Great. Thanks very much, everybody. It's my pleasure to be moderating this panel with Chris Kenney, Chief Medical Officer of Xenon. I'm sure everyone listening in knows the Xenon story at least decently well, but maybe I'll just kick it over to Chris to give a couple-minute opening on where you guys are with the X-TOLE phase III program, MDD, and anything else you'd like to highlight. Chris, take it away. Thank you very much.
Yeah, thanks, Paul. Really appreciate this opportunity. It's great to share what's going on at Xenon with the company in general and specifically azetukalner. I would say the punchline or the theme of this conversation is going to be that 2025 is going to be a really big year. We're really excited about a bunch of things going on. Right now, I would say it kind of falls into three different buckets. One is azetukalner in focal onset seizures, which will be our first planned approval for the drug. The second bucket are the three other indications that we're working for on azetukalner. The third are the incredible advancements that the Discovery organization has made targeting drugs to other ion channels.
Starting with azetukalner in focal onset seizures, just as a reminder, we finished a phase II-B study, which we call X-TOLE, which showed really robust data. If you take a look at what it takes to be considered a pivotal trial, we believe that that study checks all those boxes. We saw the largest separation between active and placebo than any other focal onset seizure study ever done that we can find. Those patients went into an open label extension, and those patients in the open label extension are doing really well. In fact, we're seeing one in three who've been in the study for three years or more with seizure freedom of a year or more. Those patients, on average, failed six medications before they even got in the study, and they had a seizure every other day on average.
If you go to the literature and you look at the chances that someone like that would get seizure-free, it's like low single digits. The patients are doing really well in the short term. They're doing really well in the long term. What we need to submit the NDA is the first phase III study. I'm sure we'll get into this more, but we're going to flip the card on that first phase III study in the second half of this year. We're really excited about that. That will set us up with all the necessary steps to make the transition from being a pre-commercial company to being a commercial company. That's the first bucket, azetukalner in focal onset seizures. The second bucket are the three other indications for azetukalner for label expansion. One is primary generalized tonic-clonic seizures.
Those studies are inherently more challenging than focal studies to conduct. That will be an sNDA. You have known for a while that we are going forward in major depressive disorder. We can go into more details to the extent that you want, but we have three large phase III studies in MDD. We just announced recently our interest in a fourth indication, which is bipolar depression, not bipolar mania. I am looking forward to hopefully going into some of the rationale for that. The first MDD phase III study has been up and running since the end of last year. The second one will get kicked off mid-year. The first bipolar study will also get kicked off in the middle of the year. Those are the first two buckets. The third bucket is the Discovery organization.
We're making backup compounds with the same mechanism as azetukalner, the KV7 mechanism for other neuropsych indications and pain. We're also interested in NaV1.1 for Dravet. I'm sure we'll spend some time talking about NaV1.7, which is a really interesting target for pain. We are doing IND-enabling studies for all three of those targets this year. We expect to submit an IND for the NaV1.7 first compound and be charging forward with first in human study later this year. A lot of cool stuff going on in 2025.
Yeah. Okay. Great, Chris. Thank you so much. Exciting times for Xenon. Maybe with epilepsy, what can you say about how enrollment is progressing with the first phase III? At this point, it's mid-March. Should we expect the data to be late this year at this point?
We're really comfortable with the guidance that we've provided, which is that the data will come out in the second half of 2025. I'm sure that you and everybody else is pressing for more detailed information. We will narrow that guidance as we get closer. For right now, very comfortable that this data will be available in the second half of 2025. That will be what we need to begin putting together the NDA, which will be submitted early next year.
Okay. Fair enough. What do you see as the biggest replicability risk for the phase II-B data? What have you guys done to try to mitigate this risk?
Yeah. I mean, the question is focused on epilepsy. The answer is really quite different for MDD. The.
Yeah, epilepsy.
