line data, we'll definitely be refining there.
Speaker Change: In terms of the patient.
Speaker Change: Patient baseline kind of the demographics as your question on on fewer AED that I would even broaden out and it's more than just very early days, but I think that's a good one to track and obviously, we track all of that.
Speaker Change: What we're I'm not going to give you a specific number right now because the study is still ongoing and so those things can change, but we are getting close to the end of the study and so.
Speaker Change: As you heard in our prepared remarks and in some of the Q&A already is that we're seeing kind of consistency with the X Tole study. So I think the way that you can interpret those comments is that we believe that the patient population overall in phase III will be.
Speaker Change: We will be consistent with the phase II population.
Speaker Change: Great. Thanks.
Speaker Change: Your next question comes from Joseph <unk> with TD Cowen.
Speaker Change: Hi, there good evening. Thank you for taking my questions maybe the first one on the inclusion of the bipolar one patients maybe if you could just give us a little bit more detail.
Speaker Change: Why you decided to include both bipolar one and bipolar II patients in this study, especially given the Biomarin data that came out earlier. This year and then maybe just a second question on the final phase two obviously, it's small but I think in that study the patients were taking two pills of 10 milligrams.
Speaker Change: I guess, assuming and then obviously your phase III was 20 milligrams. Once a day do you think there is anything in sort of a two tablets versus one tablet that could have led to the.
Speaker Change: Greater results here and are you are you thinking about changing anything relative to that obviously you know it's a small.
Speaker Change: Study thank you.
Speaker Change: Thanks, Joe.
Speaker Change: Chris do you want to just comment on BP.
One and two and just make sure that we're clear that obviously, we're not it's not.
Speaker Change: Medications that were for.
Speaker Change: Ah patients was made here that we're enrolling so maybe you can just go through a few details there and and also just a clarification on.
Speaker Change: On the dosing from the ISG.
Speaker Change: Yeah sure. So I mean, yes, I mean, what Ian just said it is critically important so you're talking about.
Speaker Change: The same patients between the bio study and ours in the sense that they have bipolar, but they're very different Brazil. Those are type one by definition because they have these manic episodes.
Speaker Change: But but we're interested in.
Speaker Change: A portion of the disease, where these patients are struggling with most of the time, which is depression.
Speaker Change: So.
Speaker Change: <unk>.
Speaker Change: The underlying pathophysiology of the depression is thought to be pretty similar between type one and type two and we sought out advice from multiple key opinion leaders, who spend time in this area of research and <unk> got a pretty consistent message that it was worth studying both so we think that the chance of success.
Speaker Change: Is good while those patients are in a depressive state and yes I mean.
Speaker Change: The fact that you know.
Speaker Change: The media study was negative from bio Haven.
There's been a very limited release of information. So I think it's hard to kind of know what to glean from that.
Speaker Change: I mean, one thing thats reassuring, assuming that placebo and drug behaves similarly, it tells us that the.
Speaker Change: The mechanism doesn't exacerbate anemia, which I think is somewhat reassuring as we go forward into bipolar depression, but I think if you take a look at the totality of the.
Speaker Change: The data that exists there is a much stronger argument to go forward into bipolar depression.
Speaker Change: And I think I actually said the same thing in the last earnings call, which is before those data came out.
Joseph: Thanks for the question Joseph.
Oh tablets, yeah, so, saying, yes, and just on the numbers.
Joseph: The quick answer is don't think that that should make any difference whether they are taking two turns or or $1 20 same same formulation. The drug has a long elimination half life and so it probably makes very little difference, whether the drug is being taken once or twice and whether youre, taking it says $2.
Joseph: <unk> tablets.
Joseph: 120, so I don't think that explain any of the differences I think I think look I mean again zoom out like there is a consistency of separation between drug and placebo on the shops and the module and to controlled studies with is that to calendar <unk>.
Speaker Change: Supporting data from from it's all getting and you're talking about small studies right. It's all being 46 patients are our study had about 55 patients per arm. In this study. The investigator initiated trial was about 30 patients per arm. So theres small studies and I think youre going to end up with.
Joseph: Gary ability and I wouldn't I would be cautious to kind of Cobra interpret a point your point there.
Speaker Change: Chris just to I just wanted to be clear I know they were taking to 10 milligrams, but it was QD dosing I'm sorry again.
Speaker Change: Yeah, and the IFC, so Joe just to be clear that was just.
Speaker Change: Based on drug supply that was available but.
Speaker Change: But it was.
Speaker Change: Two channels versus 'twenty, but it was <unk>.
Speaker Change: So we wouldn't have expected.
Speaker Change: Any differences in any of their results based on a change in dose.
