BridgeBio Pharma, Inc. — Call Transcript 2026

All right, welcome everyone to the 44th annual J.P. Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the Senior Biotech Analysts here at JPMorgan. I'm joined by my squad, Priyanka Grover, Joyce Zhou and Rathi Pillai. Kicking off the conference we have BridgeBio. And then presenting on behalf of the company, we have CEO Neil Kumar. Neil. Well, thanks everyone for taking the time this morning. I'd like to thank Mike, Ben and the entire JPMorgan team for having us here, again this year. This morning I was reminded that BridgeBio turns 10 this year. For a vast majority of those years we've had the absolute privilege of being cajoled, challenged and sometimes supported by the man to the left of me here, Anupam. So thank you for the partnership through the years Anup. Maybe I'll continue in that vein of thinking and thank all of the investors both in the room and on the line for the support over the last decade. Together we have created the second or third most efficient R&D engine for patients suffering with genetic diseases. Three approved products to date, with hopefully three more to come in the next 12 months. Almost 20 INDs generated and most importantly, nearly 10,000 patient lives affected. With hopefully many tens of thousands of more to come in the coming years and decade. But you didn't come here this morning to hear me talk about the past. You came to hear me talk about where we're going and where we're headed over the coming weeks, months and years. For that we continue to believe that it is day one in this era of genetic medicine. I'll give you updates today, all new information across the three different stages of our business. First, and importantly, our commercial franchise in ATTR cardiomyopathy. Second, updates both on the data front and regulatory front for our late stage franchises in achondroplasia, LGMD2I, ADH1 and Canavan disease. And then finally, I'll touch on some of that early stage research substrate that's exciting us so much and give you a good example of some of the early stage research we're doing with our EPP, potentially best in class asset that just cleared its phase II-A. But let me start with the most important slide in this document. We are preannouncing today our Q4 revenue number of $146 million. And the reason we get excited about this number is that it suggests we are helping ever higher numbers of patients with ever more numbers of physician partners. $146 million of revenue is a 35% growth over our last quarter and suggests about a 60% CAGR. And just as another reminder, this is actually more revenue generated in the fourth quarter of launch than tafamidis generated as it came out of the gates. This brings our total in our first four quarters of revenue to $362 million. And even more heartening than this number are the numbers that lie underneath it. Some 6,629 unique U.S. patients that we've been able to serve with Attruby in partnership with over 1,600 physicians. And as you all know, we focus greatly on MBRX share. MBRX share, given the dynamics in this commercial marketplace we believe is suggestive of ultimate TRX. Our goal being 30%-35% peak year share by volume. We're well on our way with greater than 25% MBRX already just one year into our launch. Altogether, with our partner Bayer's efforts in Europe, we believe that the Attruby franchise in 2026 will generate over $1 billion of revenue. Of course, all of this is possible given the unique biochemical and clinical characteristics of the molecule. As you all know in this room, it is the first and only near complete stabilizer as labeled by the FDA and has provided what we call 3-42-50. At three months, statistically significant separation from placebo. At 30 months, a 42% relative risk reduction against those same characteristics of all-cause mortality and cardiovascular hospitalization, and at 30 months a whopping 50% reduction in hospitalization, suggesting we're able to help patients live longer and healthier lives out of the hospital setting. Over the course of the last 12 months you've seen from us over 50 publications and abstracts delving into various aspects of this overall value proposition as well as trying to better understand where our drug best performs for patient populations like the variant population or patient populations like the AFib population. Today I want to focus a little bit on one of the aspects that I think has been underappreciated, which is the assets early separation from placebo. Some data that we published at HFSA that I think honestly was missed by most investors and actually a lot of physicians was that we had indeed observed a numeric separation in cumulative morbidity as early as one month with our drug. Now that's a bit of a head scratcher because obviously if you think about the kinetics within the heart, it's probably not the impact of a turning down of the amount of toxic monomer that's depositing in the heart that's actually driving this impact. And so we sort of scratch our heads and ask the question, what might be driving this? It took us to analyzing some of the very unique hemodynamic and cardiorenal properties of this asset. I won't spoil, nor do I have time to go through the whole story here, but you will see a series of publications over the next 12 months suggesting that Attruby actually has renal protective attributes analogous to the SGLT2 and ARB class and totally unique to this compound. Now, why might that be? Obviously it is because Attruby is delivering the highest known kinetic and overall levels of stabilization in this space. I've said it before and I'll say it again, an Attruby simply sees more of the target TTR, it binds it more effectively with a superior KD2 binding as compared to tafamidis, and ultimately does a better job of gluing the tetramer together over time. For those of you that have been following the preclinical work in this space, you'll have seen the PNAS or Proceedings of National Academy Sciences paper that came out about a month ago with some really beautiful mass spec work, and I'll read the conclusion from the authors. Just briefly, Our thermodynamic analysis further supports the notion that binding enthalpy, not affinity KD or a change in Gibbs free energy, better predicts the conformational stabilization imparted by these kinetic stabilizers. As many of you know, and as we published in Miller et al, using an ITC approach, we have a vastly superior enthalpic binding mode as compared to tafamidis. Now the good news is we don't even need it because we also have a superior binding approach, and it wouldn't be a talk from me unless I trotted out a new quote from Jeff Kelly. As many of you know, the inventor of tafamidis and the founder of FoldRx. This is an email that he sent our founders Isabella and Mamoun some time ago and he says given the variability in stoichiometry in the experiments between tafamidis and AG10, which is acoramidis or Attruby and TTR. The data will always tell the same story, that AG10 is better than tafamidis, as would be expected from the determined binding constants. We wholeheartedly agree and will continue to interrogate the advantages of this ever better stabilization for the patients that we serve. Today we're announcing something in tandem to those efforts. We've long sought the ability to pair upstream turning down of the toxic monomer that deposits in the heart because recall both knockdowns and stabilizers are trying to turn off the faucet of toxic monomeric deposition in the heart with an agent that helps clear the already deposited plaque. Because by and large we are diagnosing patients too late and at a point where there is already pathogenic deposition of amyloid plaque in their hearts. And the right way to do this is to establish a depleter or antibody-associated program that promotes the clearance of that already deposited plaque. We've been greatly privileged to be working with Dr. Richard Scheller, our Chairman of R&D, who as many of you know, ran R&D at Genentech for a very long period of time and was associated with Herceptin amongst many other great antibodies. He’s been leading this project for the last couple of years alongside our colleague Christine Zhang. What we wanted to do within this space was to build on prior efforts and really optimize an antibody against four key dimensions. First, obviously, we wanted to bind more target. We wanted to find, and in this case, a cryptic previously described but not employed binding site within the fibril to go after. Secondly, we wanted to clear more target by better recruiting macrophages to our antibodies upon binding. Then third and fourth, we wanted to improve antibody half-life by optimizing pH sensitivity within the endosome and then ultimately taking advantage of some of the novel literature on FcRn binding that many of you are familiar with to improve antibody half-life, therefore making it more effective and hopefully more convenient over time. And we're heartened to say that we've been able to create an antibody to date that actually checks off all those boxes very close to development candidate, and we anticipate moving this program into the clinic in the coming 18 months. Okay, so I'd like to turn now from ATTR cardiomyopathy to our development franchise and I'll start with our profound results that we published just a few months ago in the context of limb-girdle muscular dystrophy type 2I. As a reminder, this is a deleterious condition with no available pharmacologic therapy that affects almost 7,000 patients between the United States and the EU. Two and a half months ago, we published the interim phase III results from our trial that sought to look initially at biochemical impact against the causal biochemical damage associated with this condition. The bad news around this condition is that there are no available therapies. The good news is it's remarkably well described biochemically owing uniformly to conformational loss of function mutations in an enzyme called FKRP, which leads to a lack of glycosylation of what's called the alpha-dystroglycan complex in the muscle. And we sought to turn up that glycosylation level so that we could go forward and help patients. We powered a trial so that we could look at biochemical glycosylation of the ADG complex in tandem with a measure of muscle damage called CK. And sure enough, after one year, as we looked at the trial, we found a 1.8x increase, even more profound than we observed in phase II in ADG glycosylation and an 82% decrease concomitant in a measure of muscle damage called CK. So those were very heartening, but what we saw next we didn't expect. We saw statistically significant improvements against measures of both ambulation and breathing. This is the first data set that looks like this, as far as I know, in the muscular dystrophy space. And what was even more encouraging was for each of those two measures, both ambulation and breathing, we saw a decline in the placebo arm and an incline or improvement in the therapeutic arm, suggesting that we are improving patients, and in some cases on breathing and on EEG, returning a few patients back to normal within a year. That is a profound advance. When we talk about therapeutic cure in the context of what we do, we don't often think about small molecules, but this is truly therapeutic cure for a few of the patients that we have treated here. I want to elaborate on that data that we announced at Topline with a bit more detail. These are data that we shared with the agency in mid December, and these are the forest plots against all of the primary and key secondary endpoints that I just mentioned, and I don't have time to go through each single one of these plots, but I think you will see that the consistency of the plots and the statistical robustness are encouraging. Furthermore, what you can see from this drug is treatment and effective treatment across a number of different subcategories suggesting either early stage or late stage disease, so for instance, for compound heterozygotes that tend to be more severe in this disease, we see marked efficacy consistent with what we see in the "milder" condition, which is the L276I homozygous population. Additionally, we see consistent efficacy from young to old people who have had the disease for a long time versus people who have just been diagnosed and at different baselines of FVC. So beautifully consistent data that we were able to share with the agency. Perhaps the most important data pertains to the modified North Star test. As many of you know, this division of the FDA likes to look at North Star or modified North Star, a very difficult endpoint against which to achieve statistical significance. We designed our trial to do so after almost three years. After looking at the interim data one year in, what we showed was a 2.6 delta, again with a decline in placebo and an improvement in what we saw on active with robust statistical significance. This was certainly our trial was certainly not powered to show this and we were extremely encouraged to see this data coupled with the data I just shared with you. We took all of that data in to a presentation to the agency in mid December and they, quote, were very pleased that we had demonstrated consistent treatment effects on multiple efficacy endpoints and upon seeing the data asked us to file our NDA toward traditional and full approval versus accelerated approval. Knowing that leaving kids on placebo arm for the entirety of the design trial would likely be unethical. We anticipate filing this NDA sometime mid this year. I'll turn now to our efforts in ADH1. As many of you know, ADH1 is a condition that affects almost 12,000 Americans alone, making it one of the larger markets and certainly one of the more underdiagnosed conditions that we go after. Again, the good news here is that this condition is remarkably well described owing uniformly to gain of function mutations in the calcium sensing receptor, and we are going after this condition having designed a negative allosteric modulator of the calcium sensing receptor. Again, just about a couple of months ago we were privileged to announce our phase III results in this category where we demonstrated a 76% responder rate following encaleret treatment. Now, response here is actually normalization of urine and serum calcium, which are the two things that drive all of the conditions in this disease. So low serum calcium levels is what drives tetany, brain fog and ultimately seizures. And high urine calcium levels drive downstream nephrolithiasis, CKD, kidney stones and the like. Recall also that standard of care, which only had a 4% response in our clinical trial, is simply calcium supplementation. So even when patients can get back to normal levels of serum calcium, they're actually downstream harming themselves by loading up their kidneys with calcium. A 76% full normalization of patients once again applies to this concept that I talked about during my comments on LGMD2i. This is therapeutic cure for these patients. They are back to normal levels of calcium and could undergo and live a relatively normal life on a go-forward basis. Hearteningly, we also showed in 90+% of patients response to the drug. So there's normalization and then there's response. 90+% of patients were normalized as you look at their PTH and they moved in the right directions when we thought about urine and serum calcium levels. So very few segment of this patient population would not be served with encaleret on a go-forward basis. How do we find these patients? As I mentioned at the outset, this is a relatively underdiagnosed disease. How do we go about starting to find patients that would find this therapy useful? The team has done a really nice job of providing really three angles to this. The first is to improve genetic testing and to partner with Prevention and other local providers so that we might offer a panel to identify pathogenic variants associated with the calcium-sensing receptor. As many of you know, we've also published some literature on what those variants are and really drilled into the constellation of known pathogenic variants as opposed to the VUS's in this gene. Second, our commercial team created an ICD-10 code so that we might better codify and identify patients with frank ADH1 as opposed to chronic hypopara throughout the course of time. And then finally actually the guidelines were updated to suggest genetic testing for those with nonsurgical hyperparathyroidism so that they might see whether or not they're ADH1 patients actually hiding within the context of that broader HP community. It's not unlike actually ATTR cardiomyopathy or even hypertrophic cardiomyopathy when I got started. These patients are hiding within the context of HFpEF. We needed to find them here. Again we need to establish the algorithm to find the patients that would best benefit from this drug product. And extremely excitingly, what the results of these efforts have been to date is the identification of 1,700 unique patients based on again the efforts of these alone, plus the medical education that we've been doing. This underlies our projection that are about 3,000-5,000 identified patients associated with ADH1 today. But more importantly in my mind suggests that we have the right approach to continue to find new patients over time, especially after the therapy launches. This is pretty robust growth given the fact that the therapy is not even approved or in the commercial marketplace today. Okay, turning finally to an update on the encaleret program as it applies to an additional indication, chronic hypoparathyroidism. As you all know, for every medicine that we interrogate, our responsibility is to figure out all of the different ways it could be applicable to human health. In this case, the phenotype of restoration of urine and serum calcium suggested to us that this may be a useful and the first oral product in the context of CHP and indeed in a very small but robust in terms of its signal clinical trial in about 10 patients. What we showed was 80% normalization of urine and serum calcium in the context of chronic hypoparathyroidism. We took that data coupled with the mechanism, coupled with what we learned from our ADH1 trial to the FDA and we aligned on an extremely exciting trial that we intend to prosecute starting mid-year. We call it the RECLAIM-HP trial. What you can see from this trial design are really two salient characteristics. One, this is a six-month trial. We intend to relatively quickly interrogate this compound to better understand whether or not as an oral agent it could provide the types of efficacy we see with PTH replacement therapy or even better. Secondly, the primary endpoint, the proportion of participants achieving albumin-corrected blood and urine calcium within the target range. Now recall our phase II data. This suggests a very high probability of technical success associated with this clinical trial, so we are excited not only to launch an