Xenon Pharmaceuticals Inc. (XENE) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to the Xenon Pharmaceuticals Corporate Update Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Sherry Allen, Chief Financial Officer. Please go ahead.

Good morning, everyone. My name is Sherry Aulin, Xenon's Chief Financial Officer, and I will be moderating the call this morning. Thank you for joining us to discuss our top line results from the Phase II proof-of-concept X-NOVA clinical trial of XEN1101 for the treatment of major depressive disorder, or MDD. Joining me on today's call are Ian Mortimer, Xenon's President and Chief Executive Officer; and Dr. Chris Kenney, Xenon's Chief Medical Officer; Dr. Chris Von Seggern, Xenon's Chief Commercial Officer, will join us for the Q&A session following our prepared remarks. For those of you on the webinar, there are slides accompanying today's presentation, which has now been uploaded to Xenon's investor website. Please be advised that during this call, we'll make a number of statements that are forward looking, including statements regarding the potential efficacy safety profile future development plans, addressable market, regulatory success and commercial potential of XEN1101, the efficacy of our clinical trial designs, the anticipated initiation of future clinical trials for XEN1101 and the timing and results of our planned interactions with regulators regarding XEN1101, our ability to successfully develop and obtain regulatory approval of XEN1101 in one or more indications and our intent to explore future development of XEN1101 in MDD and potentially other indications. Forward-looking statements are subject to numerous risks and uncertainties and many of which are beyond our control, including the risks and uncertainties described from time to time in our SEC filings. Our results may materially differ from those projected on today's call. We undertake no obligation to publicly update any forward-looking statements. A news release summarizing the X-NOVA top line results, which was issued this morning will be filed with an accompanying Form 8-K with the SEC and on SEDAR and will be made available under the Investors section of our website at www.xenon-pharma.com. Now I'd like to turn the call over to Ian.

Thanks, Sherry. Good morning, everyone, and thank you for joining us. I want to touch on a few highlights from today's results before turning the call over to Chris Kenney, our Chief Medical Officer, who will review the X-NOVA efficacy and safety data in more detail. We will then put these data into context with the epilepsy landscape and XEN1101's differentiated profile. In summary, today's results, in our opinion, are very compelling and continue to support our belief that XEN1101 will be an important medicine with potential broad therapeutic utility. The growing body of efficacy and safety evidence across different indications combined with the important pharmaceutic properties of XEN1101 clearly sets this molecule apart from other KV modulators in development. Focusing in on today's results from our proof-of-concept X-NOVA Phase II clinical trial, XEN1101 demonstrated clinically meaningful dose-dependent activity in depression and anhedonia. Although we did not reach statistical significance in the primary [ MADRS endpoint, ] there was a clinically meaningful separation of greater than three points between placebo and 20 milligrams of XEN1101, and statistical significance was achieved on a number of important endpoints. XEN1101 achieved statistical significance at week 6 in the Hamilton Depression Rating Scale, or HAMD-17 a scale that has been used as a primary endpoint in depression studies. XEN1101 achieved statistical significance on change in the St Hamilton Pleasure scale or SHAPS measuring anhedonia of week 6. XEN1101 achieved statistical significance in MADRS at week 1, demonstrating early onset of efficacy. And XEN1101 achieved statistical significance in reporting of at least minimally improved symptoms of depression as assessed by physicians using the clinical global impression of improvement or CGI-I. In addition, XEN1101 was well tolerated with a low incidence of treatment-emergent adverse events and no serious adverse events in either of the XEN1101 dose groups. Many of our discussions with investors prior to these results focused on the safety profile of XEN1101 in depression. And importantly, the tolerability was better than we expected. And with the caveat of a cross-trial comparison, the safety and tolerability profile in X-NOVA was better than we observed in epilepsy patients in [ X-TOLE ]. So overall, we believe this is a very compelling data set, clear dose-dependent drug activity and the 20 milligrams of XEN1101, reduction in MADRS and HAMD 17 and that are highly competitive when compared to recent MDD data sets from other molecules. The totality of these data excite us about the breadth of opportunity for XEN1101 and we are actively planning for what future development outside of epilepsy could look like. So I'll now turn the call over to Chris Kenney, who will provide additional detail on today's data. Chris?