Yeah. For epilepsy, the X-TOLE was fantastic. I think the guiding principle is do exactly what you just did and replicate it. We have made some subtle changes. The study is a little bit bigger. The pivotal trials are typically 12 weeks instead of 8 weeks. For the most part, we have tried to keep it the same otherwise and keep the similar percentage of patients in North America versus ex-North America and keep the inclusion-exclusion criteria the same and all that. If you look at the history of going from phase II to phase III, we can only find one example of an anti-seizure drug that failed to make that transition. Epilepsy, it is interesting. It is an anomaly in CNS. I am sure you know this. You spent so much time in CNS.
It's an anomaly in the sense that once you get that phase II data, at least historically, you've been golden. We're pretty confident that we'll be fine. Also, it's not like the phase II data was on the margins. It was wildly positive. In fact, for the high dose, if you just wanted to compare the high dose to placebo, you could get away with a study of about 80 or 100 patients. It's really over, it's like powered 99% for that high dose. We're not that concerned about repeating the phase II data. That said, we're not naive. What's clear is that placebo effects go up in certain geographical regions. We've been careful about where we've conducted the study. We have a very high standard for the sites we use.
The guiding principle is that we want sites that are dedicated to taking care of patients in epilepsy. Full stop. There are exceptions. We have other really good sites that are interested in other therapeutic areas. In general, the people we work with are epileptologists who have dedicated their lives to treating these patients and conducting clinical trials. The last thing, which we also used in phase II, was the electronic diary. We had a low placebo response in the phase II program. It was about 18%. We are hoping to replicate that. Time will tell if we can. We think that the electronic diary played a big role.
If someone is walking into the doctor's office and then filling out his or her seizure diary from a week ago or a month ago, the quality of that data isn't going to be as good as an electronic diary where they're sort of locked in and putting it in in real time. Those are the things that we're doing. We're feeling pretty confident, as confident as you can going into phase III readout.
Yeah. Okay. That's great. It's great to hear, Chris. Where are you with generating enough long-term safety data? I guess by the time this study reads out, will you have met the ICH guideline exposure, 300-6 months, 100?
Yeah. Are we going to be okay? Yeah, I would actually use the word golden. We are going to be golden. For those of you who do not live and breathe the ICH guidelines every day, you need 1,500 unique exposures. You need between 300-600 at six months, and then you need at least 100 for a year. We are way beyond that, and we will be way beyond that in a number of ways. Just as an example, the phase II-B study has an open label extension going. We have just within X-TOLE and X-TOLE OLE over 700 patient years of exposure. That does not count all the phase I work, the depression work, the other phase III studies. We have an enormous number of patient years.
If you look at just the X-TOLE OLE, we have just shy of 150 patients who have been treated for three years. We are way beyond ICH guidelines on all three fronts: uniques, six months, and a year. I will stop there and see if there was another aspect to that question.
No, I think that makes a lot of sense. I feel like at this point, right, you guys are confident in the trial. The data is guided for this year. You've got a ton of safety data. I mean, it's always our job to try to just pick out what are the outstanding risks, if any. You can't say there's no risk. I mean, maybe just the last piece of this is just from an FDA regulatory perspective, how are you thinking about, I guess, disproving the negative on the pigmentation risk concept that stems from ezogabine? Do you feel like the FDA is going to want something specific, be it like ocular assessments or anything, just to make sure that your label is totally clean on this point?
Yeah, definitely. They do want to make sure that we prove the negative, and we're doing a bunch of work. Let's talk about that. I talked about the 700 patient years of exposure from just the phase II-B study and the open label extension. The reason why I bring it up, not just because of ICH guidelines, but because of this safety. Just as a reminder, ezogabine was removed from the market, treated focal onset seizures, very similar mechanism of action to ours. What it caused was pigmentation in the skin, in the finger nail beds, in the pharynx, and also in the retina. To the extent that it occurred with ezogabine, the fact that we haven't seen any of that after 700-plus patient years of exposure, we think we're good.
