Be going with our next company presenter. Thanks for joining us for the BofA Annual Healthcare Conference. My name is Jason Gerberry. I'm one of the Biotech Analyst at BofA. I'm pleased to be introducing Xenon Pharmaceuticals. We've got CE O, Ian Mortimer, and CFO, Sherry Aulin. Both of you guys, thanks for joining us. Do we wanna jump right into the Q&A? Do you have any prepared comments you wanna make ahead of the start of that?
Well, one, thanks for having us. We'd, we don't have any prepared remarks. I can give maybe a quick introduction.
Sure.
Make sure we're all, we all have the same information, let's jump into Q&A as well. I think many people know Xenon well. We're a neurology company, really focused on drug and ion channels in the CNS. Been doing this for more than 15 years. Lead program, which we'll focus on, is XEN1101. This is a potassium channel modulator, in a broad and ambitious phase III program. In epilepsy, we announced yesterday with the earnings that we have our third phase III trial up and running now.
Mm-hmm.
We've got two studies ongoing, X-TOLE2 and X-TOLE3, in focal onset seizures, and then we have our X-ACKT study in primary generalized tonic-clonic seizures. I know we'll talk about today that we've got an MDD readout later this year as well.
Great. Well, maybe we'll jump into focal onset epilepsy, and maybe start with the big picture question. If we just think about the space, there's obviously a lot of approved generics. There was a very successful drug in Vimpat. It achieved the blockbuster revenue status, and it recently lost its patent exclusivity. As you just think of sort of the market environment for a new brand, is it conducive to can we see another blockbuster drug launch in the space? You know, in terms of investors thinking about sort of the opportunities that you're seeking out and developing drugs for and if large commercial opportunity success stories can still be had.
Yeah, I think that's a great question, Jason. As you mentioned, you know, Vimpat's done really well in the space. There's obviously other drugs, ASMs, that have done quite well. Keppra is another one that really reached blockbuster status. When you think about drugs like Vimpat and Keppra, I think the commonality is that they were, you know, easy to prescribe drugs, I would say, from a physician's perspective. Good tolerability profile, really kind of limited from a safety and monitoring perspective and low DDI risk. As you mentioned, you know, Vimpat did $1.8 billion in sales in its last year before losing exclusivity. We really think, given the profile of XEN1101, that we could be positioned potentially as a first-branded agent.
When you look to the sort of branded environment today, there's really sort of a, there's been really a bifurcation of, you know, the kind of haves and have-nots, with Vimpat being in the haves category. There's other branded agents that haven't done so well from a sales perspective, you'd really have to go through sort of each one and look at, you know, the characteristics and the profile to sort of, you know, kind of go through each one and highlight, you know, the challenges that they had. We really think given the profile of XEN1101 with novel mechanism, QD dosing, no titration, quick onset to efficacy, that we have an opportunity to be that first branded agent.
I guess one other important one to highlight is, you know, XCOPRI is the most recently branded ASM, that launch has gone reasonably well from our perspective. You know, they did launch during COVID.
Mm-hmm
Which can pose challenges. I think that drug, you know, has shown to have good efficacy, but it does come with some challenges, including a long titration period to mitigate or manage the risk of potential DRESS. There's more monitoring required on the part of physicians. What we've heard from, you know, KOLs that we've spoken to is that it's definitely used in later lines of therapy for that reason, and often before a patient goes to surgery consult. We think, you know, when we look at a number of years down the road when XEN1101 will be on the market and XCOPRI will be the only other branded agent, that we definitely have an ability to be-
Mm-hmm
... positioned ahead of XCOPRI.
As we think about your second confirmatory study, what aspect of the profile is most critical for you to replicate, do you think, of all the features? You talked about good efficacy, easy to give, it's reasonably well-tolerated, so.
Yeah.
It's a novel mechanism action. That's not gonna change, right?