Okay. Thanks a lot, Ian. It's a pleasure to be able to speak to everyone today and review the data generated from the X-NOVA clinical trial. Before I dive into the details, as a reminder, X-NOVA was designed as a randomized double-blind, placebo-controlled, multicenter Phase II proof-of-concept clinical study that would include approximately 150 patients with 50 subjects per arm. Given a once-daily dose with food of either 10 milligrams XEN1101, 20 milligrams XEN1101 or placebo. The primary objective was to assess the efficacy of XEN1101 compared to placebo and improvement of depressive symptoms in subjects diagnosed with moderate to severe MDD using the Montgomery-Asberg Depression Rating Scale, or MADRS, score change through week 6 from baseline. A secondary prespecified objective included assessing the efficacy of XEN1101 compared to placebo and improvement of anhedonia symptoms using the SHAPS score change through week 6. In addition, our aim was to gather data on the overall safety and tolerability seen with XEN1101 in these patients diagnosed with moderate to severe MDD. Following randomization, the completed X-NOVA study included a total of 167 treated subjects in the safety population and 164 subjects in the modified intent-to-treat population for the efficacy analysis. Let's now turn to the primary efficacy endpoint. I'll begin today by going through a summary of top line efficacy results. As noted, the primary endpoint of the study was a change in the MADRS score at week 6. The mean reduction in modes was 13.90 in the placebo group, 15.61 in the XEN 10-milligram group and 16.94 in the XEN1101 20-milligram group. A clear dose response and a clinically meaningful 3.04 difference between placebo and the XEN1101 20-milligram group, P-value equals 0.135 was observed as represented in the top figure. Notably, the 20-milligram group may not have reached maximal efficacy at the end of the double-blind period given the continued reduction in MADRS from week 4 to week 6. And as a reminder, we saw a continued reduction in seizure rates in the [X-TOLE] study during the 8-week double-blind portion of the study and even greater reduction in seizure rates thereafter in the open-label extension. So to put these data in context, as a reminder, the placebo-controlled study with ezogabine showed a mean reduction in moderates in the active arm at week 5. So we observed a comparable drug effect with the XEN1101 20-milligram group. In addition, when we look at other successful depression studies, the XEN1101 20-milligram dose compares well in absolute efficacy in Madres with the caveat that cross-trial comparisons have limitations. Although we saw a strong drug effect in the 20-milligram dose, our mean reduction in moderates in the placebo arm was higher than anticipated, and therefore, statistical significance was not met. Although we're still analyzing a significant amount of data, our early perspective is that the placebo rate could have been higher in this study due to a slight imbalance in the severity of depression across the treatment arms where the placebo arm baseline modular score was 1.4 points higher than the 20-milligram arm as well as the potential impact of having two active drug arms in the study. Turning to the lower figure, X-NOVA data showed that statistical significance was achieved in MADRS at week 1 with a mean reduction of 4.88 in the placebo group and 7.54 in the XEN1101 20-milligram group. P-value equals 0.047 demonstrating early onset of efficacy. This statistically significant efficacy at week 1 is consistent with our results in X-TOLE seen in focal onset seizure patients where XEN1101 also demonstrated statistically significant efficacy at week 1, and our market research supports that there's an unmet need for medications with rapid onset of efficacy in both the treatment of epilepsy and MDD. We also saw an improvement in depressive symptoms as assessed by the HAM-D17, which was also a prespecified endpoint. Statistical significance was achieved at week 6 with a mean reduction of 10.18 in the placebo group and 13.26 in the XEN1101 20-milligram group. P-value equals 0.042. Several recent depression studies have used the HAM-D17 as the primary endpoint as it is a validated and a commonly used clinical scale of depression. In addition, when we look at other recent depression studies using HAM-D17, including zuranolone and avacopan the XEN1101 20-milligram dose demonstrated the greatest placebo adjusted mean reduction in HAM-D 17, again, with the caveat that cross-trial comparisons have limitations. We also assess the efficacy of XEN1101 compared to placebo on improvement of anhedonia symptoms using the SHAPS score change through week 6. As shown in this table in graph, Statistical significance was achieved on this key secondary endpoint with a reduction of 5.30% in the placebo group and 7.77 in the XEN1101 20-milligram group. P-value equals 0.046. As a reminder, currently approved therapies do not adequately address anhedonia, which represents a commonly noted comorbidity of depression and often a lingering symptom of current standard of care and has been an important dimension of interest around XEN1101 and given the clinical support for the Kv7 mechanism to ameliorate anhedonia. We now have clinical evidence to support XEN1101 and demonstrating improvements in anhedonia, which based on our market research, could be viewed as an important differentiator in the eyes of prescribing physicians. And finally, statistical significance was also achieved in reporting of at least minimally improved symptoms of depression as assessed by physicians using the clinical global impression of improvement or CGI-I with a P-value of 0.004 and the XEN1101 20-milligram group when compared to placebo. Let's turn to safety and tolerability. Overall, the results demonstrate that XEN1101 was well tolerated with similar rates of adverse events reported across all treatment arms. The rates of adverse events are listed in the press release. So I won't go through the details other than to say we're very pleased to see how well tolerated. XEN1101 was in this study with an AE profile consistent with our understanding of this mechanism and our prior experience. And importantly, given the significance to this patient population, I should note that XEN1101 was not associated with clinically meaningful weight gain or sexual dysfunction, which are common side effects of many antidepressants. Rates of discontinuation were similar across all treatment arms and rates of discontinuation due to treatment emergent adverse events were low with three patients in the XEN1101 20-milligram group, 5.4% as compared to two patients in the placebo group 3.6%. Notably, both active doses of XEN1101 were better tolerated in the X-NOVA patient population as compared to the X-TOLE epilepsy patients with lower rates of CNS-related adverse events and lower rates of discontinuations overall and due to treatment-emergent adverse events. We're further reassured by the consistency of data we continue to generate with XEN1101 in a broader context. To date, we have generated a significant amount of long-term safety data on this molecule with more than 500 patient years and the X-NOVA data are further supportive of a well-tolerated profile. To conclude on the safety topic in X-NOVA, we saw no serious adverse events or SAEs in the true active treatment groups with XEN1101. As noted in this table, there were two patients representing 3.6% of that cohort in the placebo group who experienced a serious adverse event. In summary, we're encouraged by the data we have generated with XEN1101 in this proof-of-concept study. We see clear dose-dependent drug activity in both depression and anhedonia scales as well as early onset of efficacy with statistical significance at week 1. Importantly, XEN1101 was well tolerated in this patient population with a low incidence of treatment-emergent adverse events similar discontinuation rates across all arms and no serious adverse events in either active treatment groups. Overall, there continues to be a strong need for treatment options for MDD and we believe XEN1101 presents attractive qualities such as a novel mechanism, early onset of action and overall favorable tolerability and safety profile as well as further differentiation based on its impact on anhedonia. I'd like to turn to our epilepsy program as we believe that the data from the X-NOVA study in depression has the potential to further build upon XEN1101's compelling product profile in epilepsy. For reference, this slide summarizes our ongoing Phase III development in epilepsy. XTOLE2 and XTOLE3 are assessing the effects of XEN1101 and versus placebo on reducing focal onset seizure frequency, and we expect patient enrollment in XTOLE2 to be completed in the second half of 2024. X-ACKT is assessing the effect of XEN1101 versus placebo on reducing primary generalized tonic-clonic seizure frequency. Depression is a common comorbidity of persons living with epilepsy with prevalence rates in the literature ranging from 15% to 50%. Studies have also shown that greater severity of depression is associated with higher seizure frequency. Further, a lifetime history of depression may predict resistance to treatment and depression is a significant factor contributing to non-adherence to taking anti-seizure medications. In our past market research with physicians, they have highlighted the importance of underlying mood disorders in treatment selection. In addition to the literature, we've also recently generated our own data assessing the burden of illness as reported by patients with focal onset seizures and we will be sharing these data at the upcoming annual meeting of the American Epilepsy Society being held in early December in Orlando. Results from this company-sponsored survey indicate that depression and anxiety are common comorbidities in epilepsy that further exacerbate the burden of epilepsy and may require additional care or support. Of the patients reporting mood symptoms as a non-seizure symptom, 74% experienced mood symptoms at least once a week and 53% consider their mood symptoms highly severe. 40% of patients in the survey indicated a physician-reported diagnosis of depression, yet 63.6% exhibited moderate to severe depression symptoms based on the PHQ-9 scores. A scale that assesses and monitors depression symptom severity. These results are consistent with findings from our market research and interactions with epilepsy clinical investigators and key opinion leaders that the burden of depressive symptoms is high in patients suffering with epilepsy and even higher in those with difficult-to-treat epilepsy where rates are higher than reported in the literature. Overall, we believe depressive symptoms are more common and potentially underappreciated given the significant impact of quality of life in patients with epilepsy that we're seeing. Therefore, being able to address both seizures and depression in epilepsy patients would be highly advantageous. As a neurologist, I believe these X-NOVA data are important for the work we are doing in epilepsy. I'd like to turn the call back over to Ian, who will provide some summary comments. Ian?