ADH1 but also to serve patients with chronic hyperparathyroidism on an ongoing basis. I'd like to turn now to our achondroplasia and hypochondroplasia franchise associated with our small molecule, infigratinib. As a reminder, this affects some 55,000 individuals between the U.S. and EU and represents a significant unmet need. For those of you interested in this program, I would suggest that you listen in to the webinar that was recently published on Friday. Our colleagues Justin To, Daniela Rogoff, and Dr. Legare; we're very privileged to have her on the line. Both talk about the architecture of this condition as well as how meaningful infigratinib could potentially be to the folks we're trying to serve within this population. On that webinar, Justin mentioned that we have achieved last patient, last visit against our phase III in achondroplasia and anticipate reading out that data to everyone sometime in Q1 of this year. Importantly, we also have first patient enrolled in our pediatric and toddler study. Recall, PROPEL 3 already is interrogating the broadest set of ages within the achondroplastic trial setting from three to 18, but we'd like to go all the way down to as low an age as possible, and therefore PROPEL INT is important, and then really excitingly, we have full enrollment completed for our phase II portion of our hypochondroplasia study. Again, a related condition arising from a different but still activating mutation in FGFR3. As Justin mentioned during the webinar and I think it's important to reinforce, this is the best and most advantaged approach within the context of achondroplasia. First, it is the only approach mechanistically to target this condition at its source, FGFR3 over activation. Secondly, in the definitive animal model, it provides not only quantitative advantages as compared to the CNP class of medicines, but also qualitatively is able to deliver results against things like foramen magnum surface area and things outside of long bone growth that ultimately are important to the community that we serve. Third, and most importantly, in the New England Journal of Medicine last year we published quantitative outperformance of this agent in the context of achondroplasia, both when looking at change from baseline in AHV as well as absolute AHV, and then coupling that with maybe perhaps the best endpoint given the variance associated with AHV, which is the Z score, where we showed a 0.36+ standard deviation at month 12. The community was incredibly excited about these results. In addition to the fact that we were able for the first time to provide a statistically significant result against proportionality, a decrease of 0.12, we're the only agent in this space that's received breakthrough designation suggesting that the FDA sees this as a marked leap against standard of care. And finally, and importantly, as we've done our market research, this is a convenient, safe and oral medicine that allows all kiddos that might want to try this agent to be able to try it in a convenient manner. And just so I can elaborate on that a little bit, here you can see a picture of the capsules on your left hand side. Again, 17 mm long, very easy to swallow. And if you have trouble swallowing that, you can break this up into the granules, which are 2 mm long and easily mixable with soft foods. Okay, so what does this look like in terms of the marketplace? We obviously have to start thinking about our commercial efforts. And for those of you that were here a couple of years ago, you'll remember that as we were getting set to launch in ATTR, we had done quite a bit of market research in using a couple of different tools to better estimate what our share would be and how to size our sales force. And I think actually those projections have been fairly accurate and we marry those now with a third tool that I'll talk about in a moment. So the first way that we try to understand how this agent might perform is by taking a variety of TPPs and using it in the context of market research, where we're able to go out to 80% of the physicians by volume that are prescribing today's currently available CMPs. The second is that we look at analogs and 3,500 molecules, many of them that are oral versus injections, et cetera. So we were able to look at the appropriate analogs to estimate what peak year market share might look like in this space. And then finally, in collaboration with MIT, Andrew Lo and his QLS group, we have launched a revenue institute where we will be publishing on in the next few months a brand new algorithm that helps us better predict how our molecules will launch over time and indeed how other molecules hopefully will launch in a future state. So I won't talk about all of the research here. You could expect to hear updates from us in the months to come, especially as we get a glimpse of our phase III data. But here's the TPP that we actually tested in market research most robustly. And you can see again an indication that's the broadest indication in terms of age range being interrogated in our trial in MOA. That's a selective FGFR 1, 2, 3 inhibitors, the dosing and administration, that's a real marked step forward. A daily oral as opposed to a daily or a weekly injection. We put our delta in HV change from baseline at the tippy top of what CMPs have been able to achieve. 1.5 cm per year. And we put a well tolerated AE profile into the TPP, which is effectively all of the safety that you've seen from this compound to date. Less than 10% hyper phos and importantly, avoidance of injection site reactions, hypotension, because recall, that's really where the CMP category comes from. And the excessive hairiness that has been otherwise observed with some of the CMP products. And what we found based on that TPP was a stubbornly consistent 52% market share. We believe that we will take a vast majority of this market, but we will, at least given the market research, take a majority of the market, given the profile shown on the left. So again, we anticipate data so we can fill this in for real and go and take somewhere between a majority and vast majority of the market based on data to come. Last, but certainly not least are our efforts in Canavan disease. As many of you know, Canavan is an extraordinarily rare, extremely deleterious neurodevelopmental disease. We've been taking a gene therapy approach to see what we can do to serve children affected with this condition. I don't have time to walk through many slides on this, but what I will show you in this single slide associated with Canavan is the evolution of the data that I presented last year where you can see at our 10 to the 14 high dose robust and profound decreases in the causal biomarker associated with this disease, which is urine NAA and mirrored by CSF. Very hearteningly you see a dose responsive improvement in the behavior of these children. Improvements such as sitting, head control, reaching and grasping, and in certain cases ambulation where you would certainly not expect to see it. We continue to dose children and assess the safety and efficacy of this product and we anticipate filing its BLA sometime in 2027. Okay, so hopefully three launches upcoming. How are we going to do it? That's a lot for a small biotech and we think we can employ this decentralized model that we have to continue to scale launches. Those three launches, hopefully if we're lucky with the achondroplasia top line and hopefully launches to come with some of these additional indications that I talked about. And what we've done here is we've preserved the affiliate structure so that we have the teams that are close to the physicians in any given therapeutic area, that are close to the patient and patient advocacy groups and that are close to the data really running the launches. But they're doing so in partnership with the wonderful team that Matt Outten and our commercial colleagues have put together, therefore making it such that we don't have to re spend the money to set up the infrastructure. As many of you know, in rare disease, the preponderance of spend is not against FTE or the field force every time, but rather against the back end of market access, patient services, analytics, etc. So we can use that already established expertise and apply it to launch after launch in tandem with the affiliates. So that's what we intend to do over these next three launches and hopefully maybe five launches associated with the comments I've made to date. But the question is where else do we want to take this platform in the years to come? That takes me to the final points maybe I'll make on why we believe it is still day one in this era of genetic disease. I won't belabor it because I think many of you in the room know this, but about three years ago I was up here chatting with Anup about this concept of missing heritability. Why is it that so much of what we see in terms of phenotype is not well captured by genetic information? And it turns out, as many of you know who have been following the literature, that just an increase in whole genome sequences versus exome sequences, coupled with a higher density of data has allowed us to really fill in the gaps around missing heritability and to begin to really tamp that down. But maybe most excitingly, we're able to start to identify these new variants and then connect them with mechanism, and then connect that mechanism with phenotype. What's allowing us to do that? Obviously advances in long read sequencing, allowing us to identify things like structural variants. Obviously advances in things like having a pan genome, a better reference against which we can understand variants, the prior and aforementioned increase in data density associated with these databases like UK Biobank and the like, and then really importantly, the ability to interrogate the function of these variants in cell and tissue specific experiments so that we can tease out their function and better design therapeutics that target well described conditions at their source. A fingerprint of all of these advances is simply the pipeline that we see at GondolaBio, a company, as you know, that is a sister company to BridgeBio and a company that you collectively own as investors in BridgeBio. Here you can see 17 different programs in a span of just a year, all pretty early stage, advancing all the way from early stage research to phase II. But in important areas of high unmet need, investors will be familiar with areas like EPP, ADPKD, Alpha-1 Antitrypsin, CMT1A, neurofibromatosis type 1 and the like. I don't have time to go through all of these programs obviously, but I'd like to touch on one example of again the well described process that we put forward at BridgeBio, which is to take generally small molecules and target these well described conditions at their source. So I want to talk a little bit about our EPP program. Most of you in the room, I think and on the line are familiar with EPP. But for those of you that are not, it is unfortunately a very large unmet need affecting some 20,000-25,000 people between the United States and the EU. So that makes it one of the larger disease states that we work on. When it does affect people, unfortunately it affects them with deleterious morbidity associated with skin damage and excruciating pain, as well as downstream liver disease. That's the bad news. The good news is that the pathomechanism of this condition has been very well described over the years. What we can see here from the cartoon on the left-hand side of this slide is that this condition uniformly arises from mutations in the heme synthesis pathway, most commonly through mutations in ferrochelatase. And what that does is it promotes the production of a compound called PP9, which then is present in the plasma, the skin and the bile at too high a concentration. And because PP9 is photosensitive, it drives the phototoxicity and pain that I just mentioned. Now there are many different ways to go after this condition. There are non causal ways to go after it, like using tanning agents. That has been the approach of Clinuvel, Mitsubishi Tanabe. And then there are different ways to target this causal pathway. Certainly Disc Medicine has one where they try to inhibit the intake of glycine. And we looked at that product and we started to ask ourselves, how do we improve upon it? The intake of glycine and its inhibition takes a very long time to provide PP9 reduction. It's not able to provide PP9 reduction to the marked levels that would be required to take people back down to, let's say, quote, a normal range of PP9. And you can't do it safely. As you know, GlyT1 inhibition, which is associated with glycine intake, comes from the schizophrenia field and is associated in EPP trials alone with high levels, almost 50% of dizziness and other AES. We asked ourselves, how else might we target this well described condition at its source, but do so avoiding some of those handicaps? What we decided on in collaboration with Dr. Ma at University of Pittsburgh was to inhibit the egress of PP9 from the red blood cell by inhibiting potently its solitary transporter, which is ABCG2. We have designed a compound by the name of Port-77, which is an orally bioavailable, highly potent inhibitor of ABCG2 that in cellular models, animal models and the like, has provided best in class efficacy and a beautifully safe profile that allows us to turn down levels of PP9 in the plasma and importantly and uniquely PP9 levels in the bile, staving off both the phototoxicity and pain that patients suffer from, but also the downstream liver disease. So I'll just go right to the point here, which are the results of our phase II-A trial which we recently just generated about a month ago. And here you can see the design of our gateway trial effectively to interrogate two different doses of Port-77 and to look at the change in plasma PP9 as compared to baseline and a run-in placebo. We also obviously wanted to interrogate PK safety and tolerability. So what did we find? Firstly and hearteningly we found a profound impact in terms of the diminishment of PP9 in the plasma. This has not been seen before. 75% reduction in PP9 levels. And even more importantly, because every minute matters for the patients that we serve, we were able to take action in a matter of hours as opposed to weeks from Disc Medicine's drug, and within days we reached steady state at 75% reduction. So the marked efficacy associated with this compound is unique in this space. But perhaps even more encouraging to me was the next slide. I have sat on many clinical trials and I rarely get this level of consistency from a phase II-A. Here you can see all 12 patients and I'll just take your eye to the dark blue lines here. Every single patient dosed with high-dose Port-77 experienced a reduction in PP9 levels. Maybe the smallest reduction observed was 57% and again the mean was 75%. So not only do we see profound reductions in PP9 levels, not only do we see relatively quick reductions in PP9 levels, we see very consistent action from this drug across the patient population. And importantly we are doing it safely. You can see a numeric imbalance in actually favor of the treatment as compared to placebo in most of these rows. This is importantly different than the other molecules in this space. Okay, so what I hope I've convinced you of in a few brief slides, and we will certainly be elaborating on this more in talks to come, is that we have a ABCG2 inhibitor that applied in its application to EPP, allows for potential best in class PP9 reduction. It has a dual mechanism that targets all aspects of the condition, has a clean safety profile, and that we're able to see it and that reduction within hours, not days to weeks. This is just one snapshot of all of the progress that you as investors own across the ecosystem of BridgeBio. We've got BridgeBio and its late-stage franchises. We certainly have early-stage research ongoing as I highlighted with the Depleter program. There are other programs in that same vein at BridgeBio. We have all of what's happening at GondolaBio, and indeed you are substantial owners of BridgeBio Oncology Therapeutics, where the CEO of that effort, Eli Wallace, will be talking a bit later today about some of the exciting updates against its franchises as well. So lots going on, lots to do for the patients that we serve. This is just a summary of all of the issues that I've covered today. Commercial momentum, late stage development momentum, early stage research and development momentum, all portending, I hope, in partnership with you all in this room, the ability to serve many more patients in the years to come. It wouldn't be a JPM slide if I didn't end on the comment that we are well financed to undertake all of these activities in the coming years and that all collectively these activities will create a steady drumbeat, hopefully, of advances for both the patients that we serve and investors in and around the stock. With that, I will thank you all for your attention. If we have time, I'll take a question or two. Neil, your presentation was so robust, I do not have any questions. Thank you. Thank you, Anup. I see the strategy. Great job. [inaudible] Welcome everyone to the 44th annual J.P. Morgan Healthcare Conference. My name is Tess Romero and I'm one of the senior biotech analysts here at J.P. Morgan. Our next presenting company is Xenon Pharmaceuticals. And presenting on behalf of the company we have President and CEO Ian Mortimer. Ian, over to you. Thank you, Tess. Good morning everyone. Great to be here. Kick off the year at JPMorgan and a really big update for Xenon. It's been a very important and impressive year over the last 12 months and now we're right on the doorstep of our first phase III clinical data, so we'll go through that today. I'm joined by some of my colleagues here. To my immediate left, Chris Kenney, our Chief Medical Officer. And to his left, Darren Cline, our Chief Commercial Officer. And Tucker Kelly, our CFO is here as well. Tucker and Darren are newer members of the team, have joined over the last 12 months. Both have significant experience in forward integration into a commercial organization, which is our strategic goal, so really nice to have them as part of the Xenon team here at JPMorgan this year. I will be making some forward-looking statements. So I do refer you to all of our risk factors that are filed with the SEC. So let's get started. Today we're going to spend time talking about our lead molecule, azetukalner, both in epilepsy and in psychiatry. This is the most advanced potassium channel modulator in late-stage clinical development today. And really the only Kv program that is unblinded clinical data and over 800 patient years of both efficacy and safety data. So I'll go through a number of those points throughout the presentation. We also have a really nice emerging earlier-stage pipeline that I'm going to spend some time on. We've got two phase I molecules right now that eventually