That's not gonna change. Yeah. Yeah, I think you can put. You could probably characterize from an attributes point of view, stuff that's not gonna change, right? We'll be an only in class mechanism when we launch. These patients are treated in polypharmacy. We wanna combine different mechanisms together. That's not gonna change. The drug doesn't have to be titrated. That's not gonna change either. What are we trying to replicate in phase III? Just as a reminder, if we go back to the phase II data, XEN1101 in, at three different doses was stat sig at every seizure reduction endpoint at all doses. At the two doses in phase III, obviously we wanna replicate how we're doing on the efficacy side.
Sherry mentioned, but just to make the point again, one of the differentiating features of XEN1101 is the early onset to efficacy.
Mm-hmm.
We are statistically significant at week one. That is something we're trying to replicate in phase III. It is part of the statistical hierarchy in phase III. You know, it is further down the hierarchy, but that has an opportunity for us to have that discussion from a labeling perspective at the time. From a tolerability point of view, yeah, I mean, we're comfortable that this drug is generally well-tolerated. We see the adverse events that we would expect to see for a very active CNS drug. They are known, and they can be, they can be addressed, and they're in a dose-dependent fashion as well.
I think if we can replicate the profile of XEN1101 or close to it in phase III, all of the things that Sherry has mentioned on where we believe this drug could fit in from a prescriber point of view, should play out.
Yep. Okay. I think when we think about the efficacy in the subsequent phase IIIs, it. If I have it right, sort of in your prior phase III-B, the deck was somewhat stacked against you in terms of.
Yeah.
How severe these patients were and if anything, you know, because you enrolled that trial during COVID? You're not promising or guiding to like maybe a less severe patient population where your drug did, I think, better, right? That's certainly like a possibility that as enrollment factors get more balanced versus like traditional ASM studies. Just if you can speak to that dynamic and how you'd anticipate that evolving?
Yes. It's, you know, difficult to predict today, but let's dig into it a little bit. What we're trying to do in X-TOLE 2 and X-TOLE 3 in the phase III program, the reason we very purposefully call them X-TOLE 2 and X-TOLE 3 is we're trying to replicate the X-TOLE data.
Mm-hmm.
Nothing is changing from an inclusion/exclusion criteria perspective, to be clear. As you mentioned, this was a much more severe or refractory population than we expected going in, and there's three different ways we measure that. We measure that by the number of drugs that the patients have failed, the number of drugs that they were on, and their baseline seizure burden. We look at the literature, there hasn't been a more severe population that's been trialed in focal epilepsy. The median patient had failed six drugs, was on three drugs, and had 13 and a half seizures per month, which is significant seizure burden and had, you know, would be considered a more highly refractory patient.
Yes, we ran the study during COVID. I think there the hypothesis that the patient population could be less severe in phase III, I think is completely a reasonable question to ask. We will know as we get through the study what the baseline characteristics are on a blinded basis. Obviously, we get to the end of the study.
Yeah.
I think it would be difficult to fathom that the patient population is gonna get more challenging.
Mm-hmm. We're in a little bit of a window of time here the next year and a half or so where we don't have any data, and all we're gonna do is, you know, nitpick and focus on little aspects of the trial. When you complete enrollment, would you plan on sort of communicating any facets of the study population that you observe on a blinded basis, or is that sort of TBD?
Yeah. That hasn't been the way that we've communicated historically. You know, right now we're getting to the end of screening in our MDD study.
Mm-hmm.
We're not gonna be sharing a bunch of the characteristics of that patient population before we unblind data and provide top-line data. I just think, you know, very difficult to try to interpret blinded data.
Yeah.
It's not something that we've done in the past, and I don't expect to do in the future. Going into our epilepsy phase III readouts, although we monitor that because I think it's important for us to monitor.
Mm-hmm.
A number of things in the study to make sure that the study is being well run, that's not something that would be part of our public disclosure.
Yeah. Okay. Broadly in the space, clinical trial enrollment delays have been a topic amongst investors. You know, what you guys see that may be underpinning this, and I know that you feel like you've provided a conservative enough of a timeline to investors that you have some room to operate within that, and you don't see it as an issue for you guys per se, but, you know, maybe just what gets you comfortable with that?