Thanks, Chris. I'll start by building on your comments on the opportunity for XEN1101 in epilepsy and then I'll summarize our overall perspective on the X-NOVA data. We believe XEN1101 has a compelling profile in epilepsy. To summarize the value proposition, including the data generated from our Phase II XTOLE study and our ongoing open-label extension. XEN1101 demonstrated its potential best-in-category efficacy profile in XTOLE including early onset with statistical significance at week 1, made more impressive given the difficult-to-treat population enrolled in the study and their prior and current ASM use. Data generated through the XTOLE open-label extension support even greater seizure reduction over time. With a novel mechanism of action, XEN1101 may facilitate combination use with other drugs in a polypharmacy approach. The safety and tolerability profile to date in epilepsy shows XEN1101 is well tolerated and in line with other ASMs, and we now have more than 500 patient years of safety data generated to date. And XEN1101 has strong ease of use characteristics, including daily dosing with food with no titration required. Adding to this already compelling profile of XEN1101 in epilepsy, these newest X-NOVA data support that XEN1101 may have an impact on mood. And this could be a striking differentiator in epilepsy, given the significant comorbidity of depression in this patient population as outlined by Chris. Importantly, most anti-seizure medications are neutral. Certain ASMs such as levetiracetam and parampenol are associated with unwanted mood symptoms. Of the ASM landscape of over two dozen approved medication, Lamotrigine is the only mood-positive medication. As a result, there is a significant opportunity for an ASM with an antidepressant effect in addition to benefit on reducing seizures. Given the substantial efficacy demonstrated in our previous XTOLE results, combined with the positive implications from the X-NOVA study and all we have learned from our market research we believe the profile of XEN1101 has the potential to significantly improve the standard of care for epilepsy patients. In summary of today's announcement, we believe the totality of data from X-NOVA demonstrates clinically meaningful drug activity of XEN1101 in depression and anhedonia. Early onset of efficacy and a favorable safety profile. And therefore, we are actively exploring the future development of XEN1101 in MDD and potentially other indications. As we believe this mechanism has potential broad applicability and the opportunity to have meaningful impact on patients. In closing, I'd like to extend our gratitude to the patients and physicians who participated in the X-NOVA clinical trial and our Xenon team who supported the study, leading us to these results today. We're excited to connect with many of you at the upcoming AES meeting in Orlando, and we look forward to keeping you updated on our progress as we continue to advance XEN1101 and the rest of our neurology-focused pipeline. I'll now ask the operator to open the line for questions. Given that we do have limited time, please limit to one question and then reenter the queue. If we do not manage to answer all of the questions today, we'd be happy to follow up with each of you throughout the rest of today and this week. Operator, we can now start the questions.