will be developed in the pain space. I'm going to actually show a little bit of data and updates on one of those programs this morning. If we look at our pipeline, there's really three key areas of today's presentation. I'm going to talk most of the presentation on our lead molecule, which is azetukalner. We have six ongoing double-blind phase III clinical trials for azk. That's what we call the shortened version of azetukalner, three in epilepsy and three in neuropsychiatry. Today we'll spend time on the epilepsy program, we'll spend time on the psychiatry program. Then as I mentioned, the third thing is to give an update on some of our earlier-stage molecules that have transitioned now into human clinical development. If we start with the azetukalner, just more broadly, before I get into the epilepsy program, the feedback we're getting from physicians, both in the psychiatry space as well as in the epilepsy space, is there's high anticipation for a drug with a novel mechanism. There are no potassium channel modulators available either in epilepsy or in psychiatry. The other feedback we get are really the attributes of the drug. This drug is easy to administer, it's a QD drug. Once a day, daily dose and no titration. A lot of neurology drugs and drugs in the CNS, you have to start low and go slow. You're on a therapeutic dose on day one for azetukalner. We also have no meaningful DDIs, so we don't have to make adjustments to other background medications. The drug is backed by a significant amount of clinical data already. As I mentioned, we have over 800 patient years just in patients with focal onset seizures. We have some patients that have been dosed for more than five years now. So I'll go through both the clinical data as well as the safety profile of the drug. Both in efficacy or both in epilepsy as well as in neuropsychiatry. So let's start on the epilepsy side. So if we just take a quick look at the epilepsy market. So epilepsy is actually more common than I think many people recognize. It's the fourth most common neurological condition. You have a one in 26 lifetime risk of developing epilepsy. Epilepsy, if you look at the right, it's a breakdown of the different epilepsy subtypes. There's about three million Americans that have epilepsy. The most common form is focal onset seizures, or about 60% of the market. In terms of the generalized epilepsy market, the most common form of generalized epilepsy are these patients with primary generalized tonic-clonic seizures. And for azetukalner, as you'll see throughout the presentation, we're developing the drug both in FOS as well as in PGTCS, so the most common forms of epilepsy. What we find when we do all of our primary and secondary market research is about half of the patients are not getting good treatment today. So there are many drugs available to treat epilepsy. We recognize that this is a novel mechanism. And about half of the patients are still requiring better therapy, either because of efficacy or because of side effects. So the total addressable market that we think for a branded ASM in the conditions that we're developing is about a million patients in the U.S. Our excitement and our confidence in epilepsy really is off of our phase II-B trial that we unblinded in 2021, really underpinning our key leadership position in the epilepsy space. This was our X-TOLE study. This was a study where we randomized 325 subjects. It was a four-arm study, three active doses and placebo. Now we're following those patients in open-label extension. I'll go through both the double-blind data as well as the OLE data in today's presentation. If we first look at the efficacy data that we unblinded, there's two different graphs on this slide. On the left is what we call the MPC. This is looking at the percent reduction in seizures. This is the key primary endpoint for FDA. On the right is a responder analysis. So this is the percent of patients that have at least a 50% reduction in their seizure burden when we compare the double-blind period to the baseline period, and that's the key primary endpoint for European health regulators. I'm just going to focus on the left for a second, but you can see it on both graphs. There's a clear dose-response. So as we move from 10 mg to 20 mg to 25 mg, you get a deepening of the seizure reduction and the response. You'll also notice that we had p-values of less than 0.05 at all seizure reduction endpoints all doses and obviously even more significant p-values as you move up in dose. If we just look at the 25 mg dose on the left, that was the 52.8% reduction in seizures. And we placebo can adjust that. The high dose minus placebo, that placebo-adjusted MPC. This is the greatest reduction in seizures ever seen in an FOS study that's been unblinded. In a patient population that has been the most severe or most refractory that's ever been tested based on our review of the literature. We look at that severity of patients based on three different measures. We look at the number of drugs that these patients have failed, the number of background medications they are coming on to study, as well as their baseline seizure burden. The median patient in our phase II program had failed six drugs. They were on three background medications and they had 13 and a half seizures per 28 days. Quite a severe population. Another thing that we looked at in the phase II program and we're going to look at in phase III is also the rapidity of onset, so this is a similar analysis to the last slide. The last slide was on a monthly basis. This is looking at the data on a weekly basis, so what you'll see on the left graph, it's again, we're looking at both the reduction in seizures as well as the responder analysis, but just focusing on the left graph for a minute, you'll see quite a deep response at week one, so all doses were statistically significant or less than 0.05 at week one, so not only do we see a deepening of response over time, but you see a rapidity of onset. For these patients that are having breakthrough seizure, for them to have an immediate seizure reduction within days or within the first week of being on drug is really important for these patients. As I mentioned, we continue to follow these patients in open label extension. What started as a one-year OLE has been extended to a three-, five-, and now a seven-year open-label extension. We have a huge amount of both efficacy and safety data in the long term. At the American Epilepsy Society meeting every December, we mature these data and we show these data to the epilepsy community and get feedback. This is the 48-month data that we presented last month at the AES meeting. A couple of key messages from this slide. One, overall, we're getting over a 90% reduction in seizure burden for the population. As I mentioned, this was a very severe and refractory population. We actually, if we look at those patients that were on fewer background medications, either one or two background ASMs, you have 100% reduction in seizure burden for these patients. They're not having any seizures at all. It's quite remarkable when we look at the overall. What's otherwise interesting to notice is not only do we get a reduction immediately, as we talked about at week one, but it looks like that response is deepening over time. Looks like there's a deepening of the response a few months into the open label, and then again as we look out about 12 months or so. We've also been looking at seizure freedom. I wouldn't say there's a consensus definition for seizure freedom, but overall, when we talk to epileptologists and neurologists, patients being seizure free for 12 months is incredibly important. This provides patients independence because in most jurisdictions, if you have no seizures over a 12-month period, you can drive again. We're looking at all of the patients in our open label that have been dosed for 48 months and what you'll see, about two in five patients, or just under 40% have had 12 months of seizure freedom. So if you remember, these patients were having a seizure every other day. And now we're getting these long periods of seizure freedom with the medicine. And what we're hearing back from physicians, their patients are gaining more independence, they're working more, they're having more social interactions. Not shown on this graph, but if you look at our AES data from last month, we also looked at those patients that had a breakthrough seizure. And this was an analysis that we don't believe ever has been done before. So people can have a breakthrough seizure for a number of different reasons. It could be a missed medication, it could be a change, something in their lives. And what we found is that if you have a breakthrough seizure on azetukalner, you can regain seizure freedom for long periods of time and the majority of patients can regain seizure freedom for six or more months. So I think that's really important as we start to think about this drug in the real world. Patients are not going to necessarily be seizure free forever, but if they have a breakthrough seizure they should remain on therapy and they can do well over longer periods of time. So what I've really shown over the last number of slides is a huge amount of efficacy data overall for azetukalner in epilepsy. When we look at safety and tolerability, this drug is very active in the CNS and it has an adverse event profile that you would expect for a drug that's consistent with other ASMs and consistent with a drug that's active in the central nervous system. So we do see treatment-emergent adverse events, things like dizziness and somnolence, many of these in a dose-dependent manner. But overall the safety profile is something that we're very comfortable with and the feedback we've had from treating physicians as well. Also nice to know is that we're not seeing new adverse events in open label extension. As we mentioned, we now have patients that have been on the drug for more than five years and we have the safety profile in open label extension is consistent with the safety profile that we see in the double blind period. All of these data have given us a huge amount of confidence to go into a large phase III program. This phase III program was started a few years ago after an end of phase II meeting with FDA in focal onset seizures. We're running two phase III clinical trials in parallel. They're exactly the same. X-TOLE2 and X-TOLE3, two active doses of the drug versus placebo. Each study was targeted to randomize 360 subjects. For X-TOLE2 we have completed randomization. We've randomized 380 subjects. Randomizations were complete last fall. The last few patients are just going through their final follow-up visits. We'll be analyzing the data and as we guided this morning we'll have our first phase III clinical readout in March of this year. X-TOLE3 is a little bit behind but we did have an important announcement this morning as well. We've completed an ethnobridging study, a phase I study in Japanese subjects, and we had last fall a meeting with the PMDA, the Japanese health regulator, and we're now including Japanese subjects into X-TOLE3, so of the 360 subjects, 60 of them will be Japanese subjects, and what's really important here is we're not going to have to run separate phase III clinical trials in Japan. We can incorporate that into the global phase III program into X-TOLE3. The non-Japanese subject enrollment will be completed this year. That was another update and milestone we announced this morning. And then we'll incorporate Japanese sites and Japanese subjects into X-TOLE3 as well. As I mentioned, we're continuing to do work outside of FOS and we have an ongoing phase III clinical trial in primary generalized tonic-clonic seizures. What's a little bit different on this approach versus what other companies have done in epilepsy is we're running this study in parallel with our FOS study. Very common. You choose your high dose to randomize versus placebo. This says 25 mg versus placebo. Sample size of about 160. These studies do take a little bit longer than the FOS study. So the study continues to recruit and randomize patients. So that's the update on epilepsy. Really exciting, exciting time to be on the doorstep of unblinding our first phase III clinical trial with top line data as I mentioned in March of this year. So if we now expand the azetukalner opportunity outside of epilepsy and give an update in neuropsychiatry, we ran a smaller phase II study. This was really more signal finding, what we would call a proof of concept study in MDD. So a smaller study that unblinded in the fall of 2023, we were looking at two active doses of the drug, 10 mg and 20 mg versus placebo. Key primary endpoint was a clinical scale of depression called the MADRS scale. This drug works in the reward circuitry in the brain. One of the, based on the preclinical data and some other clinical data that was generated, we've also been looking at a scale of anhedonia and this scale is called the SHAPS scale. I'll walk through the data from the phase II study, which supports us moving into the large phase III program in major depressive disorder that we have ongoing. If we look at the MADRS, this was the primary endpoint. A couple of key points from this slide, one, you see a clear dose response. The 10 mg arm outperformed placebo and the 20 mg arm outperformed the 10 mg arm at every time point. What you'll actually see, again, very consistent with epilepsy, you see that rapid response immediately. This is really important in depression. Many of the drugs that are used to treat depression right now take weeks if not months to show an effect. So to be able to have early onset of efficacy is important. We were able to show that in this study as well. We had about a three-point separation on MADRS between the top dose of 20 mg versus placebo. So a little bit of a high placebo rate in this study and a p-value based on sample size of 0.135. Interesting. We looked at a different scale of depression, which is called the HAMD-17 scale. And we also had a three-point separation, but a p-value less than 0.05. And the reason that was based on variability. So what we saw when we looked at HAMD-17 is we saw less variability in that endpoint compared to the MADRS scale. And so now in phase III, we're looking at HAMD-17 as the primary endpoint. As I mentioned, we looked at a clinical scale of anhedonia called the SHAPS scale, again very similar. We saw a clear dose response and separation between the two active doses in placebo. About a 2.5 point difference between active and placebo at the high dose and also a p-value of less than 0.05. When we looked at the safety and tolerability data in depression, this was actually quite surprising to us. It looks like the tolerability profile is a little bit softer in the depression patients versus the epilepsy patients. Obviously this is a cross trial comparison, but overall it was quite a benign adverse event profile in depression. And importantly, when we think about depression, we didn't see any notable weight gain and no notable sexual dysfunction and we do see that with some of the current standard of care. When we think about our approach in psychiatry, a novel mechanism, rapidity of onset and having a different adverse event profile is the feedback that we're receiving from the psychiatry community is really important in the advancement of this new medicine. We now are in a large phase III program in major depressive disorder. Two ongoing phase III clinical trials, currently X-NOVA 2 and X-NOVA 3. A significant number of differences that we made between the phase II program and phase III, obviously a huge increase in sample size, one to one randomization using HAMD-17 as the primary endpoint, as well as we're looking at patients that are a little bit more severe coming into study. That cutoff of patients to get into study as a more severe depressed population. We also announced this morning, execution on these studies have been going really well and we'll have X-NOVA 2 data in the first half of next year. We've expanded in neuropsychiatry beyond major depressive disorder, also into bipolar depression. Really significant unmet medical need in bipolar depression. Fewer mechanisms and fewer drugs available for these patients. So we started a study mid year last year called the X-CEED study where we're looking at patients with both bipolar I and bipolar II. We're looking at scales of clinical depression as measured by MADRS single dose of 20 milligrams versus placebo. So as I mentioned, we also wanted to give an update. Obviously a huge amount of the focus for investors is on azetukalner, both in epilepsy as well in psychiatry. But we've made some great progress on the early stage portfolio and I wanted to provide an update this morning. I'm going to focus on our Nav1.7 program. We do have a second program that's targeting a potassium channel called Kv7 that's also in a phase I clinical trial. Today, in the interest of time, we're going to focus on our Nav1.7 program. The genetics of Nav1.7 are absolutely remarkable. Xenon led some of this work. About 20, 25 years ago, the history of the company started as a genetics company. These patients in a gene called SCN9A which encodes for a protein called Nav1.7. If you're complete loss of function for Nav1.7 or even a partial loss of function of about 75%-85% loss of function, these patients feel no pain. They feel no pain regardless of noxious stimuli. There's also gain of function in the channel. If you have too much activity in Nav1.7 you feel non precipitated severe pain. There's a genetic condition called inherited erythromelalgia where these people have extreme pain in their extremities. It was an absolutely remarkable genetic target when it was identified about 25 years ago. For years pharma, almost every of the large pharma companies were trying to drug this target. It's proven to be very challenging to target from a chemistry point of view. I think we've really made a breakthrough over the last couple of years. Some of the challenges with the first, what we would call kind of the first and second generation molecules against Nav1.7, we didn't have the potency and selectivity, so they didn't have isoform subselectivity on the sodium channels. We need to selectively hit Nav1.7 while not hitting the other isoforms. Many of the drugs also had significant protein binding, so they didn't have enough free fraction to interact with the target. And many of them were restricted to the peripheral nervous system, so they didn't act centrally. And if we want to mimic the human genetics, which is what we're trying to do as a novel analgesic, we believe we have to mimic where the target is, which is both in the peripheral nervous system as well in the central nervous system. So what we've been saying is that our lead molecule, XEN1701, which is now in a phase I clinical trial, has a profile that addresses all of these limitations and has a profile that's never been tested in a