We did touch on this, Jason, yesterday on our earnings call as well. I mean, we remain very comfortable and confident in our ability to execute on the phase III program. I mean, our confidence comes from multiple facets, I would say. You know, obviously, we have experience running a large epilepsy study with X-TOLE, I think that goes a long way. That was a study that was 325 patients across 80 sites, as Ian mentioned, our phase III studies are designed very closely to X-TOLE. We're really looking to replicate what we achieved or accomplished with X-TOLE in these phase III studies.
I think importantly as well, you know, we're gonna leverage a lot of the same sites in X-TOLE. We do expect that a significant number of those sites will participate in our phase III program, and we are seeing some of that happening already. The investigators have experience with the drug and have had patients have success on the drug. We have an active drug, obviously, which is a little bit different than trying to enroll a study where you have no proof of concept data.
Mm-hmm.
You know, keeping those relationships with key investigators is a big part of, you know, how we see our ability to succeed in the phase III program. Overall, you know, we're comfortable with where we are right now. As you mentioned, we haven't provided specific guidance on timelines, but we've provided in rough terms that we do expect, you know, the study to take about as long as X-TOLE did, which was 2-2.5 years. As we move along the remainder of the year, we'll be in a better position to see, you know, exactly how site initiation and patient enrollment is tracking against our internal expectations, and we'll be in a position to provide some more actual, you know, specific guidance later this year.
Now you recently announced the decision to expand XEN1101 epilepsy development to adolescents just with a pediatric formulation. Maybe can you just talk a little bit about what drove that decision and a little bit about the market opportunity in pediatric epilepsy?
Sure. I'll talk a little bit about the development plan, and Sherry can go over the market opportunity and market size. We have an obligation to do pediatric development, as part of, as part of our adult development. That's a pediatric development plan that we negotiate and have conversations with FDA. Those have been taking place over some time. I think our level of comfort in providing more information publicly is that those conversations have taken place, and we have an agreed-upon pediatric plan with the agency. Here we need to talk separately about focal onset seizures versus primary generalized tonic-clonic seizures. In focal epilepsy, there is an extrapolation rule, so there is regulatory guidance where you can get into younger cohorts of patients over time. You can do open label.
This is in patients, but you do open label, essentially PK data, and then you can get the label into younger patients over time. In primary generalized tonic-clonic seizures, as a reminder, what's unique about Xenon and our development plan from other epilepsy companies is we're doing focal epilepsy and primary generalized in parallel instead of doing those in series. There isn't that same regulatory construct in terms of the PK extrapolation. In our conversations with FDA, there was a request, at least in primary generalized tonic-clonic seizures, to today go down to 12-year-olds. We're making that amendment. In that phase III trial that we call X-ACKT, instead of 18 and above, it's going to be 12 and above. We are in parallel. We've already started this work, and it'll continue this year to do specific pediatric formulation development.
For 12 and above, they can take the adult dosage form. As you get into younger patients, you're going to need a different presentation. We're doing that work now. As we think about younger patients, we're going to need to do pediatric form dev. We're also going to have to do some juvenile tox work as we get into much younger patients, and that'll happen over time.
Okay.
When we think about the pediatric population, in the U.S., there's close to half a million pediatric patients that have epilepsy. Very similar to the adult population, the split of focal versus primary generalized is quite similar. About 60% have FOS, about 30% have PGTCS, and the other 10% do not have a primary diagnosis or maybe have a mixed phenotype. From a treatment paradigm perspective, I mean, it very closely mirrors the treatment paradigm for adults where children who have epilepsy will be put on a generic agent first, and depending on tolerability and efficacy, you know, may be either switched to a different agent or may have additional agents added.
Similar again to the adult patient population, there's still, you know, quite an unmet need here for novel mechanisms. You know, there's still quite a number of patients that are having, you know, breakthrough seizures with the current therapies that are available.