[Operator Instructions] Our first question comes from the line of Paul Matteis with Stefan Nichols.

I was wondering, just on the clinical side, can you provide a little bit more color on the disturbance and attention adverse event the duration, intensity of it and whether it drove discontinuations? And then Ian, it sounds like you're really encouraged by these data. I guess, put into context for us, how embolden are you to move forward here and embark on a big MDD program? And what could the timing look like?

Thanks, Paul. Chris Kenny, the first one on just some comments on disturbance and attention, discontinuation rates. So maybe we can just talk about the data that we've also generated in the X-TOLE because I think there's a lot of safety data there that's supportive and then I can talk about next steps in the program.

Yes. I mean, in terms of -- so Paul, thanks for the question. In terms of the data that we have as part of the top line, it really focuses on the incidence of the adverse events that we're seeing. So as far as being able to comment on exactly how the severity breaks out and the duration we have yet to look at that. I would just say that in terms of the overall tolerability with decreased rates of dropouts and dropouts due to adverse events relative to the focal onset seizure population that I would predict that it would be as good or better than what we've -- we've already seen. As far as these adverse events, the way they're captured, they're not captured in a narrative form as you would expect with a serious adverse event. So this is the extent of the information that we have right now.

Thanks, Chris. And Paul, in terms of next steps, I mean, I think we've been clear both in the prepared remarks and in the press release, we're excited about the opportunity to continue to evaluate where else we could take XEN1101. And I think from my perspective, we're just seeing remarkable consistency in the data set. We're seeing -- if we look at what we've generated in X-TOLE and X-NOVA, we're clearly seeing a dose response and drug activity in both indications the early onset of efficacy and just the consistency across all of the different endpoints. And so from our perspective, this absolutely gives us confidence in evaluating where else we could take the drug outside of epilepsy. And then I would also mention just the safety profile is giving us a lot of comfort around consistency. And as I mentioned in the prepared remarks, I think the safety profile was better than our expectations going in. Overall, we're planning now on where else we could go outside of epilepsy. And as we continue to refine that thinking, we'll be sharing that with you and everyone.

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

Maybe just kind of elaborating on the prior question. I'm curious -- what are the aspects that are going to guide how you think about next steps? Are there elements of the data that you're seeing here or other commercial aspects like rebating dynamics or sales infrastructure build that would potentially steer you towards broad MDD versus other neuropsych indications, perhaps anhedonia or bipolar? And then I guess, as a corollary to that on -- as you look towards next steps, what will we be looking for in the data in terms of PK/PD relationship to guide whether you might explore even higher doses given the tolerability you're seeing here?