human clinical trial previously. Here's just a little bit of the early preclinical data. What you'll see on the left part of the slide on the graph is that we have molecules, and specifically 1701, but other molecules in other chemistries that are order of magnitude is more potent than the previous drugs that were targeting Nav1.7, shown here as both a Pfizer molecule as well as a Genentech molecule, which was actually our drug in collaboration with Genentech. We had a large collaboration with Genentech, Roche for many years. So we have significant increases in potency and significant increases in selectivity as well. What the right graph shows is that we need to get into the brain. So if you can get into the brain and you can have free drug in the brain, that can drive efficacy. So that's important for the profile overall. What we announced this morning, which I think is incredibly exciting, we're partway through the phase I clinical trial, but we've already reached exposures in the SAD portion of the study that are above concentrations predicted to mimic the human genetics. We don't believe that something like this has ever been seen in a healthy volunteer study. We will wrap up these phase I studies later this year and we're excited to get into a proof of concept study, probably something like bunionectomy before the end of 2026. In addition to the work on azetukalner, really nice progress on the early stage pipeline as well. Just to wrap up in milestones before we hit Q&A, as I said, it's been a really important year of execution for Xenon across a number of our clinical trials. We have six ongoing phase III clinical trials for azetukalner in both epilepsy and in psychiatry. The first of those is going to read out in March of this year, which is our X-TOLE2 study in focal onset seizures. That'll be followed by a number of clinical readouts in the coming quarters and coming years, both in epilepsy and in psychiatry. And we have a really nice maturing early stage portfolio and pipeline as well and some really nice progress on our Nav1.7 program. So thanks very much. An exciting year for Xenon coming up. And Tess, I'll pass it back to you for Q&A. Okay, thank you, Ian. So I thought I'd actually start our conversation with a little bit of a bigger picture strategic question for you. Just around how you think about investment and balancing it across azetukalner and epilepsy, but also neuropsychiatry and maximizing the value there, but also expanding some of your pipeline? Yeah, I think it's a great question. A couple of comments. One, we've been really clear on what our strategic objective is. We want to be a fully integrated biopharma company. We want to discover, develop and commercialize our own molecules. We have deep expertise, I didn't mention this at the beginning. In drugging ion channels in the CNS. We've been doing this for many, many years. I think that expertise is world class. So obviously a huge amount of focus is on azetukalner. That's where the vast majority of our effort is, the vast majority of our spend is. And not only are we going to have our phase III X-TOLE2 readout in March of this year, that'll be followed by a new drug application in the second half of this year and put us in a position to get our very first drug approved. But as you mentioned, we really want to build a world-class company, which means we have to think about the portfolio. That's both the expansion of azetukalner into psychiatry, but also the early stage portfolio. And as I mentioned, two molecules transition in the phase I clinical trial last year and you'll see more molecules transition from our labs into human clinical development over the coming years. So we know now that top-line results from the phase III X-TOLE2 trial are expected in March. And you know, quite frankly I feel like we've been talking about this trial and expectations for a long time, but I'll just ask it to be complete here. What would you consider a win in terms of efficacy and safety here and how could the longer treatment duration, 12 weeks versus eight weeks in X-TOLE impact the results? Sure, I'm happy to start and make a few comments, but I think Chris should provide his perspective, and then I want Darren to weigh in as well as we think about just the overall profile and the importance of that from a commercial perspective. So you've asked a couple of questions in there. One of the principles that we had at Xenon, given the great success we had in our phase II-B X-TOLE study, is that X-TOLE2 and X-TOLE3 should be very similar studies, and so if you look at the inclusion and exclusion criteria, the phase III program is exactly the same as the phase II program. You did mention one difference, and one difference is that the double blind period is 12 weeks in phase III, it was eight weeks in phase II. When we look at the open label data, it actually looks like those patients continue to have a deeper response over time. So I think moving from eight weeks to 12 weeks, we're very comfortable with the 12-week double blind period overall. In terms of just kind of managing expectations going into data, obviously that's a question we get a lot. I think you did really nice work, Tess, in your preview for Xenon coming into the conference and coming into our X-TOLE2 data, so I would encourage people to look at the analysis that you've provided. You know, I think at the highest level, obviously this study needs to be positive, it needs to be statistically significant, which will put us in a position to file a new drug application later this year. Obviously, every study is a little bit different. We have already commented that the patient population in phase III looks very similar to phase II and the open-label extension rollover rate in phase III is very similar to phase II. So that gives us a lot of confidence going into it, and I think I also always want to remind people that the X-TOLE study will be on-label. Right. That study's already been complete with the best placebo adjusted efficacy ever seen in a focal onset seizure study, and so this is really a study that'll add to that and be part of the new drug application. Chris? I think you covered it. Darren, do you want to provide just your perspective on the overall profile? Yeah, I think, you know, when you think of the X-TOLE data, it really has set the precedent. And when you think about the prescribing epileptologist, general neurologist, the novel mechanism of AZK is really going to be transformative in there. It's just not another sodium channel blocker. And so commercially we already know, based on our market research, our discussions most recently at AES, there's a tremendous amount of excitement for, as Ian outlined, the attributes of azetukalner and particularly with the general neurologist, they view this as a really easy therapy to incorporate into their practice. And so I think with the backdrop of the clinical data, the safety and tolerability, we're pretty excited to get this to physicians and their patients. Okay. And I did get this question this morning. I thought it was kind of a good one. Have there been any protocol amendments to X-TOLE2 or X-TOLE3? Chris? Yeah, there have been some amendments, but nothing that has. I mean, to Ian's point, basically the spirit of X-TOLE2 was to maintain consistent with X-TOLE. And so if you look at the major sort of inclusion and exclusion criteria, you look at the baseline characteristics, you look at the geographical spread, specifically percentage of patients from the U.S., we're seeing a great deal of consistency. So there isn't anything within any of the differences between those protocols that we think are substantive and would drive a difference in efficacy. With all that in mind, what keeps you up at night on this study? I can start and then Chris can add, you know, look, every clinical trial, you know, we're enrolling a large number of patients dispersed throughout a number of clinical sites. But I think, you know, what gives us great confidence is we have the most experience of running epilepsy studies over the last decade. And so I think both internally in our team, we have epileptologists and psychiatrists that work at Xenon that have a huge amount of experience. We've run the largest, you know, the largest study ever run in FOS that's been unblinded. So I think we have tremendous confidence. So I wouldn't say that there's anything that we're really concerned about as we think about the epilepsy work. Obviously, with psychiatry, we're always these studies in terms of execution is critically important as we spend a lot of time working with the sites and making sure that we're getting the right patients into a psychiatry study. So that's something that we spend a lot of time thinking about as well, and then as we think about the early stage portfolio, it's really the excitement of where we could take this. I think if we have a novel analgesic and non-opioid mechanism with the profile of our Nav1.7 program, I mean, the opportunity to have an oral non-opioid chronic pain drug is incredible, and so there's a lot of excitement and thinking internally about how do we develop that in the most efficient way? Chris? Yeah, I mean, I think we're in as good a shape as we possibly could be for all the reasons that Ian and I have mentioned so far, so I'm sleeping well. Okay. And you know, as maybe this is a zoom ahead question here. So beg your pardon, but how should we think about the marketing message here? And is there any kind of key differences that you expect there could be between epileptologists and general neurologists? Yeah, you know, traditionally with anti-seizure medications, typically the epileptologist or the early adoption, which is not surprising. Right. Everybody, every patient they see in their practice every day are patients with seizures and typically refractory seizures. Right. So they're getting referred to the epileptologist because of the severity of their disease. And then the general neurology community, they are typically a more late adopter. And remember, when we are approved and launched, it'll be an eight-year gap between the last time a branded ASM was approved. And so there's been this kind of period of really nothing new for the general neurologist. And so from the last branded medication that was approved, you know, the general neurologists are really finding that medication difficult because of the ability to have to titrate both up with the medication and down on other ASMs and other issues. Again, back to my earlier comment. I think with azetukalner, it's very clear that the ease of use, and then you're talking about kind of what will make a difference here. And I think because of the daily dosing, the novel mechanism, no drug-drug interactions, titrated dose right out of the gate. Tremendously excited to bring this to the general neurologist. So they're able to incorporate this into the patients that they're currently managing, keep getting them to get seizure control, potentially seizure freedom and not have to refer and be able to manage that. And again, all our market research suggests that this is the perfect medication for them to do that. And so I think the messaging for us is going to be around the attributes that we're able to to really see in X-TOLE and what we anticipate, an X-TOLE2. Any other learnings of like what the keys to success are for a branded epilepsy launch and what Xenon may be doing differently or similarly to others? Yeah, there's several. I think as I think about commercial success, there are a few different areas. One is it's all centers on the data. Right. So we feel confident there and then it's about how. How do you think about patient identification, the treating physicians and really think about those epileptologists, the general neurologists and also the advanced practice APPs that are in the community that are more and more getting involved in patient management. So we look at where do we think about taking the AZK message depending on where the patients are. So that's the key and then those key messages and what have you. But then there's other key stakeholders involved. Obviously the payer, that landscape is, you know, can underestimate how important that is. And again, I think the ability for us, which we'll start executing on post data late this year, is that engagement with payers. Right. Again, that kind of gap between the last launch to be able to bring them up to speed on the current practice of treating epilepsy patients, seizure patients, and really understanding and letting them understand still what is a tremendous unmet medical need. And so making sure that upon launch that we could have as quick an update as possible. The other component is, you know, that patient experience I think is critical to a successful launch. How do you set up your distribution, your patient support, all those services that really make what I say, you want that patient to have that outstanding experience early on. All those things hinge around. The last thing that I think is absolutely critical is the team that you build. And I think that when I think of a commercial team that we're starting to build, really a lot of deep, deep epilepsy experience both across all facets. Sales, marketing on the payer side. And then I believe one thing about epilepsy and it's a lot of people, if you think about sales representatives, people in the field, MSLs, they commit their careers to epilepsy. And so I think we'll be able to attract the top talent that will want to come with this new medication with the impressive efficacy, the opportunity to bring something new and novel to their customers. And so I think those are the things that I think about that make this a successful launch. Maybe I could just add, on the talent side, azetukalner based on the profile so far has the opportunity to be a generational asset. Right. The profile is different than we have seen in so long in the epilepsy space. And the team to execute is critically important. You know, Darren joining as chief commercial officer involved in the launch of Epidiolex, the most successful epilepsy launch ever. Darren has already added to his team in terms of head of market access, head of sales and marketing who has probably some of the deepest epilepsy experience over the last two decades. And Chris, on the medical side, we've had MSLs in the field for the last 18 months. So we have already invested in building relationships in the epilepsy community for Xenon as a trusted partner, and is azetukalner a trusted brand. I think our data disclosure and our relationships and information and scientific sharing with the community has been incredibly well received. We had over 50 employees at the American Epilepsy Society meeting and there's a real buzz around Xenon in the epilepsy community. Well said. Tess, will you indulge me with one thing? So just real quick. You know, Ian talked a lot about how well patients are doing in our open label extension study in epilepsy. It's really quite impressive. If you take a look at how they're doing compared to the double blind period, over 90% of them had a 50% reduction in seizures. A lot of the data we show starts at the baseline of the open label. So if one were to compare the phase III open label studies, and one comparison you were looking at the beginning of the double blind and the other you were looking at the beginning of the open label, it would be a comparison that would be tough to make. So I just want to point that out. Thanks. Thinking through the expansion potential of azetukalner here, you know, how does the next three to five years look for Xenon if you are successful in both epilepsy and neuropsych versus just epilepsy? Sure. Darren, do you want to talk about kind of the launch first in epilepsy and then as we'd expand? And actually maybe even before that, Chris, one of the things that we haven't talked about today that I think is important is maybe talking about the comorbidities in epilepsy as well, and that we're looking at endpoints of depression and anxiety in our epilepsy studies. That's probably a nice segue to psychiatry. Sure. We haven't shared the baseline characteristics of X-TOLE2 just yet, but we're expecting them to be quite similar to X-TOLE. Depression, anxiety, migraine, headaches are all very common comorbidities. We're expecting to be able to gather that data in the ongoing phase III program. Yeah, I think, you know, obviously epilepsy is the focal seizure launch is the initial focus. But if we were being so fortunate to have great data in MDD, that's a tremendous opportunity and we would pivot to, you know, building out that psychiatry business. And again, Ian pointed it out today, tremendous unmet need. A lot of patients that suffer with MDD that could be helped by the novel mechanism, the rapid onset and really, really favorable safety profile. So, yeah, tremendous. That would be. That'd be a nice outcome. Just last question for me here is just on formulation. Are you exploring any other formulations of azetukalner? Are you specifically thinking about intravenous? Yeah. Yeah. So often in epilepsy, we think about kind of two parts of life cycle management. One is on the pediatric side and one is on the IV side. So, yes, all of that work is ongoing. We have agreed upon pediatric development plans with FDA as well with EMA. So over time, we will get into younger and younger patients. Obviously, adolescents can take a pill, but as you get into younger patients, you need a specific pediatric formulation. So a lot of that work has already taken place, and we'll get into younger patients over time. The other thing, often that the epilepsy community is asking for is whether you have an IV formulation. So as patients come into the hospital that they may start on an IV formulation and then they leave the hospital with an oral formulation. So that works ongoing as well. Great. Thank you. Thank you. Thanks, Tess. Thanks.

Speaker 5: All right, welcome everyone to the 44th annual J.P. Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the Senior Biotech Analysts here at JPMorgan. I'm joined by my squad, Priyanka Grover, Joyce Zhou and Rathi Pillai. Kicking off the conference we have BridgeBio. And then presenting on behalf of the company, we have CEO Neil Kumar. Neil. All right, welcome everyone to the 44th annual J.P. all right welcome everyone to the 44th annual j.p Morgan Healthcare Conference. morgan healthcare conference My name is Anupam Rama. my name is anupam rama I'm one of the Senior Biotech Analysts here at JP Morgan. i'm one of the senior biotech analysts here at jp morgan I'm joined by my squad, Priyanka Grover, Joyce Zhou and Rathi Pillai. i'm joined by my squad priyanka grover joyce zhou and rathi pillai Kicking off the conference we have BridgeBio. kicking off the conference we have bridgebio And then presenting on behalf of the company, we have CEO Neil Kumar. and then presenting on behalf of the company we have ceo neil kumar Neil. neil