Okay. Maybe if you could just talk a little bit about your open label extension and follow-up of patients to help characterize your safety profile. I think you've now followed patients as far as three years now, with, I believe, every six month scans, brain scans, things like that. Maybe just your level of confidence, you know, in terms of your understanding of the safety profile and that effort that you're doing.
After patients finish the double blind period in X-TOLE, they have the ability to go to open label extension. We had 97% of patients that finished the double blind moved over. We have a large database that has moved through open label extension. That started at 275 subjects, and it's gotten a little bit smaller over time. Yes, we continue to monitor those patients both from an efficacy and a safety point of view. I would say the comments we make in open label, specifically to your question around safety, the comments we make in open label is there hasn't been any new safety signals in open label that we didn't see in the double blind period, and a very consistent adverse event and safety profile across the board.
Something that we would expect. We will give future updates later this year. There's a European Epilepsy Meeting in September where we're going to focus on some open label extension data, including quality of life data that we haven't previously presented. We have a couple of podiums at that conference. We will be submitting abstracts. The abstract submission deadline's coming up for the American Epilepsy Society meeting in December. That's where we're going to look at more mature open label data. As you mentioned, we do have patients now that have been dosed more than three years. We've kind of got hundreds of years of patient safety data. We will do later this fall in preparation for AES, a 30-month cut of the data. Last December, it was an 18-month cut.
This will be a 30-month cut. It still means many patients have been exposed much, much longer than that, but at least that's a mature data set to look at efficacy. Specifically on the efficacy side, one of the things that we're really interested to continue to provide information publicly is around the seizure freedom rates.
Okay. You know, we get a lot of questions just about the competitive landscape with other KVs in the space. I think your success has motivated others to come, which is not an uncommon phenomenon in the biopharma space. As we think about, a, the importance of setting an efficacy bar that's just high to beat and first mover advantage and how important you think that is. Then when we try to cross-trial compare the relative safety profiles of, say, your medication versus, say, Biohaven's drug, you know, is the best comparison really in healthy volunteers?
Just kind of curious your perspective at all because it's obviously difficult to tease out, your data when, you know, it's layered in terms of a combination with a number of other CNS agents.
I mean, I think we completely agree with your first part. I think anytime you've got a compelling mechanism, and a, and a compelling drug, it's going to bring competition. I think we're going to see other potassium channel modulators being developed. You've mentioned one company, but there are others as well that we're keeping a close eye on. We absolutely have a leadership position in this field. We've been drugging ion channels in the CNS. Just from a basic diligence point of view, we can profile other drugs, we can give ourselves a level of comfort.
I think we set a very high bar with XEN1101. From the attributes of the drug, not only the pharmacology, but the attributes of the drug, it being clearly a QD drug, the half-life of the drug, the early onset to efficacy. Those aren't related to the mechanism. Those are related to the pharmaceutic properties of XEN1101, which I think are very special. As you mentioned, just from an efficacy point of view, on a placebo-adjusted basis, this is the best efficacy we've seen as for an anti-seizure medicine. That bar is extremely high, whether you're a follow-up molecule with the same mechanism or whether you're a molecule with a different mechanism.
Although we are, you know, definitely tracking people, we're the only KV drug with clear efficacy in end of phase II meeting, and a clear path to market with a broad phase III program ongoing.
Okay. Then in terms of safety, do you feel like you have a good handle? I know that competitors try to, like, make claims about GABA and somnolence profile and-
Yeah.
Any caveats that you would throw in there in terms of making comparisons to some full data that were thrown out there, you know, regarding, you know, limited rates of somnolence with competitor drug?
Look, happy to address that head on. We've done the experiment. XEN1101 has no activity on GABA A. We're very comfortable with that. I would say, if we look at drugs, antiseizure medications that are active in the CNS, that decrease hyperexcitability in the brain have adverse events associated with them. We've seen that regardless of mechanism. You see Cmax-related adverse events, dizziness, somnolence, fatigue, and headache, and you just see different rates depending on the drug. To give you a bit of an example, Keppra, the most successful antiseizure medication, had a 15% somnolence rate, which is exactly the same as XEN1101.
