We don’t have to specify on what type of food the drug is taken with. So, hopefully, that addresses the food question. Chris, do you want to talk about our thinking around DDI and adjunctive?
Dr. Chris Kenney: Sure. So, in terms of DDIs, I mean, things have evolved over the past couple of decades or so. I think, from the standpoint where even if you didn’t predict a specific DDI, you would sometimes do a drug-drug interaction study with a drug and another drug, say, an anti-seizure medication or antidepressant that’s used quite a bit. The field has kind of gone away from that because we’ve gotten pretty good at predicting drug-drug interactions. And so, as it pertains specifically to antidepressants, we don’t foresee any major issues whatsoever in terms of drug-drug interactions with any of the antidepressants used. So, the current — so we don’t see any need to do those additional NDA-enabling studies and we haven’t had any regulatory feedback to suggest that there was disagreement.
Basma Radwan: Thank you. That’s very useful.
Ian Mortimer: Thanks. Thanks, Chris.
Operator: And your next question comes from a line of Andrew Tsai from Jefferies.
Andrew Tsai: Hey. Thanks. Good afternoon. Thanks for taking my question. Can you just remind us how long it took X-NOVA to start up and generate the topline data and whether you think the Phase 3s should also have a similar timing? Thank you.
Ian Mortimer: Thanks, Andrew. Sherry, do you want to go through the X-NOVA timing?
Sherry Aulin: Yeah. Absolutely. So, yeah, just as a reminder, X-NOVA took us about 18 months, I would say, from start to finish. As a reminder, we randomized just over 160 patients in that study. As Ian mentioned earlier, these Phase 3 trials are going to be powered well for Phase 3, so we’re going to see multiples of the number of patients that we saw per arm in a 1-to-1 randomization. So, think about a study size that’s 2x to 3x the size of X-NOVA. These studies do take, I would say, generally less time to enroll than epilepsy. There’s just more patients out there that meet the enrollment criteria. So, we do expect that the timing will be not too dissimilar to X-NOVA, so probably somewhere kind of in the two-year range, I would say, Andrew, if you think about start to finish for each of the Phase 3 studies.
We’re not going to start them all practically. These studies are typically staggered a little bit. So, as we’ve said, the first study will initiate later this year. Practically, though, there will be a little bit of a stagger a number of months to the second study and then, again, a number of months to the third study. Hopefully, that helps.
Andrew Tsai: Very helpful. Thank you.
Operator: And your next question comes from the line of Peyton Bohnsack from TD Cowen.
Peyton Bohnsack: Hi. Good afternoon and thank you for taking our questions. Just a quick one from us. Can you remind us on what you’re doing to control placebo rates in the MDD program in the Phase 2 trials and highlighting any changes that may have come from the learning from the X-NOVA trial and the interactions with the FDA? Thank you.
Ian Mortimer: Great. Thank you, Peyton. Chris, do you want to walk through both what we had done and maybe a focus more on what we expect to do to continue to keep an eye on placebo rate in the Phase 3 MDD program?
Dr. Chris Kenney: Yeah. Absolutely. So, I mean, X-NOVA, we’re quite pleased with the results that we saw with the X-NOVA study. And so, in terms of trying to control placebo effect to the extent that we could, we really focused on choosing a CRO that was highly experienced in major depressive disorder. We used the SAFER criteria to make sure that appropriate patients were getting into the study. So, that’s an external group that has no skin in the game in terms of whether a patient is enrolled or not. We also obviously chose really high quality sites with lots of experience in MDD, made sure that the training on the scales was done appropriately so. And then there’s a bunch of ways that you can keep an eye on data in real time to make sure that you’re not seeing anything unusual either in a patient or at a site level, or of course, at the study level.
Obviously, you keep an eye on the baseline demographics and make sure that you’re putting together a population that you expect. And then going forward, one thing that’s absolutely clear in these studies is that a handful of patients can really have an untoward effect on all of the results. And one of the things that we’ve seen as a common theme in successful MDD studies is a real focus on making sure that patients with mild, on the milder end of the spectrum, don’t get into the study. And so, as we share these design elements, you’ll see that we’re using a slightly higher cutoff on the EMD. That’s one thing. And then we’re doing some other things too that we’ll share publicly when the time is right. So, we’re really focused on trying to minimize the placebo effect to the extent that we can.
And the only other thing I will say is that compliance is a major issue and so that we’re in the psychiatric population. And so we’re going to be doing as much or more as we transition to Phase 3 to ensure compliance to the extent that you can.
Ian Mortimer: Thanks, Chris. And the only other one that I would add to Chris’ list that we’ve talked about publicly is in the Phase 2 program. We had two active arms versus placebo. And in Phase 3, as we’ve talked about, we’ll go to a 1-to-1 randomization. And so, the literature teaches us that that should have an impact on the placebo rate by lowering the placebo rate in terms of expectation bias.
Peyton Bohnsack: Great. Makes a lot of sense. Thanks for taking our questions.