Speaker 3: Well, thanks everyone for taking the time this morning. I'd like to thank Mike, Ben and the entire JPMorgan team for having us here, again this year. This morning I was reminded that BridgeBio turns 10 this year. For a vast majority of those years we've had the absolute privilege of being cajoled, challenged and sometimes supported by the man to the left of me here, Anupam. So thank you for the partnership through the years Anup. Maybe I'll continue in that vein of thinking and thank all of the investors both in the room and on the line for the support over the last decade. Together we have created the second or third most efficient R&D engine for patients suffering with genetic diseases. Three approved products to date, with hopefully three more to come in the next 12 months. Well, thanks everyone for taking the time this morning. well thanks everyone for taking the time this morning I'd like to thank Mike, Ben and the entire JP Morgan team for having us here, again this year. i'd like to thank mike ben and the entire jp morgan team for having us here again this year This morning I was reminded that BridgeBio turns 10 this year. this morning i was reminded that bridgebio turns 10 this year For a vast majority of those years we've had the absolute privilege of being cajoled, challenged and sometimes supported by the man to the left of me here, Anupam . for a vast majority of those years we've had the absolute privilege of being cajoled challenged and sometimes supported by the man to the left of me here, anupam So thank you for the partnership through the years Anup. so thank you for the partnership through the years anup Maybe I'll continue in that vein of thinking and thank all of the investors both in the room and on the line for the support over the last decade. maybe i'll continue in that vein of thinking and thank all of the investors both in the room and on the line for the support over the last decade Together we have created the second or third most efficient R& D engine for patients suffering with genetic diseases. together we have created the second or third most efficient r& d engine for patients suffering with genetic diseases Three approved products to date, with hopefully three more to come in the next 12 months. three approved products to date with hopefully three more to come in the next 12 months Almost 20 INDs generated and most importantly, nearly 10,000 patient lives affected. With hopefully many tens of thousands of more to come in the coming years and decade. But you didn't come here this morning to hear me talk about the past. You came to hear me talk about where we're going and where we're headed over the coming weeks, months and years. For that we continue to believe that it is day one in this era of genetic medicine. I'll give you updates today, all new information across the three different stages of our business. First, and importantly, our commercial franchise in ATTR cardiomyopathy. Second, updates both on the data front and regulatory front for our late stage franchises in achondroplasia, LGMD2I, ADH1 and Canavan disease. Almost 20 INDs generated and most importantly, nearly 10,000 patient lives affected. almost 20 inds generated and most importantly nearly 10,000 patient lives affected With hopefully many tens of thousands of more to come in the coming years and decade. with hopefully many tens of thousands of more to come in the coming years and decade But you didn't come here this morning to hear me talk about the past. but you didn't come here this morning to hear me talk about the past You came to hear me talk about where we're going and where we're headed over the coming weeks, months and years. you came to hear me talk about where we're going and where we're headed over the coming weeks months and years For that we continue to believe that it is day one in this era of genetic medicine. for that we continue to believe that it is day one in this era of genetic medicine I'll give you updates today, all new information across the three different stages of our business. i'll give you updates today all new information across the three different stages of our business First, and importantly, our commercial franchise in ATTR cardiomyopathy. first and importantly our commercial franchise in attr cardiomyopathy Second, updates both on the data front and regulatory front for our late stage franchises in achondroplasia, LGMD2I, ADH1 and Canavan disease. second updates both on the data front and regulatory front for our late stage franchises in achondroplasia lgmd2i adh1 and canavan disease And then finally, I'll touch on some of that early stage research substrate that's exciting us so much and give you a good example of some of the early stage research we're doing with our EPP, potentially best in class asset that just cleared its phase II-A. But let me start with the most important slide in this document. We are preannouncing today our Q4 revenue number of $146 million. And the reason we get excited about this number is that it suggests we are helping ever higher numbers of patients with ever more numbers of physician partners. $146 million of revenue is a 35% growth over our last quarter and suggests about a 60% CAGR. And just as another reminder, this is actually more revenue generated in the fourth quarter of launch than tafamidis generated as it came out of the gates. And then finally, I'll touch on some of that early stage research substrate that's exciting us so much and give you a good example of some of the early stage research we're doing with our EPP, potentially best in class asset that just cleared its phase II-A. and then finally i'll touch on some of that early stage research substrate that's exciting us so much and give you a good example of some of the early stage research we're doing with our epp potentially best in class asset that just cleared its phase ii-a But let me start with the most important slide in this document. but let me start with the most important slide in this document We are preannouncing today our Q4 revenue number of $146 million. we are preannouncing today our q4 revenue number of $146 million And the reason we get excited about this number is that it suggests we are helping ever higher numbers of patients with ever more numbers of physician partners. $146 million of revenue is a 35% growth over our last quarter and suggests about a 60% CAGR. and the reason we get excited about this number is that it suggests we are helping ever higher numbers of patients with ever more numbers of physician partners $146 million of revenue is a 35% growth over our last quarter and suggests about a 60% cagr And just as another reminder, this is actually more revenue generated in the fourth quarter of launch than tafamidis generated as it came out of the gates. and just as another reminder this is actually more revenue generated in the fourth quarter of launch than tafamidis generated as it came out of the gates This brings our total in our first four quarters of revenue to $362 million. And even more heartening than this number are the numbers that lie underneath it. Some 6,629 unique U.S. patients that we've been able to serve with Attruby in partnership with over 1,600 physicians. And as you all know, we focus greatly on MBRX share. MBRX share, given the dynamics in this commercial marketplace we believe is suggestive of ultimate TRX. Our goal being 30%-35% peak year share by volume. We're well on our way with greater than 25% MBRX already just one year into our launch. Altogether, with our partner Bayer's efforts in Europe, we believe that the Attruby franchise in 2026 will generate over $1 billion of revenue. Of course, all of this is possible given the unique biochemical and clinical characteristics of the molecule. This brings our total in our first four quarters of revenue to $362 million. this brings our total in our first four quarters of revenue to $362 million And even more heartening than this number are the numbers that lie underneath it. and even more heartening than this number are the numbers that lie underneath it Some 6,629 unique U.S. patients that we've been able to serve with Attruby in partnership with over 1,600 physicians. some 6,629 unique u.s patients that we've been able to serve with attruby in partnership with over 1,600 physicians And as you all know, we focus greatly on MBRX share. and as you all know we focus greatly on mbrx share MBRX share, given the dynamics in this commercial marketplace we believe is suggestive of ultimate TRX. mbrx share given the dynamics in this commercial marketplace we believe is suggestive of ultimate trx Our goal being 30%-35% peak year share by volume. our goal being 30%-35% peak year share by volume We're well on our way with greater than 25% MBRX already just one year into our launch. we're well on our way with greater than 25% mbrx already just one year into our launch Altogether, with our partner Bayer's efforts in Europe, we believe that the Attruby franchise in 2026 will generate over $1 billion of revenue. altogether with our partner bayer's efforts in europe we believe that the attruby franchise in 2026 will generate over $1 billion of revenue Of course, all of this is possible given the unique biochemical and clinical characteristics of the molecule. of course all of this is possible given the unique biochemical and clinical characteristics of the molecule As you all know in this room, it is the first and only near complete stabilizer as labeled by the FDA and has provided what we call 3-42-50. At three months, statistically significant separation from placebo. At 30 months, a 42% relative risk reduction against those same characteristics of all-cause mortality and cardiovascular hospitalization, and at 30 months a whopping 50% reduction in hospitalization, suggesting we're able to help patients live longer and healthier lives out of the hospital setting. Over the course of the last 12 months you've seen from us over 50 publications and abstracts delving into various aspects of this overall value proposition as well as trying to better understand where our drug best performs for patient populations like the variant population or patient populations like the AFib population. As you all know in this room, it is the first and only near complete stabilizer as labeled by the FDA and has provided what we call 3-42-50. as you all know in this room it is the first and only near complete stabilizer as labeled by the fda and has provided what we call 3-42-50 At three months, statistically significant separation from placebo. at three months statistically significant separation from placebo At 30 months, a 42% relative risk reduction against those same characteristics of all-cause mortality and cardiovascular hospitalization, and at 30 months a whopping 50% reduction in hospitalization, suggesting we're able to help patients live longer and healthier lives out of the hospital setting. at 30 months a 42% relative risk reduction against those same characteristics of all-cause mortality and cardiovascular hospitalization and at 30 months a whopping 50% reduction in hospitalization suggesting we're able to help patients live longer and healthier lives out of the hospital setting Over the course of the last 12 months you've seen from us over 50 publications and abstracts delving into various aspects of this overall value proposition as well as trying to better understand where our drug best performs for patient populations like the variant population or patient populations like the AFib population. over the course of the last 12 months you've seen from us over 50 publications and abstracts delving into various aspects of this overall value proposition as well as trying to better understand where our drug best performs for patient populations like the variant population or patient populations like the afib population Today I want to focus a little bit on one of the aspects that I think has been underappreciated, which is the assets early separation from placebo. Some data that we published at HFSA that I think honestly was missed by most investors and actually a lot of physicians was that we had indeed observed a numeric separation in cumulative morbidity as early as one month with our drug. Now that's a bit of a head scratcher because obviously if you think about the kinetics within the heart, it's probably not the impact of a turning down of the amount of toxic monomer that's depositing in the heart that's actually driving this impact. And so we sort of scratch our heads and ask the question, what might be driving this? Today I want to focus a little bit on one of the aspects that I think has been underappreciated, which is the assets early separation from placebo. today i want to focus a little bit on one of the aspects that i think has been underappreciated which is the assets early separation from placebo Some data that we published at HFSA that I think honestly was missed by most investors and actually a lot of physicians was that we had indeed observed a numeric separation in cumulative morbidity as early as one month with our drug. some data that we published at hfsa that i think honestly was missed by most investors and actually a lot of physicians was that we had indeed observed a numeric separation in cumulative morbidity as early as one month with our drug Now that's a bit of a head scratcher because obviously if you think about the kinetics within the heart, it's probably not the impact of a turning down of the amount of toxic monomer that's depositing in the heart that's actually driving this impact. now that's a bit of a head scratcher because obviously if you think about the kinetics within the heart it's probably not the impact of a turning down of the amount of toxic monomer that's depositing in the heart that's actually driving this impact And so we sort of scratch our heads and ask the question, what might be driving this? and so we sort of scratch our heads and ask the question what might be driving this It took us to analyzing some of the very unique hemodynamic and cardiorenal properties of this asset. I won't spoil, nor do I have time to go through the whole story here, but you will see a series of publications over the next 12 months suggesting that Attruby actually has renal protective attributes analogous to the SGLT2 and ARB class and totally unique to this compound. Now, why might that be? Obviously it is because Attruby is delivering the highest known kinetic and overall levels of stabilization in this space. I've said it before and I'll say it again, an Attruby simply sees more of the target TTR, it binds it more effectively with a superior KD2 binding as compared to tafamidis, and ultimately does a better job of gluing the tetramer together over time. It took us to analyzing some of the very unique hemodynamic and cardiorenal properties of this asset. it took us to analyzing some of the very unique hemodynamic and cardiorenal properties of this asset I won't spoil, nor do I have time to go through the whole story here, but you will see a series of publications over the next 12 months suggesting that Attruby actually has renal protective attributes analogous to the SGLT2 and ARB class and totally unique to this compound. i won't spoil nor do i have time to go through the whole story here but you will see a series of publications over the next 12 months suggesting that attruby actually has renal protective attributes analogous to the sglt2 and arb class and totally unique to this compound Now, why might that be? now why might that be Obviously it is because Attruby is delivering the highest known kinetic and overall levels of stabilization in this space. obviously it is because attruby is delivering the highest known kinetic and overall levels of stabilization in this space I've said it before and I'll say it again, an Attruby simply sees more of the target TTR, it binds it more effectively with a superior KD2 binding as compared to tafamidis, and ultimately does a better job of gluing the tetramer together over time. i've said it before and i'll say it again an attruby simply sees more of the target ttr it binds it more effectively with a superior kd2 binding as compared to tafamidis and ultimately does a better job of gluing the tetramer together over time For those of you that have been following the preclinical work in this space, you'll have seen the PNAS or Proceedings of National Academy Sciences paper that came out about a month ago with some really beautiful mass spec work, and I'll read the conclusion from the authors. Just briefly, Our thermodynamic analysis further supports the notion that binding enthalpy, not affinity KD or a change in Gibbs free energy, better predicts the conformational stabilization imparted by these kinetic stabilizers. As many of you know, and as we published in Miller et al, using an ITC approach, we have a vastly superior enthalpic binding mode as compared to tafamidis. Now the good news is we don't even need it because we also have a superior binding approach, and it wouldn't be a talk from me unless I trotted out a new quote from Jeff Kelly. For those of you that have been following the preclinical work in this space, you'll have seen the PNAS or Proceedings of National Academy Sciences paper that came out about a month ago with some really beautiful mass spec work, and I'll read the conclusion from the authors. for those of you that have been following the preclinical work in this space you'll have seen the pnas or proceedings of national academy sciences paper that came out about a month ago with some really beautiful mass spec work and i'll read the conclusion from the authors Just briefly, Our thermodynamic analysis further supports the notion that binding enthalpy, not affinity KD or a change in Gibbs free energy, better predicts the conformational stabilization imparted by these kinetic stabilizers. just briefly our thermodynamic analysis further supports the notion that binding enthalpy not affinity kd or a change in gibbs free energy better predicts the conformational stabilization imparted by these kinetic stabilizers As many of you know, and as we published in Miller et al, using an ITC approach, we have a vastly superior enthalpic binding mode as compared to tafamidis. as many of you know and as we published in miller et al using an itc approach we have a vastly superior enthalpic binding mode as compared to tafamidis Now the good news is we don't even need it because we also have a superior binding approach, and it wouldn't be a talk from me unless I trotted out a new quote from Jeff Kelly. now the good news is we don't even need it because we also have a superior binding approach and it wouldn't be a talk from me unless i trotted out a new quote from jeff kelly As many of you know, the inventor of tafamidis and the founder of FoldRx. This is an email that he sent our founders Isabella and Mamoun some time ago and he says given the variability in stoichiometry in the experiments between tafamidis and AG10, which is acoramidis or