We're very comfortable with the AE profile of our drug, and that it'll compare well to both drugs that are currently on the market as well as drugs that come in development.
Yep. Okay. Maybe we have ten minutes left. Maybe we'll just jump to MDD.
Sure.
Obviously Bottega showed some interesting data, and it's a motivating factor. You know, how do you think about if you have a positive trial development scenarios with MDD, either a full-blown MDD program versus just leveraging it within the context of epilepsy, where you have, kind of a very strong claim to owning perhaps that comorbid patient segment?
Yeah.
If you've got a drug with dual benefit on both, you know, seizure and mood.
Yeah. To take a step back, we're running a phase II study in major depressive disorder. I think there's good preclinical rationale and mechanistic support. As you said, the ezogabine data showed clear separation in a placebo-controlled study on clinical scales of depression and anhedonia using MADRS and SHAPS as those endpoints. We're running our own study. We are interested in running the study based on the comorbidity.
Mm-hmm.
The lifetime risk of depression in an epilepsy patient, depending on which literature you read, is 30%-50%. When you look at those patients that are more difficult to treat or more highly refractory, that number goes up even higher if you talk to KOLs. Depression is the most common comorbidity in epilepsy. If we can have a drug like XEN1101 as a novel mechanism, no titration, early onset to efficacy, compelling efficacy, and we can add mood benefit to that, I think it's just another differentiating factor as we're talking to physicians and epileptologists. I would say in one, just generating the data I think is important for the development of XEN1101 as an epilepsy drug. We do think the mechanism is well validated in depression, and we are interested.
You know, there's a number of inputs into our decision. The efficacy data is gonna be important, and we'll unblind later this year, the adverse event profile. We're doing more work in terms of the commercial market and the commercial dynamics. Yes, there is an opportunity for us to do future work in the primary indication of major depressive disorder. I think we have different avenues, and we're gonna wait. We've done the work internally that we need to do to prepare for that outcome. Once we see the data later this year, we'll have the totality of the picture and be able to give disclosure and guidance on next steps.
In general, MDD trials can be conducted faster. It could almost have a similar parallel time path as epilepsy if those data were wildly positive. Just hypothetically throwing that out there. Is that a fair assessment? 'Cause, these epilepsy trials do take a little bit longer time to run.
Yeah, that's right. I mean, the benefit that we have with XEN1101 is even outside of just the timeline of running phase III development, is we're doing all of the other things that you need to do to get a drug filed and approved, right? We're, you know, have a lot of investment into CMC and preparing for commercial supply of the drug. You know, we have an agreed-upon clinical pharmacology package that we need to do with FDA. We're doing all of the long-term toxicology work that supports that as well. The nice thing is if we move into other indications, we can leverage all of that. Yeah, I think we would generally agree with you. In our experience, depression studies are quicker to enroll than epilepsy studies.
Okay. Now, in epilepsy, I feel like a fundamental debate I hear oftentimes from psychiatrists is, well, is the, is the depression sort of secondary, outcome to, as a byproduct of the epilepsy, right? Am I, am I actually treating, you know, the mood disorder? I guess if you have data that show you actually have a benefit on mood, I guess it takes that question out of the equation, right? It's like, well, I know this works for the seizures, and I may get a mood benefit, and it really doesn't matter if it's secondary.
Yeah, I think we would agree with that, with that analysis is that the opportunity. You know, most anti-seizure medicines are considered mood neutral. There are drugs that have challenges with irritability and mood associated with them. So to have an anti-seizure medicine that clearly has seizure reduction benefit for these patients that has a benefit on mood, our feedback from, you know, from the primary market research that we've done, no surprise, I think that would be. You know, that would be something that would be very well received by the physician community.
Yep. Okay. You mentioned tolerability, and that's an important aspect of what we see with the data. Maybe talk about some of the steps that you've taken to mitigate any of the CNS-related adverse events that you'd expect with a drug like the CNS penetrant in the MDD trial.