Ian Mortimer: Thank you.
Operator: Your next question comes from a line of Tim Lugo from William Blair.
Tim Lugo: And for — again, for MDD, I know there’s been a lot of questions around MDD. But you mentioned the higher cutoff of the HAM-D to try and manage the placebo effect. But also, given the anhedonia effect and the differentiation versus the existing modalities, did the FDA kind of give you any guidance during the meeting on how heavily pre-trained the population should be or how many therapies maybe failed or cycled through prior to enrollment?
Ian Mortimer: Thanks, Tim. Chris?
Dr. Chris Kenney: Yeah. I mean, the feedback that they provided wasn’t so much in terms of medications failed or anything like that, the resistance of the population per se. They did provide some cutoff, excuse me, some feedback on cutoffs that can be used to optimize the patient population, and of course, we’re going to implement those recommendations. I promise you’ll hear more — you’ll hear the specifics on all of that before too long.
Tim Lugo: Okay. Thank you so much. And actually, one last question. So, when should we expect the Mount Sinai Phase 2 results? Is that something we’re still expecting this year?
Ian Mortimer: Yeah. We — just as a reminder, there is an IST ongoing for azetukalner in an MDD study being run by Mount Sinai and Baylor. This is looking at 20 milligrams of the drug versus placebo. The primary endpoint of that is a functional endpoint. It’s a functional MRI endpoint, but then there are secondary endpoints in clinical scales of depression and anhedonia. Tim, we don’t have specific guidance on that. We do know that there are some based on, obviously, we have a close relationship with the physicians running that study. We fully expect that the patient enrollment will complete this year and then it’ll be a conversation with the physicians in terms of where those data may be presented. So, has — we don’t — we just don’t have that information yet. As that information is available, then we’ll be able to communicate it to you.
Tim Lugo: All right. Thank you.
Ian Mortimer: Yeah.
Operator: Your next question comes from the line of Mohit Bansal from Wells Fargo. Please go ahead.
Mohit Bansal: Great. Thank you very much for taking my question. I just wanted to think about your thought process on the depression market in general. There’s a lot of development in mid- to late-stage. Recently, we have seen Kappa-opioid receptor. We have seen AMPA potentiator. Interesting data on depression scale, but there could be some effect on anhedonia and sidonia [ph] as well. So just wanted to see how do you compare and contrast with XEN1101, and these other mechanisms also look really safe. So, how do you think about the market evolving with these multiple drugs out there?
Ian Mortimer: Thanks, Mohit. Yeah. Excellent question that we think about a lot. Chris Von Seggern, do you want to walk through how we just think about the overall medical need and where azetukalner would fit in, especially considering that there are other drugs that are in development?
Dr. Chris Von Seggern: Yeah. Absolutely. I think, first and foremost, if you take a step back and you think about the major depressive market, we’re talking about an addressable population that is measured in the multi-multi-millions. As we all know, the main say of therapy in this space is SSRIs and SNRIs, of which there are many. Patients typically cycle through a couple of those options before they transition into what we consider the more of the branded market. We think there’s ample opportunity for a number of products to fill a void in the need for patients who don’t have an adequate response to an SSRI or SNRI, or importantly, have greater need as it pertains to an adverse event associated with either weight gain or sexual dysfunction.
So, we do appreciate that the competitive landscape in this space is quite a bit more than what we see in the focal onset seizure arena. But from a profile as it pertains to azetukalner, clinicians are really excited and have continued to express enthusiasm about that profile. Kv7 potentiation has a really strong link to the depressive state. The efficacy and safety profile that we’ve seen coming out of the X-NOVA study has really resonated with clinicians reaching for a novel mechanism of action. And then importantly, other attributes of rapidity of onset and the potential to address anhedonia are things that clinicians are really hungry for. So, the emergence of competition around us will further bolster some of those attributes. But there’s still plenty of opportunity for multiple successful products from a branded standpoint, given the residual unmet need that is so substantial in the major depressive market.
Mohit Bansal: Super helpful. Thank you.
Operator: Thank you. And your final question comes from the line of David Huang from Citigroup.
David Huang: Hi there. Thanks for taking my question and fitting me in. I just wanted to ask about your, I guess, latest thoughts on, given everything we know about 1101’s clinical profile, which now obviously includes a mood benefit, does that impact how you think about the peak sales opportunity for the product in epilepsy and MDD? And are there any, I guess, analogs out there historically in the market that we could think about as potential comps for 1101? I know products such as Vimpat have come up in discussions before, but just wanted to get a sense of what your current and latest thinking was on that?
Ian Mortimer: Thanks, David. Yeah. I’ll pass the call to Chris Von Seggern, because we’ve done a lot of work now on really understanding, having a mood benefit of azetukalner in epilepsy and we’ve done even more market research just over the last few months. So Chris talked about that a little bit in his prepared remarks, but I think he can go into a little bit more detail now in terms of that as a differentiator and as an opportunity from a commercial perspective.