Attruby and TTR. The data will always tell the same story, that AG10 is better than tafamidis, as would be expected from the determined binding constants. We wholeheartedly agree and will continue to interrogate the advantages of this ever better stabilization for the patients that we serve. Today we're announcing something in tandem to those efforts. As many of you know, the inventor of tafamidis and the founder of FoldRx. as many of you know the inventor of tafamidis and the founder of foldrx This is an email that he sent our founders Isabella and Mamoun some time ago and he says given the variability in stoichiometry in the experiments between tafamidis and AG10, which is acoramidis or Attruby and TTR. this is an email that he sent our founders isabella and mamoun some time ago and he says given the variability in stoichiometry in the experiments between tafamidis and ag10 which is acoramidis or attruby and ttr The data will always tell the same story, that AG10 is better than tafamidis, as would be expected from the determined binding constants. the data will always tell the same story that ag10 is better than tafamidis as would be expected from the determined binding constants We wholeheartedly agree and will continue to interrogate the advantages of this ever better stabilization for the patients that we serve. we wholeheartedly agree and will continue to interrogate the advantages of this ever better stabilization for the patients that we serve Today we're announcing something in tandem to those efforts. today we're announcing something in tandem to those efforts We've long sought the ability to pair upstream turning down of the toxic monomer that deposits in the heart because recall both knockdowns and stabilizers are trying to turn off the faucet of toxic monomeric deposition in the heart with an agent that helps clear the already deposited plaque. Because by and large we are diagnosing patients too late and at a point where there is already pathogenic deposition of amyloid plaque in their hearts. And the right way to do this is to establish a depleter or antibody-associated program that promotes the clearance of that already deposited plaque. We've been greatly privileged to be working with Dr. Richard Scheller, our Chairman of R&D, who as many of you know, ran R&D at Genentech for a very long period of time and was associated with Herceptin amongst many other great antibodies. We've long sought the ability to pair upstream turning down of the toxic monomer that deposits in the heart because recall both knockdowns and stabilizers are trying to turn off the faucet of toxic monomeric deposition in the heart with an agent that helps clear the already deposited plaque. we've long sought the ability to pair upstream turning down of the toxic monomer that deposits in the heart because recall both knockdowns and stabilizers are trying to turn off the faucet of toxic monomeric deposition in the heart with an agent that helps clear the already deposited plaque Because by and large we are diagnosing patients too late and at a point where there is already pathogenic deposition of amyloid plaque in their hearts. because by and large we are diagnosing patients too late and at a point where there is already pathogenic deposition of amyloid plaque in their hearts And the right way to do this is to establish a depleter or antibody-associated program that promotes the clearance of that already deposited plaque. and the right way to do this is to establish a depleter or antibody-associated program that promotes the clearance of that already deposited plaque We've been greatly privileged to be working with Dr. Richard Scheller, our Chairman of R&D, who as many of you know, ran R&D at Genentech for a very long period of time and was associated with Herceptin amongst many other great antibodies. we've been greatly privileged to be working with dr richard scheller our chairman of r&d who as many of you know ran r&d at genentech for a very long period of time and was associated with herceptin amongst many other great antibodies He’s been leading this project for the last couple of years alongside our colleague Christine Zhang. What we wanted to do within this space was to build on prior efforts and really optimize an antibody against four key dimensions. First, obviously, we wanted to bind more target. We wanted to find, and in this case, a cryptic previously described but not employed binding site within the fibril to go after. Secondly, we wanted to clear more target by better recruiting macrophages to our antibodies upon binding. Then third and fourth, we wanted to improve antibody half-life by optimizing pH sensitivity within the endosome and then ultimately taking advantage of some of the novel literature on FcRn binding that many of you are familiar with to improve antibody half-life, therefore making it more effective and hopefully more convenient over time. He’s been leading this project for the last couple of years alongside our colleague Christine Zhang. he’s been leading this project for the last couple of years alongside our colleague christine zhang What we wanted to do within this space was to build on prior efforts and really optimize an antibody against four key dimensions. what we wanted to do within this space was to build on prior efforts and really optimize an antibody against four key dimensions First, obviously, we wanted to bind more target. first obviously we wanted to bind more target We wanted to find, and in this case, a cryptic previously described but not employed binding site within the fibril to go after. we wanted to find and in this case a cryptic previously described but not employed binding site within the fibril to go after Secondly, we wanted to clear more target by better recruiting macrophages to our antibodies upon binding. secondly we wanted to clear more target by better recruiting macrophages to our antibodies upon binding Then third and fourth, we wanted to improve antibody half-life by optimizing pH sensitivity within the endosome and then ultimately taking advantage of some of the novel literature on FcRn binding that many of you are familiar with to improve antibody half-life, therefore making it more effective and hopefully more convenient over time. then third and fourth we wanted to improve antibody half-life by optimizing ph sensitivity within the endosome and then ultimately taking advantage of some of the novel literature on fcrn binding that many of you are familiar with to improve antibody half-life therefore making it more effective and hopefully more convenient over time And we're heartened to say that we've been able to create an antibody to date that actually checks off all those boxes very close to development candidate, and we anticipate moving this program into the clinic in the coming 18 months. Okay, so I'd like to turn now from ATTR cardiomyopathy to our development franchise and I'll start with our profound results that we published just a few months ago in the context of limb-girdle muscular dystrophy type 2I. As a reminder, this is a deleterious condition with no available pharmacologic therapy that affects almost 7,000 patients between the United States and the EU. Two and a half months ago, we published the interim phase III results from our trial that sought to look initially at biochemical impact against the causal biochemical damage associated with this condition. And we're heartened to say that we've been able to create an antibody to date that actually checks off all those boxes very close to development candidate, and we anticipate moving this program into the clinic in the coming 18 months. and we're heartened to say that we've been able to create an antibody to date that actually checks off all those boxes very close to development candidate and we anticipate moving this program into the clinic in the coming 18 months Okay, so I'd like to turn now from ATTR cardiomyopathy to our development franchise and I'll start with our profound results that we published just a few months ago in the context of limb-girdle muscular dystrophy type 2I. okay so i'd like to turn now from attr cardiomyopathy to our development franchise and i'll start with our profound results that we published just a few months ago in the context of limb-girdle muscular dystrophy type 2i As a reminder, this is a deleterious condition with no available pharmacologic therapy that affects almost 7,000 patients between the United States and the EU. as a reminder this is a deleterious condition with no available pharmacologic therapy that affects almost 7,000 patients between the united states and the eu Two and a half months ago, we published the interim phase III results from our trial that sought to look initially at biochemical impact against the causal biochemical damage associated with this condition. two and a half months ago we published the interim phase iii results from our trial that sought to look initially at biochemical impact against the causal biochemical damage associated with this condition The bad news around this condition is that there are no available therapies. The good news is it's remarkably well described biochemically owing uniformly to conformational loss of function mutations in an enzyme called FKRP, which leads to a lack of glycosylation of what's called the alpha-dystroglycan complex in the muscle. And we sought to turn up that glycosylation level so that we could go forward and help patients. We powered a trial so that we could look at biochemical glycosylation of the ADG complex in tandem with a measure of muscle damage called CK. And sure enough, after one year, as we looked at the trial, we found a 1.8x increase, even more profound than we observed in phase II in ADG glycosylation and an 82% decrease concomitant in a measure of muscle damage called CK. The bad news around this condition is that there are no available therapies. the bad news around this condition is that there are no available therapies The good news is it's remarkably well described biochemically owing uniformly to conformational loss of function mutations in an enzyme called FKRP, which leads to a lack of glycosylation of what's called the alpha-dystroglycan complex in the muscle. the good news is it's remarkably well described biochemically owing uniformly to conformational loss of function mutations in an enzyme called fkrp which leads to a lack of glycosylation of what's called the alpha-dystroglycan complex in the muscle And we sought to turn up that glycosylation level so that we could go forward and help patients. and we sought to turn up that glycosylation level so that we could go forward and help patients We powered a trial so that we could look at biochemical glycosylation of the ADG complex in tandem with a measure of muscle damage called CK. we powered a trial so that we could look at biochemical glycosylation of the adg complex in tandem with a measure of muscle damage called ck And sure enough, after one year, as we looked at the trial, we found a 1.8x increase, even more profound than we observed in phase II in ADG glycosylation and an 82% decrease concomitant in a measure of muscle damage called CK. and sure enough after one year as we looked at the trial we found a 1.8x increase even more profound than we observed in phase ii in adg glycosylation and an 82% decrease concomitant in a measure of muscle damage called ck So those were very heartening, but what we saw next we didn't expect. We saw statistically significant improvements against measures of both ambulation and breathing. This is the first data set that looks like this, as far as I know, in the muscular dystrophy space. And what was even more encouraging was for each of those two measures, both ambulation and breathing, we saw a decline in the placebo arm and an incline or improvement in the therapeutic arm, suggesting that we are improving patients, and in some cases on breathing and on EEG, returning a few patients back to normal within a year. That is a profound advance. When we talk about therapeutic cure in the context of what we do, we don't often think about small molecules, but this is truly therapeutic cure for a few of the patients that we have treated here. So those were very heartening, b ut what we saw next we didn't expect. so those were very heartening, b ut what we saw next we didn't expect We saw statistically significant improvements against measures of both ambulation and breathing. we saw statistically significant improvements against measures of both ambulation and breathing This is the first data set that looks like this, as far as I know, in the muscular dystrophy space. this is the first data set that looks like this as far as i know in the muscular dystrophy space And what was even more encouraging was for each of those two measures, both ambulation and breathing, we saw a decline in the placebo arm and an incline or improvement in the therapeutic arm, suggesting that we are improving patients, and in some cases on breathing and on EEG, returning a few patients back to normal within a year. and what was even more encouraging was for each of those two measures both ambulation and breathing we saw a decline in the placebo arm and an incline or improvement in the therapeutic arm suggesting that we are improving patients and in some cases on breathing and on eeg returning a few patients back to normal within a year That is a profound advance. that is a profound advance When we talk about therapeutic cure in the context of what we do, we don't often think about small molecules, but this is truly therapeutic cure for a few of the patients that we have treated here. when we talk about therapeutic cure in the context of what we do we don't often think about small molecules but this is truly therapeutic cure for a few of the patients that we have treated here I want to elaborate on that data that we announced at Topline with a bit more detail. These are data that we shared with the agency in mid December, and these are the forest plots against all of the primary and key secondary endpoints that I just mentioned, and I don't have time to go through each single one of these plots, but I think you will see that the consistency of the plots and the statistical robustness are encouraging. Furthermore, what you can see from this drug is treatment and effective treatment across a number of different subcategories suggesting either early stage or late stage disease, so for instance, for compound heterozygotes that tend to be more severe in this disease, we see marked efficacy consistent with what we see in the "milder" condition, which is the L276I homozygous population. I want to elaborate on that data that we announced at Topline with a bit more detail. i want to elaborate on that data that we announced at topline with a bit more detail These are data that we shared with the agency in mid December, and these are the forest plots against all of the primary and key secondary endpoints that I just mentioned, and I don't have time to go through each single one of these plots, but I think you will see that the consistency of the plots and the statistical robustness are encouraging. these are data that we shared with the agency in mid december and these are the forest plots against all of the primary and key secondary endpoints that i just mentioned and i don't have time to go through each single one of these plots but i think you will see that the consistency of the plots and the statistical robustness are encouraging Furthermore, what you can see from this drug is treatment and effective treatment across a number of different subcategories suggesting either early stage or late stage disease, so for instance, for compound heterozygotes that tend to be more severe in this disease, we see marked efficacy consistent with what we see in the "milder" condition, which is the L276I homozygous population. furthermore what you can see from this drug is treatment and effective treatment across a number of different subcategories suggesting either early stage or late stage disease so for instance for compound heterozygotes that tend to be more severe in this disease we see marked efficacy consistent with what we see in the "milder" condition which is the l276i homozygous population Additionally, we see consistent efficacy from young to old people who have had the disease for a long time versus people who have just been diagnosed and at different baselines of FVC. So beautifully consistent data that we were able to share with the agency. Perhaps the most important data pertains to the modified North Star test. As many of you know, this division of the FDA likes to look at North Star or modified North Star, a very difficult endpoint against which to achieve statistical significance. We designed our trial to do so after almost three years. After looking at the interim data one year in, what we showed was a 2.6 delta, again with a decline in placebo and an improvement in what we saw on active with robust statistical significance. Additionally, we see consistent efficacy from young to old people who have had the disease for a long time versus people who have just been diagnosed and at different baselines of FVC. additionally we see consistent efficacy from young to old people who have had the disease for a long time versus people who have just been diagnosed and at different baselines of fvc So beautifully consistent data that we were able to share with the agency. so beautifully consistent data that we were able to share with the agency Perhaps the most important data pertains to the modified North Star test. perhaps the most important data pertains to the modified north star test As many of you know, this division of the FDA likes to look at North Star or modified North Star, a very difficult endpoint against which to achieve statistical significance. as many of you know this division of the fda likes to look at north star or modified north star a very difficult endpoint against which to achieve statistical significance We designed our trial to do so after almost three years. we designed our trial to do so after almost three years After looking at the interim data one year in, what we showed was a 2.6 delta, again with a decline in placebo and an improvement in what we saw on active with robust statistical significance. after looking at the interim data one year in what we showed was a 2.6 delta again with a decline in placebo and an improvement in what we saw on active with robust statistical significance This was certainly our trial was certainly not powered to show this and we were extremely encouraged to see this data coupled with the data I just shared with you. We took all of that data in to a presentation to the agency in mid December and they, quote, were very pleased that we had demonstrated consistent treatment effects on multiple efficacy endpoints and upon seeing the data asked us to file our NDA toward traditional and full approval versus accelerated approval. Knowing that leaving kids on placebo arm