Operator: [Operator Instructions] The next question comes from the line of Tessa Romero from JPMorgan.
Tessa Romero: So with enrollment expected to complete in the second half of next year in X-TOLE2, what are the key levers to being on this sooner versus the later end of that enrollment guidance? And it was a little bit alluded to in the prior question, but what is the latest thinking on the cadence of the pivotal data sets for X-TOLE2, X-TOLE3 and X-ACKT? Should we expect X-ACKT before X-TOLE3 or how should we really thinking about that?
Chris Von Seggern: I’ll start. Chris Kenney, provide your perspective as well. Tess, I don’t think there’s any, from my perspective, specific lever to pull for patient enrollment to be completed earlier in the second half of 2024 versus later in the second half of 2024. We are executing well against the plan of site initiations and patient screenings and patient randomization. So we feel confident where we are. We do our best to predict. And as we have guidance that is out a year or so, we’re going to put some error bars there based on our best assumptions and expectations. As we get closer we’ll be able to narrow those. But I don’t think there’s any specific lever in terms of trying to make that go faster. I think we have, from the very beginning, we want to run a good study and we’ll go as quickly as we can while maintaining the integrity and the conduct of the study.
Chris, I don’t know if you have anything to add specifically there and then I’m happy to jump in on the second question on the cadence of data events.
Chris Kenney: No, I don’t have anything to add. For every patient that’s enrolled in any clinical trial, there are so many different variables and so many different variables at each site and variables at each country. And so it’s just it’s complicated to the extent that it’s hard to sort of put my finger on one or two things and say this is what’s going to drive the timeline one-way or another.
Ian Mortimer: And then your second question in terms of cadence. So obviously X-TOLE2 has been our focus, and we’ve talked often with investors that we’ve tried to leverage in X-TOLE2 as many of those relationships that we had in X-TOLE, so investigators that have experience with the drug and clinical sites that we’ve worked with in the past. And quite frankly, investigators that still have patients that are being treated with XEN1101 in open label extension from the X-TOLE study. So we’re doing all of that in X-TOLE2. When we have guidance on X-TOLE3 and X-ACKT then Tess, we can come back to the guidance on which one’s going to readout first of those two separate Phase 3 clinical trials. It’s premature to do that today.
Operator: Our next question comes from the line of Andrew Tsai from Jefferies.
Andrew Tsai: Just one on MDD reading out. We understand that AE profile of 1101 could be different from — between MDD and epilepsy. I think you’ve mentioned previously how you are monitoring blinded safety. So how are the blinded AEs and the AEs due to discontinuation rates looking compared to your internal expectations, is there anything out of the ordinary relative to what you guys assumed going on in the study? Or maybe said another way directionally speaking, are you seeing lower AE rates in the MDD study compared to your epilepsy study?
Ian Mortimer: I’m sure, this maybe the first of other questions just on some of the details of the MDD study. I’m sure you can appreciate and others can as well. The study is now complete. We’re very close to unblinding the data and we’ll have data in the coming weeks as we’ve guided in late November to mid-December. So we’re not going to make any specific comments around what we’re seeing in the data. We have said previously that, obviously, as we run any clinical study, we’re going to monitor it along the way and we’re going to do safety review committees that are required. And based on those previous safety review committees, there hasn’t need to be any adjustments in the study. But we’re not going to talk about specifics on the blinded data and we’re looking forward to sharing the full data set in the near term.
Operator: The next question comes from the line of Jason Gerbery from Bank of America.
Unidentified Analyst: This is Dina on for Jason. Congrats on the progress this quarter and thank you for taking our question. So I just had a question on the X-NOVA top-line that we’ll be seeing very shortly. I guess, if we don’t see a positive trial, does that add any risk or uncertainty in your view to being able to generate additional data for 1101 antidepressant effect in epilepsy patients? And then just wanted to sort of follow-up on the MDD market research on 1101 safety profile, kind of given that safety is kind of a major driving force in the MDD space besides the lack of serious AEs that come with the SSRIs and SSRIs that you mentioned earlier, the sexual dysfunction, weight gain. Did KOLs point out any part about 1101’s AE profile that could be sort of a positive differentiator in MDD patients? Thank you so much.
Ian Mortimer: A lot there, so I think we’ve got them all down here. But if we missed one, just jump back in. So maybe I’ll make one kind of global comment around the X-NOVA study, and then I’ll pass it to Chris Kenney just to talk about the population that is an epilepsy patient that has comorbid depression, which is different than the primary — obviously, the patient that has major depressive disorder. And so Chris, maybe you can just comment about that. And obviously, we are looking, not stratifying, but looking at some of those data in Phase 3. And then Chris, one second, we can talk about the 1101 AE profile in MDD. I think, you started your question with if XEN1101 doesn’t work in X-NOVA. I think, if we don’t see separation, we’re very confident in saying that we don’t think there’s any read through into the epilepsy program.
So I just want to be absolutely clear with that. We’re very confident in the consistency and reproducibility across epilepsy studies and the compelling profile we have from X-TOLE and the ability to execute in X-TOLE2 and X-TOLE3. So I think this is a really interesting and important readout in the near term in X-NOVA, but I don’t think the outcome of that has any read through into our epilepsy program. But why don’t we go a little deeper. Chris Kenney, just in looking at that comorbid patient or the patient that has comorbid depression that’s an epilepsy patient?
Chris Kenney: I mean, what I would say is that the underlying pathophysiology of the depressive symptoms can be different depending on whether you’re looking at a patient who has a different psychiatric issue or neurodegenerative issue or epilepsy. So just because a drug is behaving a certain way in one of those population doesn’t mean it’s going to behave exactly the same in the other. And just to be a little more concrete, in the Phase 3 program, our epilepsy patients, obviously, we’re focused on developing an anti-seizure drug and that’s the focus. But we are looking at mood using scales in that population. So once those Phase 3 studies are done, we’re going to have this enormous body of information about how those patients respond to the drug from the standpoint of their depressive symptoms.
Now the downside is we’re not purposely enriching for depressive symptoms the way we are in X-NOVA and so there are some limitations. But we’re going to let the data guide us for both studies and just acknowledge the fact that depression isn’t the same as epilepsy.
Ian Mortimer: Chris Von Seggern, a little bit more on the MDD or AE profile of 1101 in MDD?
Chris Von Seggern: So just to remind folks, if we take a step back and think about the profile that emerged from X-TOLE with the 20 milligram and the 10 milligram profile, the majority of the AEs that are reported were mild. And when you think about the difference between 20 milligrams and 10 milligrams, the 10 milligram dose was highly comparable if not indistinguishable from placebo as it pertains to the AE profile. And then the 20 milligram profile, highly consistent with other CNS active anti-seizure medication with dose limiting are really AEs that emerge at the high end of the dose paradigm, but still appropriate for that patient population. So trying to bookend the AEs in the context of the MDD market research. So are there other — the specific question was around are there other AEs that can be seen as a positive differentiator.
