Chris Kenney: Yeah. I mean on a high level, we have agreement from both FDA and EMA in terms of the plans to bring this drug into the pediatric population as it pertains to focal onset seizures with their extrapolation rules and then also with PGTCS. So there’s sort of two things that have to happen before you go into those clinical trials, Ian has already mentioned in the question — mentioned the pediatric formulation. There’s also some nonclinical work that needs to be done and then you’re able to go into open-label studies in pediatric patients usually starting at a higher age and then working your way down. So all of those plans have been agreed upon and are being finalized. And then on top of that, Ian already alluded to this, in our PGTCS study, the X-ACKT, we have brought down the age cutoff from a minimum of 18 years down to 12.
And so in the near future, we’ll start gathering data on adolescent patients in terms of efficacy, safety and PK and that will be helpful to illuminate all those plans I already mentioned that we’ve discussed with EMA and FDA. So it’s all ongoing. We think this drug has potential for adults and for patients, assuming that the safety profile supports it.
Ian Mortimer: Thanks, Chris. And then the question on kind of ex US, what is our thinking there? So I think no real update, but I’m happy to be to provide just our overall strategic approach here just to make sure that we’re clear. So we have stated for some time that we are doing all of the development for XEN1101 currently and our plans are to build the commercial infrastructure and launch the drug in the US ourselves. But the current strategic plan is not to build that infrastructure outside of the US. So at some point, we will be leveraging partners to access jurisdictions outside of the US. Obviously, we don’t guide on that timing. But that is something that, as we think about the long-term development and market access of the drugs of XEN1101, we’ll focus ourselves in the US, and then we would, at the appropriate time, engage with partners ex US.
Danielle Brill: Thank you.
Operator: Your next question comes from the line of Joseph Thome with TD Cowen. Your line is open.
Joseph Thome: Hi, there. Good afternoon and thank you for taking my questions. Maybe just one on the three Phase 3 studies for major depressive disorder. I guess, are these going to be just three replicate trials or in terms of the patient population enrolled or will you potentially use one of them to examine like an antidepressant unresponsive population or TRD, how should we think about that? And then second, just on the HAM-D measure itself, I guess, is there something mechanistically about 1101 that makes the benefit clear on the HAM-D scale versus the MADRS or was it really just what you saw in the Phase 2 and maybe some of that decreased variability in the response that made you go forward with that measure? Thanks.
Ian Mortimer: Thanks, Joe. Chris, are you good to go through the three Phase 3 studies and our thinking about the population there and then also the question around HAM-D17?
Chris Kenney: Yeah, sure. Let’s start with HAMD-17. I think I sort of already alluded to the point that I think is the major advantage for HAMD-17 over MADRS, which is really the variability, not just in our study but in other studies. And it’s not subtle. It’s really quite striking. So I think that’s the major factor for why it’s beneficial. As far as the other three studies that we’re going to do in major depressive disorder, we’re considering them to be very similar to one another, one active arm versus placebo, similar size. And the big difference from one study to the next will largely be considering different jurisdictions to be able to make sure that you can operationally execute and pull off the studies within a reasonable period of time.
But for the most part, we’re looking at them as pretty much identical and the purpose of that third study is to mitigate risk, largely similar to what we’ve done with focal onset seizures, we’ve completed X-TOLE and we’ve got X-TOLE2 and X-TOLE3 running. So similar approach to MDD and focal onset seizures.
Ian Mortimer: Great. Thank you, Chris. And Joe, maybe I can just add, just to answer your very specific question, Chris, I think, kind of, it was embedded in his answer that our current thinking is those three studies would look very much the same, which means the patient population would be the same. We wouldn’t be looking, as you asked about, like a TRD population in one of those studies. We would think about it really in the moderate to severe MDD population but not the TRD population.
Joseph Thome: Perfect. Thank you.
Ian Mortimer: Yeah.
Operator: Your next question comes from the line of Brian Skorney with Baird. Your line is open.
Brian Skorney: Hey, good afternoon everyone, thanks for taking my question. Also on the Nav1.7 program you’re working on, given what seems to be somewhat disparate results from a 1.8 inhibitor, there’s been some questions that we’ve done about differential expression in different tissues, it’s not just sort of a clinical design issue here. So I guess, how do you think about expression of Nav1.7 and how does this inform sort of what key indications do you think are sort of the most likely to be pursued for this target, I think, 1.7 preferentially expressed in DRG neurons. So just as you kind of like go forward, what do you imagine for the path for clinical development here?
Ian Mortimer: Yeah, I think it’s a really good question, Brian. It’s just very probably premature to go too far down that path. But I do want to kind of pull on the thread that you’ve made in your statement, which is I think expression matters, and so the distribution of the properties — pharmaceutic properties of the chemistries matter. And I was kind of alluding to this a little bit in one of the earlier questions, is, I think that’s a lot of what we learned, us at Xenon has been in the field for a number of years is that I do think we need appropriate molecules that are going to access the target peripherally. But as you say, there is a central expression as well. In terms of really designing out, and so we believe we have chemistries that are going to appropriately address where Nav1.7 is expressed.