Thanks, Brian. I'm happy to start and then Chris Kenney jump in with your perspective and then Chris Von Seggern, I know we've done a lot of work on just commercial dynamics, both within epilepsy and broader. So from idea perspective on where else we could go. I think now this is the first, Brian, opportunity to see efficacy data outside of seizure reduction. So this opens up -- we've done a lot of work on life cycle management and where else we could take the molecule. And now I think this broadens up an opportunity to look broadly in psychiatry, and we'll be doing that work. We've done some of it already, and we'll continue to do it in terms of what future indications could look like for XEN1101. I do want to just comment or react to your comment on PK/PD. I think that's important. We don't have the PK/PD data at top line, so that will come. But having that exposure relationship, obviously, we're seeing a dose response in the data. You can look at the curves, you can see that separation at every data point and 10 milligrams, whether looking at MADRS or SHAPS, 10 milligrams better than placebo and 20 milligrams, better than 10 milligrams. So I think we feel comfortable that we have a dose relationship there and PK/PD will give us insight into that exposure relationship as well, which will be important data as we think about your point on what would be the right dose to take forward because as I mentioned, I think tolerability was better than we expected coming into the study. And it looks like we have better tolerability in X-NOVA than we did in X-TOLE. So Chris Kenney, anything to add there? And then Chris Von Seggern, on the commercial side?

The only thing I'll add is I think that the question about 25 milligrams, which is also being discussed internally, of course, it really speaks to the tolerability of the drug. And if you think, at least for myself and for the team going back 2 years ago, we're trying to figure out whether this drug would be better tolerated in MDD compared to pass or not. And I think most of the people were weighing in and suggesting that probably it was going to be less well tolerated in MDD than focal onset seizures and the reverse appears to be true. So I think that the question about 25 milligrams obviously needs to be answered. We're working on it. PK/PD will be an important part of that evaluation. But it really speaks just the fact that we're even talking about it, I think, really speaks to just how well the drug has been tolerated in this study.

Yes. In terms of commercial in first and foremost, these data are very encouraging. And do you suggest a strong affected mood. And that does open up a potential range of indications as suggested in the broad neuro side category. So we're really excited about further evaluating the data, but also thinking about a path forward should it exist in MDD. I think that there was a component of the question that spoke to commercial dynamics across the indications. As we've said in the past, we do believe that there's an ability to have a product that exists in both the epilepsy and MDD space and from a commercial dynamic, there are available products that have similar pricing across those indications, although as mentioned, there are potentially some gross to net differences within the spaces. So lots more to do on this front, but the encouraging data potentially open up a path forward across a number of potential indications.

Our next question comes from the line of Tessa Romero with JPMorgan.

Great team. Congratulations on the totality of the updates here. So question from us on the baseline characteristics of the patients enrolled in X-NOVA and how they compare to your expectations of the phenotype that were kind of expected -- and any implications worth noting to future development here. Specifically curious, are you able to put into context a 2.5 point delta on the shaft at the 20 mg dose? And I know you've alluded to it a little bit here already, but any additional color you'd provide on key implications you see from these Phase II results to how you might design a Phase III program.

A fair number of questions in there. Chris Kenney, do we want to -- maybe you can start on just expectations around the baseline characteristics and how that may inform at least kind of moderate to severe populations as we would think about it in future developments? And any other comments you have shafts and then I can add in on future development in [indiscernible].

Yes. I mean we were following the population all along, making sure that we're ending up with patients who had moderate to severe depression. And as you look at the cutoff based upon the MADRS, basically, roughly half are in the moderate and half are in the severe. So it panned out the way we wanted. I think the learning for the future is that when you use a cutoff of the HAM-D17, it correlates really well with MADRS, but it's not perfect. And so there were a couple of patients who came in, who had they met the cutoff. They belonged in the study, but they had a relatively low MADRS score at baseline. And when you remove those subjects, it makes a big difference. And so I think there needs to be even more diligence to make sure that even one or two patients with relatively milder disease don't get in going forward. I think that's the big lesson. As far as SHAPS, I mean you can go into the medical literature and you can say, okay, what's clinically meaningful MADRS you can say, okay, it's roughly 2 points, perhaps less and we're above that and that's great. That data simply doesn't exist for the SHAPS. So all I can tell you is that it was statistically significant as whether you need to have 1, 2, 3, 4 points on the SHAPS for it to be clinically meaningful, that work just simply hasn't been done. And so any answer would just be pure speculation. We're just cite that it was [indiscernible] , and the drug appears to have [anhedonia] effects.