Yeah. I think part of that has been our decision, Jason, to include an arm with a 10 mg dose.
Mm-hmm.
Initially we had studied, or we had designed the study, with the 20 mg dose being the mid dose in our epilepsy study. We were trying to design the study closely against the ezogabine placebo-controlled study that was run at the mid dose of ezogabine.
Mm-hmm
Which is 300 mg TID. When we got the X-TOLE data, back in the fall of 2021, and we hadn't yet started the X-NOVA study, that data really had us sort of pause and think about the dose selection for the X-NOVA trial, because when we looked at the 10 mg dose, where we actually, you know, we had less power in that arm in the epilepsy study. We had half the number of patients as the placebo arm. We actually were statistically significant-
Mm.
... in epilepsy. That dose was actually quite benign from a safety profile perspective or tolerability perspective. At that point, we decided to add an additional arm to the study and add the 10 mg dose, and take a look at that as well. As you mentioned, yes, tolerability is important in this patient population. We do expect that tolerability will be different in these patients in a monotherapy study versus in patients who have had, you know, in a lot of cases, an epilepsy diagnosis for 20+ years and are on multiple background medications.
As we saw in our X-TOLE study, 50% of our patients were on 3 background antiseizure medications, and that will have an impact on how those patients are able to tolerate medications and how they react to additional agents. For sure, you know, one of the key pieces of information that we're looking to see to really drive our decision-making going forward is that tolerability profile within both the 10 mg and 20 mg arms in the X-NOVA study.
Just, you know, in terms of what gives you comfort that you may not be underdosing at 10 mgs in MDD, do you feel like you're at a dose equivalent to what Potiga was able to show efficacy in the MDD setting with the 10 mg?
Well, as I said, the 10 mg dose was statistically significant in our epilepsy study.
Mm-hmm.
The 20 mg dose was actually more efficacious in our epilepsy study than the mid dose of ezogabine was in epilepsy.
Okay.
That's how we think about it. Obviously, we'll have to wait and see the data. If you were to compare it to what we saw in epilepsy, you know, that's how I would sort of draw the comparison.
Okay. I've been asking most of my companies this question, but just, you know, IRA exposure, it's something that you guys have been vocal about. I think you have a pretty decent Medicare- ... exposure if you're, you know, you make it to the commercial end market in the U.S. If you can just talk about sort of that dynamic and how investors should be thinking about IRA exposure?
Yeah. I can make a couple comments on that. I mean, I think, t he focus is really gonna be on sort of the you know, spend categories being oncology, immunology. I think, you know, in the context of XEN1101, you know, we're not gonna be up for negotiation for seven years post-approval and then an additional two years for discount and eligibility. We're really thinking, you know, it's not gonna be until the mid-thirties that this is relevant for us. It really at that stage, XEN1101's gonna have to be hugely successful for this to be a consideration. I think, you know, ultimately a lot can change between now and then from a regulatory perspective.
Okay. For your own internal planning, like Are you assuming LOE in 2039, on the basis of your food effect and I believe it's a polymorph patent? Just your confidence in those patents being able to kind of hold up versus, I believe your 2033 patent kind of runs pretty parallel with your data exclusivity, right? I think that the longer tail patents are really the debate.
Yeah. I mean, that's definitely our. You know, we feel very confident in our patent portfolio internally. As you mentioned, the food effect and the polymorph patent taking us out to 2039, 2040. We feel very confident in that strategy.
Do you have any other IP that you're prosecuting, or is that sort of the scope and the extent of your IP around XEN1101?
Yeah. I think we, you know, We haven't said a lot publicly. You know, we're always working on other things internally. You know, when we're ready to disclose, that, we will.
Okay. Throw a zinger at you, I guess. All right. Well, we're pretty much out of time, I think we'll wrap it up there, thanks so much for joining us. Great.
Yeah.
Thank you, Jason.
Thank you for hosting us.