And as a reminder, there are these patients out there that are these homozygous loss of function where they have none of the protein and they don’t feel pain regardless of noxious stimuli. We don’t think you need that kind of receptor occupancy. Some of the genetics actually teaches us in the literature that we don’t need that kind of receptor occupancy. But I think where expression is and the properties of the drug is absolutely going to matter. As we think too far ahead around, does that give us a better indication of where we should go in terms of the ultimate therapeutic utility and how broad or narrow? I think it’s just too premature. We’re really focused on getting through IND-enabling studies and then doing some of that early human proof-of-concept work.
And then I think we can kind of broaden out a little bit more and think about the development plan from there.
Operator: Your next question comes from the line of Marc Goodman with Leerink Partners. Your line is open.
Marc Goodman: Ian, I was curious, as you’ve dove into the data from MDD, a little bit more on the safety profile, just why do you think the safety profile was just different in that population relative to the epilepsy population? And then, Sherry, maybe you could just give us a sense of R&D spend for this year? Thank you.
Ian Mortimer: Marc, yeah, I’ll kind of open up with a quick comment, but I’ll pass it to Chris Kenney to kind of give his perspective. But yeah, I would actually say that was surprising to us when we unblinded X-NOVA that the tolerability profile, and I know we had a lot of questions with investors and with analysts on what is the tolerability profile going to be like in an MDD population as we compare that to the epilepsy population and we were pleasantly surprised when we unblinded data that it looks like tolerability. We probably — again, with the caveat of a cross-trial comparison, it looks like we have a better tolerability profile in depression. Chris, maybe you can give your perspective on the reasons. And I know we may not be able to answer it perfectly, but at least some of our thinking internally on the why.
Chris Kenney: Yeah. I mean going into it, I mean, we weren’t really sure what to expect. And so it was a pleasant surprise to see the tolerability the way it was. Two reasons I can come up with why it might be tolerated better in the MDD population than the focal onset seizures. One is that the concomitant medications, remember the X-NOVA was done as monotherapy, whereas the X-TOLE study was completed as adjunct to other antiseizure medications. And they were pretty — they had pretty significant disease, that X-TOLE population. Half of them were taking three anti-seizure medications and about 40% or so were taking two. So they were taking more concomitant medications. I think that’s probably the best answer to your question.
If you want to get a little more academic, there is evidence in nonclinical experiments that Kv7 is down regulated in depression models. And so I don’t know if that’s the case in patients with depression. I don’t think we’re ever going to be able to know for sure. But if there were a down regulation of Kv7 and you’re coming in with a Kv7 opener, you might expect those patients to tolerate the drug better. I mean I think one thing not to spend too much time on this, but eventually, we’ll have safety data in the X-ACKT trial with PGTCS. They tend to be on less or fewer concomitant antiseizure medications. And so we’ll be able to compare the 25-milligram dose in that population to FOS and see if there’s any difference there, it may get to the bottom of your question.
Sherry Aulin: And Marc, just to address your point on R&D spend in 2024. So as we think about the epilepsy program, as Ian mentioned earlier, this program, each of the studies is about 80 to 100 sites, and we’re going to multiple jurisdictions. So as we think about over 2024, now we’ve got our sites fully up and running, and we’re going to complete enrollment in late ’24, early ’25. So we are going to see an incremental increase as we look at the cost across the epilepsy program. In MDD, where we’ve guided that we’re going to have an FDA interaction in April and we’re going to start our first study in the second half of the year. So we’re not going to see a significant increase as it relates to the clinical development costs yet for MDD in ’24.
We’ll see that really pick up more in ’25. And then on the preclinical programs, we are, as we discussed, moving multiple product candidates into IND-enabling studies. So we’ll see an incremental step-up as well. So overall, I think we don’t guide and give specific numbers, but directionally, we’ll see a step-up increase in ’24 over what we saw in ’23.
Marc Goodman: Thanks.
Operator: Your next question comes from the line of Mohit Bansal with Wells Fargo. Your line is open.
Unidentified Analyst: This is Adam on for Mohit. Thanks for taking the question. With enough cash runway to support Phase 3 development in epilepsy and MDD, would you be able to compare how MDD development would compare to epilepsy in terms of trial requirements and costs? And also what data from the epilepsy program you can leverage for the MDD setting? Thanks.
Ian Mortimer: Thanks, Adam. I’m happy to take the second one. And then, Sherry, do you want to provide some perspective just on kind of sizing and costs overall for MDD versus epilepsy? So in terms of — that’s — we didn’t go into this earlier, but at our end of Phase 2 meeting, one of the questions that we will be discussing with FDA is just the size of the safety database. So Chris had mentioned, we learned a huge amount with our FDA interaction with the neurology division post X-TOLE. So we had a lot of questions around — so we have a lot of comfort around the clinical pharmacology package, the nonclinical package, the overall safety database that’s going to be required in epilepsy. One of the questions that we’ll discuss with FDA in April of this year in psychiatry is how much of that epilepsy safety database can we leverage into an application or a DOTCA in depression.
So we’ll be able to get back to you on that as we’ve had those FDA interactions and what those requirements are. I mean the benefit that we have with XEN1101 right now is, and Chris mentioned this in his prepared remarks, is we have a huge amount of safety data and a real significant knowledge about the profile of the drug. We now have over 600 patient years of exposure. We have long-term dosing more than four years. We’ll have patients that will go out more than five years this year. So I think we can leverage a huge amount of what we know about the molecule and I think we’ll get credit for that in depression. The question is what else is FDA going to require, specifically, in the label population. So stand by for that. Sherry, on the costing side?