for the entirety of the design trial would likely be unethical. We anticipate filing this NDA sometime mid this year. I'll turn now to our efforts in ADH1. As many of you know, ADH1 is a condition that affects almost 12,000 Americans alone, making it one of the larger markets and certainly one of the more underdiagnosed conditions that we go after. This was certainly our trial was certainly not powered to show this and we were extremely encouraged to see this data coupled with the data I just shared with you. this was certainly our trial was certainly not powered to show this and we were extremely encouraged to see this data coupled with the data i just shared with you We took all of that data in to a presentation to the agency in mid December and they, quote, were very pleased that we had demonstrated consistent treatment effects on multiple efficacy endpoints and upon seeing the data asked us to file our NDA toward traditional and full approval versus accelerated approval. we took all of that data in to a presentation to the agency in mid december and they quote were very pleased that we had demonstrated consistent treatment effects on multiple efficacy endpoints and upon seeing the data asked us to file our nda toward traditional and full approval versus accelerated approval Knowing that leaving kids on placebo arm for the entirety of the design trial would likely be unethical. W e anticipate filing this NDA sometime mid this year. knowing that leaving kids on placebo arm for the entirety of the design trial would likely be unethical. w e anticipate filing this nda sometime mid this year I'll turn now to our efforts in ADH1. i'll turn now to our efforts in adh1 As many of you know, ADH1 is a condition that affects almost 12,000 Americans alone, making it one of the larger markets and certainly one of the more underdiagnosed conditions that we go after. as many of you know adh1 is a condition that affects almost 12,000 americans alone making it one of the larger markets and certainly one of the more underdiagnosed conditions that we go after Again, the good news here is that this condition is remarkably well described owing uniformly to gain of function mutations in the calcium sensing receptor, and we are going after this condition having designed a negative allosteric modulator of the calcium sensing receptor. Again, just about a couple of months ago we were privileged to announce our phase III results in this category where we demonstrated a 76% responder rate following encaleret treatment. Now, response here is actually normalization of urine and serum calcium, which are the two things that drive all of the conditions in this disease. So low serum calcium levels is what drives tetany, brain fog and ultimately seizures. And high urine calcium levels drive downstream nephrolithiasis, CKD, kidney stones and the like. Recall also that standard of care, which only had a 4% response in our clinical trial, is simply calcium supplementation. Again, the good news here is that this condition is remarkably well described owing uniformly to gain of function mutations in the calcium sensing receptor, and we are going after this condition having designed a negative allosteric modulator of the calcium sensing receptor. again the good news here is that this condition is remarkably well described owing uniformly to gain of function mutations in the calcium sensing receptor and we are going after this condition having designed a negative allosteric modulator of the calcium sensing receptor Again, just about a couple of months ago we were privileged to announce our phase III results in this category where we demonstrated a 76% responder rate following encaleret treatment. again just about a couple of months ago we were privileged to announce our phase iii results in this category where we demonstrated a 76% responder rate following encaleret treatment Now, response here is actually normalization of urine and serum calcium, which are the two things that drive all of the conditions in this disease. now response here is actually normalization of urine and serum calcium which are the two things that drive all of the conditions in this disease So low serum calcium levels is what drives tetany, brain fog and ultimately seizures. so low serum calcium levels is what drives tetany brain fog and ultimately seizures And high urine calcium levels drive downstream nephrolithiasis, CKD, kidney stones and the like. and high urine calcium levels drive downstream nephrolithiasis ckd kidney stones and the like Recall also that standard of care, which only had a 4% response in our clinical trial, is simply calcium supplementation. recall also that standard of care which only had a 4% response in our clinical trial is simply calcium supplementation So even when patients can get back to normal levels of serum calcium, they're actually downstream harming themselves by loading up their kidneys with calcium. A 76% full normalization of patients once again applies to this concept that I talked about during my comments on LGMD2i. This is therapeutic cure for these patients. They are back to normal levels of calcium and could undergo and live a relatively normal life on a go-forward basis. Hearteningly, we also showed in 90+% of patients response to the drug. So there's normalization and then there's response. 90+% of patients were normalized as you look at their PTH and they moved in the right directions when we thought about urine and serum calcium levels. So very few segment of this patient population would not be served with encaleret on a go-forward basis. So even when patients can get back to normal levels of serum calcium, they're actually downstream harming themselves by loading up their kidneys with calcium. so even when patients can get back to normal levels of serum calcium they're actually downstream harming themselves by loading up their kidneys with calcium A 76% full normalization of patients once again applies to this concept that I talked about during my comments on LGMD2i. a 76% full normalization of patients once again applies to this concept that i talked about during my comments on lgmd2i T his is therapeutic cure for these patients. t his is therapeutic cure for these patients They are back to normal levels of calcium and could undergo and live a relatively normal life on a go-forward basis. they are back to normal levels of calcium and could undergo and live a relatively normal life on a go-forward basis Hearteningly, we also showed in 90+% of patients response to the drug. hearteningly we also showed in 90+% of patients response to the drug So there's normalization and then there's response. 90+% of patients were normalized as you look at their PTH and they moved in the right directions when we thought about urine and serum calcium levels. so there's normalization and then there's response 90+% of patients were normalized as you look at their pth and they moved in the right directions when we thought about urine and serum calcium levels So very few segment of this patient population would not be served with encaleret on a go-forward basis. so very few segment of this patient population would not be served with encaleret on a go-forward basis How do we find these patients? As I mentioned at the outset, this is a relatively underdiagnosed disease. How do we go about starting to find patients that would find this therapy useful? The team has done a really nice job of providing really three angles to this. The first is to improve genetic testing and to partner with Prevention and other local providers so that we might offer a panel to identify pathogenic variants associated with the calcium-sensing receptor. As many of you know, we've also published some literature on what those variants are and really drilled into the constellation of known pathogenic variants as opposed to the VUS's in this gene. Second, our commercial team created an ICD-10 code so that we might better codify and identify patients with frank ADH1 as opposed to chronic hypopara throughout the course of time. How do we find these patients? how do we find these patients As I mentioned at the outset, this is a relatively underdiagnosed disease. as i mentioned at the outset this is a relatively underdiagnosed disease How do we go about starting to find patients that would find this therapy useful? how do we go about starting to find patients that would find this therapy useful The team has done a really nice job of providing really three angles to this. the team has done a really nice job of providing really three angles to this The first is to improve genetic testing and to partner with Prevention and other local providers so that we might offer a panel to identify pathogenic variants associated with the calcium-sensing receptor. the first is to improve genetic testing and to partner with prevention and other local providers so that we might offer a panel to identify pathogenic variants associated with the calcium-sensing receptor As many of you know, we've also published some literature on what those variants are and really drilled into the constellation of known pathogenic variants as opposed to the VUS's in this gene. as many of you know we've also published some literature on what those variants are and really drilled into the constellation of known pathogenic variants as opposed to the vus's in this gene Second, our commercial team created an ICD-10 code so that we might better codify and identify patients with frank ADH1 as opposed to chronic hypopara throughout the course of time. second our commercial team created an icd-10 code so that we might better codify and identify patients with frank adh1 as opposed to chronic hypopara throughout the course of time And then finally actually the guidelines were updated to suggest genetic testing for those with nonsurgical hyperparathyroidism so that they might see whether or not they're ADH1 patients actually hiding within the context of that broader HP community. It's not unlike actually ATTR cardiomyopathy or even hypertrophic cardiomyopathy when I got started. These patients are hiding within the context of HFpEF. We needed to find them here. Again we need to establish the algorithm to find the patients that would best benefit from this drug product. And extremely excitingly, what the results of these efforts have been to date is the identification of 1,700 unique patients based on again the efforts of these alone, plus the medical education that we've been doing. This underlies our projection that are about 3,000-5,000 identified patients associated with ADH1 today. And then finally actually the guidelines were updated to suggest genetic testing for those with nonsurgical hyperparathyroidism so that they might see whether or not they're ADH1 patients actually hiding within the context of that broader HP community. and then finally actually the guidelines were updated to suggest genetic testing for those with nonsurgical hyperparathyroidism so that they might see whether or not they're adh1 patients actually hiding within the context of that broader hp community It's not unlike actually ATTR cardiomyopathy or even hypertrophic cardiomyopathy when I got started. it's not unlike actually attr cardiomyopathy or even hypertrophic cardiomyopathy when i got started These patients are hiding within the context of HFpEF. these patients are hiding within the context of hfpef We needed to find them here. we needed to find them here Again we need to establish the algorithm to find the patients that would best benefit from this drug product. again we need to establish the algorithm to find the patients that would best benefit from this drug product And extremely excitingly, what the results of these efforts have been to date is the identification of 1,700 unique patients based on again the efforts of these alone, plus the medical education that we've been doing. and extremely excitingly what the results of these efforts have been to date is the identification of 1,700 unique patients based on again the efforts of these alone plus the medical education that we've been doing This underlies our projection that are about 3,000-5,000 identified patients associated with ADH1 today. this underlies our projection that are about 3,000-5,000 identified patients associated with adh1 today But more importantly in my mind suggests that we have the right approach to continue to find new patients over time, especially after the therapy launches. This is pretty robust growth given the fact that the therapy is not even approved or in the commercial marketplace today. Okay, turning finally to an update on the encaleret program as it applies to an additional indication, chronic hypoparathyroidism. As you all know, for every medicine that we interrogate, our responsibility is to figure out all of the different ways it could be applicable to human health. In this case, the phenotype of restoration of urine and serum calcium suggested to us that this may be a useful and the first oral product in the context of CHP and indeed in a very small but robust in terms of its signal clinical trial in about 10 patients. But more importantly in my mind suggests that we have the right approach to continue to find new patients over time, especially after the therapy launches. but more importantly in my mind suggests that we have the right approach to continue to find new patients over time especially after the therapy launches This is pretty robust growth given the fact that the therapy is not even approved or in the commercial marketplace today. this is pretty robust growth given the fact that the therapy is not even approved or in the commercial marketplace today Okay, turning finally to an update on the encaleret program as it applies to an additional indication, chronic hypoparathyroidism. okay turning finally to an update on the encaleret program as it applies to an additional indication chronic hypoparathyroidism As you all know, for every medicine that we interrogate, our responsibility is to figure out all of the different ways it could be applicable to human health. as you all know for every medicine that we interrogate our responsibility is to figure out all of the different ways it could be applicable to human health In this case, the phenotype of restoration of urine and serum calcium suggested to us that this may be a useful and the first oral product in the context of CHP and indeed in a very small but robust in terms of its signal clinical trial in about 10 patients. in this case the phenotype of restoration of urine and serum calcium suggested to us that this may be a useful and the first oral product in the context of chp and indeed in a very small but robust in terms of its signal clinical trial in about 10 patients What we showed was 80% normalization of urine and serum calcium in the context of chronic hypoparathyroidism. We took that data coupled with the mechanism, coupled with what we learned from our ADH1 trial to the FDA and we aligned on an extremely exciting trial that we intend to prosecute starting mid-year. We call it the RECLAIM-HP trial. What you can see from this trial design are really two salient characteristics. One, this is a six-month trial. We intend to relatively quickly interrogate this compound to better understand whether or not as an oral agent it could provide the types of efficacy we see with PTH replacement therapy or even better. Secondly, the primary endpoint, the proportion of participants achieving albumin-corrected blood and urine calcium within the target range. Now recall our phase II data. What we showed was 80% normalization of urine and serum calcium in the context of chronic hypoparathyroidism. what we showed was 80% normalization of urine and serum calcium in the context of chronic hypoparathyroidism We took that data coupled with the mechanism, coupled with what we learned from our ADH1 trial to the FDA and we aligned on an extremely exciting trial that we intend to prosecute starting mid-year. we took that data coupled with the mechanism coupled with what we learned from our adh1 trial to the fda and we aligned on an extremely exciting trial that we intend to prosecute starting mid-year We call it the RECLAIM-HP trial. we call it the reclaim-hp trial What you can see from this trial design are really two salient characteristics. what you can see from this trial design are really two salient characteristics One, this is a six-month trial. one this is a six-month trial We intend to relatively quickly interrogate this compound to better understand whether or not as an oral agent it could provide the types of efficacy we see with PTH replacement therapy or even better. we intend to relatively quickly interrogate this compound to better understand whether or not as an oral agent it could provide the types of efficacy we see with pth replacement therapy or even better Secondly, the primary endpoint, the proportion of participants achieving albumin-corrected blood and urine calcium within the target range. secondly the primary endpoint the proportion of participants achieving albumin-corrected blood and urine calcium within the target range Now recall our phase II data. now recall our phase ii data This suggests a very high probability of technical success associated with this clinical trial, so we are excited not only to launch an ADH1 but also to serve patients with chronic hyperparathyroidism on an ongoing basis. I'd like to turn now to our achondroplasia and hypochondroplasia franchise associated with our small molecule, infigratinib. As a reminder, this affects some 55,000 individuals between the U.S. and EU and represents a significant unmet need. For those of you interested in this program, I would suggest that you listen in to the webinar that was recently published on Friday. Our colleagues Justin To, Daniela Rogoff, and Dr. Legare; we're very privileged to have her on the line. Both talk about the architecture of this condition as well as how meaningful infigratinib could potentially be to the folks we're trying to serve within this population. This suggests a very high probability of technical success associated with this clinical trial, so we are excited not only to launch an ADH1 but also to serve patients with chronic hyperparathyroidism on an ongoing basis. this suggests a very high probability of technical success associated with this clinical trial so we are excited not only to launch an adh1 but also to serve patients with chronic hyperparathyroidism on an ongoing basis I'd like to turn now to our achondroplasia and hypochondroplasia franchise associated with our small molecule, infigratinib. i'd like to turn now to our achondroplasia and hypochondroplasia franchise associated with our small molecule, infigratinib As a reminder, this affects some 55,000 individuals between the U.S. and EU and represents a significant unmet need. as a reminder this affects some 55,000 individuals between the u.s and eu and represents a significant unmet need For those of you interested in this