Speaker Change: Okay. That's very helpful. Thank you.
Speaker Change: Your next question comes from Jason <unk> with Bank of America.
Hey, Good evening. This is Dan on for Jason. Thank you guys for taking our question.
Speaker Change: First one apologies if a similar question might have already been asked but can you just remind us for X still too where seizure freedom measure kind of fits into the statistical hierarchy and if you have any assumption for how seizure freedom rates will kind of shake out relative.
Chris: Two the Chris.
Speaker Change: Chris.
Speaker Change: High single digit percentage that we saw and external.
Speaker Change: And then for.
Speaker Change: Dean 1120, just how are you guys thinking about lead indication selection and you can maybe speak to what you're hoping to see from the drug's pharmacology profile in phase one testing. Thank you.
Speaker Change: Thanks Dana.
Speaker Change: I'll do Chris why don't I do the X gene $11 20 question first and then maybe I can start on the on the seizure freedom question and then.
Speaker Change: Please provide your perspective as well so on <unk> hundred $11 20, so really great progress.
Speaker Change: Overall incredibly pleased with the progress that we've been making on our discovery portfolio. If you just think about it we're in the last couple of months.
Speaker Change: <unk> filed.
Speaker Change: Cta for three to $5, five which is a molecule that we synthesized.
Speaker Change: Have 1612 inhibitor.
Speaker Change: We have filed a cta or in first in human for <unk> 'twenty and in the next couple of months, we'll be in the clinic with an NAV. One seven we finished the <unk> life for that so <unk> is in a pretty short period of time for <unk>.
Speaker Change: For the early stage portfolio. So I think it is really exciting times. The first in human in Frac sand 11, 20 to answer your specific question there will be a traditional healthy volunteer study.
Speaker Change: Where we're going to want to see a number of things we're going to look at obviously, the pharmacokinetic profile as well as the adverse event profile at a variety of different dose levels.
Speaker Change: And then as we think about future development, what we said in our prepared remarks is we'd like to take this molecule.
Speaker Change: Two a proof of concept study in pain.
Speaker Change: We think there is good.
Speaker Change: Clinical.
Speaker Change: Validation and rationale to go into pain.
Speaker Change: And I think that would really broadened out the applicability for the mechanism and so thats. The current plans for <unk> hundred 11 20.
Speaker Change: On your question on on the epilepsy program in terms of seizure freedom.
Speaker Change: When we think about seizure freedom. So I'll just make kind of some global comments because I think it's important to set context and then Chris can.
Chris: Get into his perspective, and some of the details is.
Speaker Change: I wouldn't say there is a standard <unk>.
Speaker Change: Finishing for seizure freedom, but generally when we talk to clinicians as they really think about the patients over a one year period. So have they had any seizures over one year. So obviously thats something thats not tested in.
Speaker Change: And in the double blind portion of the clinical study because the double blind portion.
Speaker Change: Eight weeks or 12 weeks, depending on the study.
So you really are are following those patients in open label extension and CMA, how theyre doing over a longer period of time and that's what's really important.
Speaker Change: As we look at that kind of a 100% reduction in seizure burden and that's why the open label data.
Speaker Change: We continue to generate and we continue to present at medical Congresses. As a reminder, we started with a one year open label extension study for <unk>, we extended it to three and then five and now it's a seven year study. So we have patients that have been on an is that your calendar for many many years and we can look at those seizure freedom rates.
Speaker Change: Which we've published which we think are really impressive over time.
Speaker Change: Chris maybe just talked about that 100% of seizure reduction in the double blind period.
Speaker Change: Yes, sure I mean, I think that it's worth emphasizing that the epileptic allergist when they think of seizure freedom, they're looking over a really long time horizon.
Speaker Change: Matt.
Speaker Change: Eight weeks or 12 weeks.
Speaker Change: Specifically the question was about whether seizure freedom and the statistical hierarchy. It isn't we're interested in the rapidity of the onset that we saw in X tole and so the week. One time point is in the statistical hierarchy of announced seizure treat and then where we're really focusing on the seizure freedom is.
Speaker Change: The data that we're seeing over several years and the and the extra OLED and then obviously eventually in the phase III open label as well.
Speaker Change: Thanks for the question.
Speaker Change: Thank you.
Speaker Change: I will now turn the call back over to Sherry <unk> for closing remarks.
Thanks, everyone for joining us today on our call I know there were a few with you that we didn't get.
Speaker Change: We didn't manage to get to your questions. During the allotted time, so we will reach out can't directly after that.
Speaker Change: Operator, we will now end the call.
Speaker Change: Ladies and gentlemen that concludes today's call. Thank you all for joining you may now disconnect.
Speaker Change: [music].