And maybe Tessa, a few comments to add. I mean, as Chris mentioned, I think there's more limited data in the literature on SHAPS, but at least when we compare it to some of the data that's available. I think this is really competitive. So that's positive. When we think about -- you kind of had this question around key implications as we move forward, and we've talked about some of this in terms of answering other questions, and Chris has gone through how would we think about the patient population in a future study. I think a couple of other things we've talked about this morning already about dose selection. So PK/PD will be informative there. And I think a 1:1 randomization. We had a higher placebo rate in the study, and we could speculate on the reasons why, as we said in the prepared remarks, there was a slight imbalance between the depression scores in placebo and in the 20-milligram arm in the study, but there was also two active doses. And so in the informed consent, patients know that there's a 2/3 chance that they will be on the active drug versus placebo. And I think in future development, we look to 1:1 randomization regardless of what dose we select. And I think the decision to look at both 10 and 20 milligrams we stand by that was absolutely the right decision for this X-NOVA proof-of-concept study because we needed to learn about the dose and the dose response and the tolerability at different doses. And so we've gained a huge amount of information and data from this study that can inform what future development would look like.

Our next question comes from the line of Andrew Tsai with Jefferies.

Congrats on the positive findings and thanks for the updates here. So -- our question is more about the week 1 endpoint that you're seeing. Can you talk about the significance of the separation and how that compares to other MDD drugs? And how do you take advantage of what you're seeing here? Does it make sense to talk to the FDA to potentially seek a label claim that as rapid acting, for instance?

Thanks, Andrew. Maybe we'll -- maybe both Chris can comment on this folks from the medical as well as the commercial perspective. And I think we should just talk about week one. Obviously, we'll talk about the X-NOVA data because that's the data that we presented this morning. But I think it's worth reminding folks, Chris Kenney of just what we saw in XTOLE and having that as part of the statistical hierarchy in our Phase III program the XTOLE2 and XTOLE3.

Yes. Okay. Sure. So I mean, what I would say in terms of the you think about historically where we were going back, say, a decade ago or so, the antidepressants didn't kick in for a while. You usually needed a few weeks. And then the only alternative really, if you wanted to wrap it onset of antidepressant effect was electroconvulsive therapy. I mean, fortunately, the landscape has changed somewhat. But if you look at the options pharmacologically in terms of a quick onset of action, it's pretty limited out there. So we're excited about this. In terms of the clinical meaningfulness, we saw more than a 2-point separation at week 1, which is considered a clinically meaningful extent. So I would characterize that separation at week 1 as clinically meaningful based upon just sort of the cutoff that's typically used on the MADRS.

And then maybe an epilepsy also, Chris.

Yes, sorry. So then in an epilepsy I mean, it's obviously the fact that we saw that not just one study, but in two studies. And also, just to remind you, in the XTOLe focal-onset seizure study. It wasn't just that we saw a rapid onset within 1 week of antiseizure activity in one dose. It was really in all active doses. So if you kind of take a step back and you say, okay, one focal-onset seizure study with all active dose -- doses showing rapid onset within one week and then also in conjunction with what's going on in X-NOVA, I mean it's pretty enticing in terms of appearing to be a real signal. As far as what we do to leverage this, I mean we've had the data for a relatively short period of time. We need to have more discussions in Phase III in epilepsy went pretty far and actually included it within the statistical hierarchy. We haven't -- we're not ready to sort of commit to something like that right now. We need to understand the data better.

And then Chris Von Seggern, just what we see in our market research in terms of early onset in different therapeutic areas.

Yes. No, absolutely. So as we said in the past, from an epilepsy standpoint, week 1 efficacy is very compelling, but as a differentiator against the other therapeutics that are available, the other antiseizure medications that predominantly require titration to achieve full therapeutic effect. And our market research leading up to X-NOVA we tested the potential for early onset of efficacy at week 1 as well to understand the degree to which prescribing clinicians view that as a favorable element. And it most certainly did emerge as an interesting end point, as Chris had alluded to, because of the fact that the mainstay of therapy does take some time to reach clinical effect or maximum clinical effect. So we view this as part of the compelling data set that supports the interesting findings coming out of X-NOVA.

Our next question comes from the line of Jason Gerberry with Bank of America.

Ian, just wanted to come back. You alluded to the benefit on mood in epilepsy patients as sort of a unique differentiator for 1101. So I'm curious how you can piece together a data-driven story to clinicians around this benefit? I imagine you probably don't have enough patients for a prespecified subgroup in any of the individual XTOLE studies. But perhaps are you looking maybe down the line to pool data from the XTOLE studies to perhaps be able to have a meaningful sized subgroup of patients with mood disorder and epilepsy that you could convey to physicians the benefit in that subgroup? Or would it have to be a unique stand-alone study.