To prove absolutely that it's not happening within the retina, you have to send the patient to the ophthalmologist. There are various tests that need to be done. All that data is being gathered extensively and thoroughly with the best quality vendors that we could find. When we submit the NDA, there will be an enormous amount of data to try and help prove that negative.
Excellent. Anything else you'd like to add on epilepsy?
We have a really nice relationship with the sites. The anecdotes are just like the best part of my day. You take a look at the seizure freedom that we're seeing in the open label, where one in three who have been in this study for three years are seizure-free for a year or more. There are just these really compelling anecdotal stories of patients who have never been seizure-free in their life and have been on multiple meds, and now they're seizure-free. It's really inspiring. We want to do what we can to bring this drug to patients because we think it's meaningful. There's the robustness of efficacy, but it's also the ease of use. It's not titrated. It's used once daily. We don't have significant DDIs. We're seeing a rapidity of onset within a week.
We have not even touched on this yet, but the psychiatric interest in azetukalner and the epilepsy interest in azetukalner are not distinct circles. They are overlapping. A lot of these patients with neurological conditions like epilepsy have psychiatric comorbidities. There is potential there to try and hopefully kill two birds with one stone. It is going to be a big year. I am looking forward to flipping that card.
Yeah, I am too. Probably not as much as you, but I am too. Okay, awesome. Let's talk a little bit about depression. You want to just give us a brief snapshot of where you are with the program as it relates to the phase III studies?
Yeah, let me do that. Let me just make sure to kind of set the historical context here very briefly. There's a bunch of preclinical work that has suggested that this mechanism may be helpful in depression. There was an ezogabine proof of concept study with 46 patients, which also suggested that this mechanism could be helpful for moderate to severe MDD. That was the precursor to our X-NOVA study. X-NOVA study rolled out at the end of 2023. We saw evidence of improvement in depression and anhedonia, again, a rapidity of onset. It was really well tolerated. You're talking about a mechanism of action that's incredibly different than anything that's on the market for MDD. That was the context for us to charge forward into phase III. So far, the phase III program's going well.
We announced publicly that the first phase III program was up and running at the end of last year. It's going as planned. By the middle of the year, we'll have the second study up and running. We're expecting approximately a six-month stagger to get the third one up and running as well. That's proceeding nicely. Yeah, I mean, we're excited. When we do our market research and we talk with physicians and you take a look at the medications that are available and you look at the attributes of azetukalner in the context of MDD, it definitely has a place. We're really pleased with the safety and the tolerability profile, no weight gain, no sexual side effects, those sorts of things.
All of that, I would say, I'm sure we're going to get to bipolar, but everything I just said is, I would say, even more relevant in the bipolar realm. So far, so good.
Yeah. Yep. Okay. Depression's like a different animal, right? And I'm a believer that this drug has a real antidepressant effect, especially you take your phase 2, you take the ezogabine study. I mean, that's a pretty good combination. That being said, whereas in epilepsy, you've got this big effect size margin to play with going to phase 3. In MDD, you guys saw the typical three-ish point placebo-adjusted difference. The hope is that that holds up, or maybe you can even expand that by better controlling placebo in phase 3. Maybe talk about that, right? I mean, the margin here is not as wide. MDD is harder. What are the things that you guys are working on that you're working on to try to maximize probability of success?
Yeah, the word that I use is MDD is unforgiving. It will tolerate no mistakes. Yeah. The answer I gave in epilepsy is that we're quite confident transition from phase 2 to phase 3 is pretty straightforward in epilepsy. It's the exact opposite in MDD. Just as a reminder, and you sort of alluded to this already, Paul, but we saw a three-point separation between the high dose and placebo, both on the MADRS and the HAM-D in the phase 2 study. One was significant, one wasn't. The HAM-D was significant. That wasn't driven so much by the numerical separation, but more by the noise, the standard deviation. We saw that in other depression studies as well. The first thing we did is we switched the primary endpoint from the MADRS to the HAM-D. FDA guidance allows you to use either.