Yes. Thanks, Jason. So I'll make a couple of comments, and then Chris Kenny, let's just talk about we are looking at depression as an exploratory endpoint in XTOLE2 and XTOLE3 and I know we're not stratifying, but maybe we can at least -- I know we talked about this with some folks, but we can just provide a little bit more information there. Yes, Jason, I mean, you're kind of getting into how and where would we use these data in the future and how can we build upon them. I think it's still early days to completely have all of that mapped out. If we think a few years from now, I think we're going to have a bigger body of information and data depending on what we do in terms of future development outside of epilepsy and then as Chris can go through in a minute, we are looking at depression, which we [didn't at] XTOLE we are in XTOLE2 and XTOLE3, and Chris can walk you through that. The other key point for us, which we'll be happy to share with people in a few weeks as we have this great opportunity in front of us at the American Epilepsy Society meeting, which kicks off later this week in Orlando. So we already have a significant number of meetings, both with clinical investigators and KOLs and getting that firsthand feedback from them in terms of the importance of data such as these as they think about epilepsy, I think will be an important learning that we can share as well. Chris, maybe talk just a little bit about the data that we could generate in the XTOLE program as it relates to depression and epilepsy.

Yes. So we're doing quite a bit of work in the Phase III program to keep an eye on mood. The disclaimer, I'll say at the beginning is that obviously, you need to be cautious because we're doing a Phase III epilepsy program. We're not actively enriching for depression or anxiety or any other mood disorder. Unfortunately, a lot of these patients have mood dysfunction, and so we expect the population to definitely have patients with abnormal mood. But just not -- it's obviously not the primary focus of the study. Anyway, that said, each one of the Phase III programs is using a dedicated to follow depression throughout the course of the study. And we'll be able to pull that information at the end of the day and take a look at patients who have a certain degree of severity at baseline. So we're going to learn a lot, not just about what the drug does for depression in the focal onset seizure and primary journalized tonic-clonic seizure population, but also how those patients are doing irrespective of what's going on with the drug. And if you look at the market research that we've done, it really does appear as though this may be a problem that's a little bit bigger than people appreciate. And that is what we're hearing from the physicians who are taking care of these patients day in and day out.

Our next question comes from the line of Paul Choi with Goldman Sachs.

I want to drill down a little bit more on your comments about the deepening response that you saw over time through, let's say, weeks 4 through 6. And what you thought about in terms of next steps and next trials dosing longer at the 20 mg dose. I think the investigator study sponsored study at Mount [indiscernible] is studying 1101 for 8 weeks. So I'm just curious if you've received any insights from that investigator study as to potentially dosing longer versus higher in terms of your next potential steps here?

Thanks, Paul. Yes, I think that's a really interesting question. And so yes, as you've seen those graphs, you'll see that if we look at MADRS between week 4 and week 6 it still looks like we have kind of that downward flow to the curve. It doesn't look like it's bottoming out. So yes, it does look like we are continuing to see a response over time in the X-NOVA data set. But Chris Kenny perspective on just dosing longer and obviously, we haven't designed anything for the future, but I think it's definitely something that we recognize in the data and we'll think about in terms of both duration and dose moving forward. But what's -- maybe you can give your perspective as well.

Yes. I mean, it's intriguing when you look at the shape of the curve, and so it's hard to discount, particularly in light of the seizure data that we saw, it was an 8-week double-blind study, the XTOLE study. And then as you look at patients who transitioned into open label, in that third month, they continue to get better even though they were on active for 8 weeks prior to that. So this curve in conjunction with what we saw with focal onset seizures raises the possibility of whether we should consider a longer study. I mean we haven't had the data that long. And so as far as one active dose looks enticing, but committing to it now seems premature. Longer duration of the double-blind seems enticing, but committing to it now seems premature. So we need to look into all this. The downside of going longer would be that, obviously, you're going to have probably a slightly increased dropout rate and you run into more problems with data missing is. So we're going to have to sort of thread the needle. It certainly won't be shorter than 6 weeks.

And to my question on the investigator sponsor study, have you guys received any updates on that or any...

It's a blinded. It's an ongoing blinded study -- so there isn't anything that's coming from that, that's making us think, Oh, we should go longer.

And Paul, we should expect -- although we don't have guidance on it. Obviously, we're speaking with the physicians in the IST on a pretty regular basis. And our expectation is that we'd likely see some data from that study next year.

Our next question comes from the line of Joseph Thome with Cowen.

Maybe the first one on the HAM-D, I guess, given the benefit seen at 6 weeks, are you considering switching to a HAM-D primary endpoint in a potential next study? And then second, did you get any information on symptoms of anxiety in this study, either the [ BAI ] or a similar measure on that? And maybe how do the therapy performed.

Chris Kenney, do you want to tackle both with this?

Yes. So on the first comment about the anxiety, I mean, basically, right now, we're still sort of evaluating the data. I will say to my earlier point about enriching the population, this was -- this is a population of patients who are enriched for depression, not for anxiety. What was the first question again?

The first quarter '17 is primary.

Yes. So I mean I will give you the same answer I gave about the duration and on 1 active versus 2 active all that we were. I mean, we're actively looking at all that. I would say that the data -- clearly, it's more compelling. The Hamilton than the moderates from the standpoint of statistical significance, which was driven by less variability. And the literature does support that, that scale is less prone to variability relative to the MADRS. And so it's certainly a consideration. I mean, we chose moderate because of the historical study done with ezogabine. I'm certainly not at the point right now where I would say, for sure, we need to change, but we need to rigorously look at it. How much of that was driven by the fact that we just didn't continuously check it. We check MADRS repeatedly throughout the study. So is it that we just checked it too much? Or is it actually the nature of the scale? I mean the two scales do emphasize different points. [Hamilton] has a little bit more of an emphasis on anxiety, somatic symptoms, those sorts of things. So we're trying to tease out the individual items in sub domains to sort of illuminate where to go next, but I wouldn't commit one way or the other right now.

Our next question comes from the line of Danielle Brill with Raymond James.

Congrats on the encouraging data I guess, first, as a follow-up to the prior question. Outside of MADRS, were other baseline characteristics well-balanced, including those with comorbiding Anxiety or PTSD at baseline across arms. And then I'm also curious if you looked at remission and responder rates.

Thanks, Danielle. Chris, do you want to just talk about the rest kind of what we've seen so far in the baseline characteristics and PTSD. I know -- there was maybe a little bit of imbalance between men and women in the study and maybe talk a little bit about your kind of thoughts on overall the baseline demographics.

Yes. I'll take the PTSD question first. I mean there were very few subjects that had PTSD at baseline. So we don't think that, that had any impact on the data. In terms of -- in terms of the baseline characteristics, we had a little over 50 patients per arm. And so they were pretty well balanced but not perfect. There was a little bit less of disease severity with depression that we mentioned with the MADRS in the 20-milligram group, a little bit of imbalance in terms of gender, but nothing -- as we look at gender as an example, we're not seeing that there's much of a difference between the two. So that probably didn't have a big impact. The fact that there was a little bit of an imbalance in terms of disease severity as relayed by the MADRS may have played somewhat of a role and made it more difficult for the 20-milligram group to perform at its best. But for the most part, the study was pretty well balanced.

And then, Chris, Danielle, other question was just around remission and responder rates and some other kind of detailed work on the data we're trying to more work to do.

Yes, we're still working on all that.

Our next question comes from the line of Marc Goodman with Leerink.

It sounds like you guys are going to move forward with depression. I was just curious, can you remind us what you did to try to minimize the placebo effect here in the study and what you think you can do better in the studies going forward outside of the one that you talked about?

Sure. Chris, do you want to -- I know we've done this on prior calls, but I think it's a good reminder. So thanks for the question, Marc. Chris, maybe just walk through some of the things we did, and obviously, some of the things that we would adjust going forward. And then just given the time this is going to be the last question that we'll answer. And so I know there's a number of people still in the queue, and we'd be happy to follow up with folks throughout the day. So just reach out to us, we're just mindful of time. But Chris, if you just want to talk a little bit about some of the things we've done in the study to manage placebo rate.

Yes. Let me start with kind of forward-looking, and then I'll answer the other question. So you've already mentioned the possibility of one active dose that obviously is quite enticing. And that could probably play the biggest role. In terms of there's -- I think you can't be too diligent about making sure that you're removing professional patients from the study that you're really protecting and ensuring that patients are being adherent to treatment. All those things, I think, you can always -- I think you can always try to do more and more and really plan to push the limits with the technology evolving over time. In terms of what we already did, I mean, we did quite a bit. We focused on a limited number of sites only in the United States. We focused on choosing a CRO that had a lot of experience with the therapeutic area. We got a lot of feedback from KOLs, keep the study as simple as you can with a limited number of hours that the patient is spending in the clinic. We had a safer criteria evaluation at baseline so that the appropriateness of the candidate for the study was being assessed outside the site for -- with people who had no skin in the game. So we'll continue to do a lot of that and then just try to be as careful as we can about some of the other topics I mentioned. But I think if -- should we decide to go with one active dose versus placebo, I think that will probably be the one single largest factor to help us out.

Thank you. I would now like to turn the call back over to Sherry Aulin for closing remarks.

Yes. Thank you. So yes, in closing, I just want to just say thank you to everyone for joining us today on the call. We look forward to keeping you updated on our progress. And for those of you who didn't get questions, and we're happy to connect with you after this call one-on-one. Thanks again.

This concludes today's conference call. Thank you for participating. You may now disconnect.