We had an end of phase 2, meaning we have complete buy-in to go forward with HAM-D. That is one thing. Then thinking bigger picture, we did one phase 2 study. We're not going to do one phase 3. We're going to do three in hopes that at least two are positive. That is one risk mitigation step. The studies are much larger. The X-NOVA study had about 55, 56 patients per arm, depending on which one you're talking about. These phase 3 studies are going to be nearly four times as big, basically quadruple the size, 225 patients per arm so that we can have a 90% power to show a 2-2.5-point improvement on the HAM-D. Primary endpoint, number of studies, size of studies. Again, we're using the same approach. We're really qualified sites, high-quality CRO.
One of the things that we did, keep it simple is sort of one of the things that you hear about in the depression world. The idea is that the more interactions they have with the site, the higher the placebo effect. We decreased the number of one visit we decreased. We also have a script that every patient will hear about. Look, you're in a placebo-controlled study. You don't know if you're getting placebo or you're getting active drug, just to kind of remind them of that. We decreased from two active doses to one. If you look at the literature, that usually saves people a point on the placebo effect. As you know, these psychiatric studies are notorious for poor adherence. We're using a video app to basically confirm administration of drug in every patient every single day.
Also, professional patients. We have a vendor that we're working on so that we're double-checking to try and ensure that patients aren't enrolling in more than one study or that they're not jumping from one clinical trial to another and perhaps switching from one indication to another. I honestly, oh, and then, gosh, I forgot. CTN I were working with the psychologists and psychiatrists who are mostly based out of Massachusetts General Hospital. They're reviewing patients using the SAFER criteria and also repeating the HAM-D. If there's a big difference between what the site is saying the HAM-D is and what CTN I are saying, there are questions. There are some patients being rejected as a result of that. I don't know if I can think of anything that we're not doing, Paul. I mean, can you?
I don't know. Did you say MGH SAFER criteria? Yeah. Yeah. That was the only one I was wondering if you listed that one. I mean, no, I mean, I think it's interesting because I feel like from my seat, and I know others will probably hear where I'm coming from, who talked to lots of your peer companies, Chris, like there's a lot of companies that will tell us regularly, "We're doing everything." And then when this doesn't work out, it's like, "Well, we could have done." It's hard, right? I mean, I don't blame anybody. This is not me pointing out. It's hard, right? This is a hard space. There's professional.
Nobody says that the drug isn't working, right? It's just that the placebo is too high, right?
Exactly. By the way, I've been doing the CNS thing for like 12 years, and maybe not as long as you, but I still can't figure out when we're talking about mitigating placebo effect, are we also mitigating some of the placebo effect that's embedded in the drug arm? Are we just mitigating the special placebo? I think these things are complicated, but it feels like you guys are running a rigorous program.
One other thing, Paul, the other thing is that you see these patients, if you allow patients who are on the milder end of the spectrum, like they still have moderate to severe depression, but they're on that milder end, they can kind of drag your signals on too. That's another thing. We just made the criteria a little more stringent going from phase 2 to phase 3. Yeah, I hear you, though. Everybody says they're doing everything, and then people still run into challenges. I mean, the other thing I'll say is that at our CRO, we have psychiatrists who are reviewing each patient to make sure that they're eligible. We have internal psychiatrists who are reviewing each patient to make sure that they really should be in the study.
We're keeping an eye on the data, both at the subject level, site level, and of course, at the study level. It's tricky. I think a certain amount of daily paranoia is needed in those studies. Hopefully, we have that.
That's what I want to hear. In the meantime, we're going to get this IST data from Sinai. I know that that study is underpowered, but why wouldn't that add corroboration that this mechanism is doing something? There's almost two sides of the comparison. On the one hand, it's a small underpowered study. On the other hand, you might say that academic trials have a tendency to look better for antidepressants, right? What do you think, and how should we interpret these data?
Yeah. I mean, again, the historical context here is that Dr. Sanjay Mathew and James Murrough are running this study as they did with the ezogabine study. It is a two-site study, and the ezogabine signal was clear. There was a separation between active and placebo. Why not in this study? It is underpowered. It has 30 patients per arm. It is powered for fMRI, not for the clinical scales, even though I'm sure you and I are going to go right to the clinical scales when they come out. They're following the MADRS and the SHAPS, which evaluate depression and anhedonia. We're expecting, hoping for separation between drug and placebo, whether it will be. I mean, the X-NOVA study itself was underpowered to some extent. That is why the phase 3 study is even larger.
Talking about 30 patients per arm, I think it's unlikely that it'll be statistically significant. Yeah, we're looking for a trend that supports X-NOVA, and it'll make us feel better, but we don't know.
Yeah. Yep. Okay. Do you want to briefly talk about bipolar depression? Beyond your own data in MDD, is there anything extra there that got you excited about KV7 here?
Yeah. I mean, bipolar is really interesting. I mean, first of all, just from the unmet need perspective, you think about a new mechanism, good tolerability without weight gain and sexual side effects, improvements in anhedonia, rapidity of onset. All that's real interesting in MDD. It's even more interesting in bipolar because SSRIs, while they're used in some cases and cautiously in bipolar, they can trigger a manic episode. The treatment options are far more limited in bipolar. The attributes that make azetukalner interesting in MDD are actually heightened in bipolar. Number one, there's the unmet need. What's really interesting is as we dove into the literature, we were trying to make this decision, there is a genetic link between bipolar and KV7. Specifically, there are single nucleotide polymorphisms that are risk factors for the development of bipolar.
There's also evidence in postmortem experiments that there's abnormal regulation of KV7.2 and 7.3, and specifically, 7.3 is downregulated. There's actually biological plausibility for this mechanism above and beyond the fact that it just works in MDD. I do think, look, I'm a neurologist, not a psychiatrist, and maybe I'll leave it to the psychiatrist, but there are subtle differences between the depressive symptoms in MDD and in bipolar. All the logic that allows us to be somewhat confident in MDD sort of is also parlayed into bipolar. There's some really cool genetics that make it even more interesting. I think that if you listen to the earnings call recently, it was on a Thursday, I think, and I talked about I didn't really think this mechanism made as much sense in mania as it did in bipolar depression.
Fortunately, on Monday, not fortunately, but I would have had egg on my face if otherwise, but Biohaven announced the negative results of the mania study. There was a small study done with ezogabine in mania that looked pretty lukewarm. I do not think that the negative outcome in mania really changes our enthusiasm at all. I mean, if anything, it will be interesting to see the data because if they are not, it will be good just to show that the mechanism does not exacerbate mania.
Right. Yep. Yep. Makes sense. Okay. We're basically out of time, but I wanted to maybe just ask you for everybody for the sake of completeness, just touch upon the 1.1 and 1.7 timelines and where you are with those.
Yeah. Let's talk about 1.7. Really strong genetic rationale to go after that mechanism. We've got IND enabling studies ongoing right now, and we'll be charging forward in first-in-human studies with our first NaV1.7 compound this year. That's the other thing about 2025. Big year for all the advances in discovery, not just in KV7, but also IND enabling studies in NaV1.1, which we're using to target Dravet. We have backup compounds for KV7. KV7 is really interesting for the indications we've already talked about broadly in epilepsy, depression, and bipolar. There are other psych indications that I think are worth considering, specifically PTSD and generalized anxiety disorder float to the top. Pain. There was a drug approved in Europe, flupirtine, that was used for years to help with pain.
There is clinical evidence that this mechanism should help in pain. A bunch of good stuff. We are going to be broadly going forward into epilepsy, psychiatry, and pain, taking lots of shots on goal. I think that I do not know if everything will hit, but I think we will do well this year, I think.
Okay. It'd be cool if everything hit.
Yeah. Let's go for that. I like that.
Thank you, Chris. I appreciate it. This is a great discussion.
Okay. Thanks, Paul. Have a great day.
Thanks for listening.