program, I would suggest that you listen in to the webinar that was recently published on Friday. for those of you interested in this program i would suggest that you listen in to the webinar that was recently published on friday Our colleagues Justin To, Daniela Rogoff, and Dr. Legare; we're very privileged to have her on the line. our colleagues justin to daniela rogoff and dr legare we're very privileged to have her on the line Both talk about the architecture of this condition as well as how meaningful infigratinib could potentially be to the folks we're trying to serve within this population. both talk about the architecture of this condition as well as how meaningful infigratinib could potentially be to the folks we're trying to serve within this population On that webinar, Justin mentioned that we have achieved last patient, last visit against our phase III in achondroplasia and anticipate reading out that data to everyone sometime in Q1 of this year. Importantly, we also have first patient enrolled in our pediatric and toddler study. Recall, PROPEL 3 already is interrogating the broadest set of ages within the achondroplastic trial setting from three to 18, but we'd like to go all the way down to as low an age as possible, and therefore PROPEL INT is important, and then really excitingly, we have full enrollment completed for our phase II portion of our hypochondroplasia study. Again, a related condition arising from a different but still activating mutation in FGFR3. As Justin mentioned during the webinar and I think it's important to reinforce, this is the best and most advantaged approach within the context of achondroplasia. On that webinar, Justin mentioned that we have achieved last patient, last visit against our phase III in achondroplasia and anticipate reading out that data to everyone sometime in Q1 of this year. on that webinar justin mentioned that we have achieved last patient last visit against our phase iii in achondroplasia and anticipate reading out that data to everyone sometime in q1 of this year Importantly, we also have first patient enrolled in our pediatric and toddler study. importantly we also have first patient enrolled in our pediatric and toddler study Recall, PROPEL 3 already is interrogating the broadest set of ages within the achondroplastic trial setting from three to 18, but we'd like to go all the way down to as low an age as possible, and therefore PROPEL INT is important, and then really excitingly, we have full enrollment completed for our phase II portion of our hypochondroplasia study. recall propel 3 already is interrogating the broadest set of ages within the achondroplastic trial setting from three to 18 but we'd like to go all the way down to as low an age as possible and therefore propel int is important and then really excitingly we have full enrollment completed for our phase ii portion of our hypochondroplasia study Again, a related condition arising from a different but still activating mutation in FGFR3. again a related condition arising from a different but still activating mutation in fgfr3 As Justin mentioned during the webinar and I think it's important to reinforce, this is the best and most advantaged approach within the context of achondroplasia. as justin mentioned during the webinar and i think it's important to reinforce this is the best and most advantaged approach within the context of achondroplasia First, it is the only approach mechanistically to target this condition at its source, FGFR3 over activation. Secondly, in the definitive animal model, it provides not only quantitative advantages as compared to the CNP class of medicines, but also qualitatively is able to deliver results against things like foramen magnum surface area and things outside of long bone growth that ultimately are important to the community that we serve. Third, and most importantly, in the New England Journal of Medicine last year we published quantitative outperformance of this agent in the context of achondroplasia, both when looking at change from baseline in AHV as well as absolute AHV, and then coupling that with maybe perhaps the best endpoint given the variance associated with AHV, which is the Z score, where we showed a 0.36+ standard deviation at month 12. The community was incredibly excited about these results. First, it is the only approach mechanistically to target this condition at its source, FGFR3 over activation. first it is the only approach mechanistically to target this condition at its source fgfr3 over activation Secondly, in the definitive animal model, it provides not only quantitative advantages as compared to the CNP class of medicines, but also qualitatively is able to deliver results against things like foramen magnum surface area and things outside of long bone growth that ultimately are important to the community that we serve. secondly in the definitive animal model it provides not only quantitative advantages as compared to the cnp class of medicines but also qualitatively is able to deliver results against things like foramen magnum surface area and things outside of long bone growth that ultimately are important to the community that we serve Third, and most importantly, in the New England Journal of Medicine last year we published quantitative outperformance of this agent in the context of achondroplasia, both when looking at change from baseline in AHV as well as absolute AHV, and then coupling that with maybe perhaps the best endpoint given the variance associated with AHV, which is the Z score, where we showed a 0.36+ standard deviation at month 12. third and most importantly in the new england journal of medicine last year we published quantitative outperformance of this agent in the context of achondroplasia both when looking at change from baseline in ahv as well as absolute ahv and then coupling that with maybe perhaps the best endpoint given the variance associated with ahv which is the z score where we showed a 0.36+ standard deviation at month 12 The community was incredibly excited about these results. the community was incredibly excited about these results In addition to the fact that we were able for the first time to provide a statistically significant result against proportionality, a decrease of 0.12, we're the only agent in this space that's received breakthrough designation suggesting that the FDA sees this as a marked leap against standard of care. And finally, and importantly, as we've done our market research, this is a convenient, safe and oral medicine that allows all kiddos that might want to try this agent to be able to try it in a convenient manner. And just so I can elaborate on that a little bit, here you can see a picture of the capsules on your left hand side. Again, 17 mm long, very easy to swallow. And if you have trouble swallowing that, you can break this up into the granules, which are 2 mm long and easily mixable with soft foods. In addition to the fact that we were able for the first time to provide a statistically significant result against proportionality, a decrease of 0.12, we're the only agent in this space that's received breakthrough designation suggesting that the FDA sees this as a marked leap against standard of care. in addition to the fact that we were able for the first time to provide a statistically significant result against proportionality a decrease of 0.12 we're the only agent in this space that's received breakthrough designation suggesting that the fda sees this as a marked leap against standard of care And finally, and importantly, as we've done our market research, this is a convenient, safe and oral medicine that allows all kiddos that might want to try this agent to be able to try it in a convenient manner. and finally and importantly as we've done our market research this is a convenient safe and oral medicine that allows all kiddos that might want to try this agent to be able to try it in a convenient manner And just so I can elaborate on that a little bit, here you can see a picture of the capsules on your left hand side. and just so i can elaborate on that a little bit here you can see a picture of the capsules on your left hand side Again, 17 mm long, very easy to swallow. again 17 mm long very easy to swallow And if you have trouble swallowing that, you can break this up into the granules, which are 2 mm long and easily mixable with soft foods. and if you have trouble swallowing that you can break this up into the granules which are 2 mm long and easily mixable with soft foods Okay, so what does this look like in terms of the marketplace? We obviously have to start thinking about our commercial efforts. And for those of you that were here a couple of years ago, you'll remember that as we were getting set to launch in ATTR, we had done quite a bit of market research in using a couple of different tools to better estimate what our share would be and how to size our sales force. And I think actually those projections have been fairly accurate and we marry those now with a third tool that I'll talk about in a moment. Okay, so what does this look like in terms of the marketplace? okay so what does this look like in terms of the marketplace We obviously have to start thinking about our commercial efforts. we obviously have to start thinking about our commercial efforts And for those of you that were here a couple of years ago, you'll remember that as we were getting set to launch in ATTR, we had done quite a bit of market research in using a couple of different tools to better estimate what our share would be and how to size our sales force. and for those of you that were here a couple of years ago you'll remember that as we were getting set to launch in attr we had done quite a bit of market research in using a couple of different tools to better estimate what our share would be and how to size our sales force And I think actually those projections have been fairly accurate and we marry those now with a third tool that I'll talk about in a moment. and i think actually those projections have been fairly accurate and we marry those now with a third tool that i'll talk about in a moment So the first way that we try to understand how this agent might perform is by taking a variety of TPPs and using it in the context of market research, where we're able to go out to 80% of the physicians by volume that are prescribing today's currently available CMPs. The second is that we look at analogs and 3,500 molecules, many of them that are oral versus injections, et cetera. So we were able to look at the appropriate analogs to estimate what peak year market share might look like in this space. So the first way that we try to understand how this agent might perform is by taking a variety of TPPs and using it in the context of market research, where we're able to go out to 80% of the physicians by volume that are prescribing today's currently available CMPs. so the first way that we try to understand how this agent might perform is by taking a variety of tpps and using it in the context of market research where we're able to go out to 80% of the physicians by volume that are prescribing today's currently available cmps The second is that we look at analogs and 3,500 molecules, many of them that are oral versus injections, et cetera. the second is that we look at analogs and 3,500 molecules many of them that are oral versus injections et cetera So we were able to look at the appropriate analogs to estimate what peak year market share might look like in this space. so we were able to look at the appropriate analogs to estimate what peak year market share might look like in this space And then finally, in collaboration with MIT, Andrew Lo and his QLS group, we have launched a revenue institute where we will be publishing on in the next few months a brand new algorithm that helps us better predict how our molecules will launch over time and indeed how other molecules hopefully will launch in a future state. So I won't talk about all of the research here. You could expect to hear updates from us in the months to come, especially as we get a glimpse of our phase III data. But here's the TPP that we actually tested in market research most robustly. And you can see again an indication that's the broadest indication in terms of age range being interrogated in our trial in MOA. That's a selective FGFR 1, 2, 3 inhibitors, the dosing and administration, that's a real marked step forward. And then finally, in collaboration with MIT, Andrew Lo and his QLS group, we have launched a revenue institute where we will be publishing on in the next few months a brand new algorithm that helps us better predict how our molecules will launch over time and indeed how other molecules hopefully will launch in a future state. and then finally in collaboration with mit andrew lo and his qls group we have launched a revenue institute where we will be publishing on in the next few months a brand new algorithm that helps us better predict how our molecules will launch over time and indeed how other molecules hopefully will launch in a future state So I won't talk about all of the research here. so i won't talk about all of the research here You could expect to hear updates from us in the months to come, especially as we get a glimpse of our phase III data. you could expect to hear updates from us in the months to come especially as we get a glimpse of our phase iii data But here's the TPP that we actually tested in market research most robustly. but here's the tpp that we actually tested in market research most robustly And you can see again an indication that's the broadest indication in terms of age range being interrogated in our trial in MOA. and you can see again an indication that's the broadest indication in terms of age range being interrogated in our trial in moa That's a selective FGFR 1, 2, 3 inhibitors, the dosing and administration, that's a real marked step forward. that's a selective fgfr 1 2 3 inhibitors the dosing and administration that's a real marked step forward A daily oral as opposed to a daily or a weekly injection. We put our delta in HV change from baseline at the tippy top of what CMPs have been able to achieve. 1.5 cm per year. And we put a well tolerated AE profile into the TPP, which is effectively all of the safety that you've seen from this compound to date. Less than 10% hyper phos and importantly, avoidance of injection site reactions, hypotension, because recall, that's really where the CMP category comes from. And the excessive hairiness that has been otherwise observed with some of the CMP products. And what we found based on that TPP was a stubbornly consistent 52% market share. We believe that we will take a vast majority of this market, but we will, at least given the market research, take a majority of the market, given the profile shown on the left. A daily oral as opposed to a daily or a weekly injection. a daily oral as opposed to a daily or a weekly injection We put our delta in HV change from baseline at the tippy top of what CMPs have been able to achieve. 1.5 cm per year. we put our delta in hv change from baseline at the tippy top of what cmps have been able to achieve 1.5 cm per year And we put a well tolerated AE profile into the TPP, which is effectively all of the safety that you've seen from this compound to date. and we put a well tolerated ae profile into the tpp which is effectively all of the safety that you've seen from this compound to date Less than 10% hyper phos and importantly, avoidance of injection site reactions, hypotension, because recall, that's really where the CMP category comes from. less than 10% hyper phos and importantly avoidance of injection site reactions hypotension because recall that's really where the cmp category comes from And the excessive hairiness that has been otherwise observed with some of the CMP products. and the excessive hairiness that has been otherwise observed with some of the cmp products And what we found based on that TPP was a stubbornly consistent 52% market share. and what we found based on that tpp was a stubbornly consistent 52% market share We believe that we will take a vast majority of this market, but we will, at least given the market research, take a majority of the market, given the profile shown on the left. we believe that we will take a vast majority of this market but we will at least given the market research take a majority of the market given the profile shown on the left So again, we anticipate data so we can fill this in for real and go and take somewhere between a majority and vast majority of the market based on data to come. Last, but certainly not least are our efforts in Canavan disease. As many of you know, Canavan is an extraordinarily rare, extremely deleterious neurodevelopmental disease. We've been taking a gene therapy approach to see what we can do to serve children affected with this condition. I don't have time to walk through many slides on this, but what I will show you in this single slide associated with Canavan is the evolution of the data that I presented last year where you can see at our 10 to the 14 high dose robust and profound decreases in the causal biomarker associated with this disease, which is urine NAA and mirrored by CSF. So again, we anticipate data so we can fill this in for real and go and take somewhere between a majority and vast majority of the market based on data to come. so again we anticipate data so we can fill this in for real and go and take somewhere between a majority and vast majority of the market based on data to come Last, but certainly not least are our efforts in Canavan disease. last but certainly not least are our efforts in canavan disease As many of you know, Canavan is an extraordinarily rare, extremely deleterious neurodevelopmental disease. as many of you know canavan is an extraordinarily rare extremely deleterious neurodevelopmental disease We've been taking a gene therapy approach to see what we can do to serve children affected with this condition. we've been taking a gene therapy approach to see what we can do to serve children affected with this condition I don't have time to walk through many slides on this, but what I will show you in this single slide associated with Canavan is the evolution of the data that I presented last year where you can see at our 10 to the 14 high dose robust and profound decreases in the causal biomarker associated with this disease, which is urine NAA and mirrored by CSF. i don't have time to walk through many slides on this but what i will show you in this single slide associated with canavan is the evolution of the data that i presented last year where you can see at our 10 to the 14 high dose robust and profound decreases in the causal biomarker associated with this disease which is urine naa and mirrored by csf Very hearteningly you see a dose responsive improvement in the behavior of these children. Improvements such as sitting, head control, reaching and grasping, and in certain cases ambulation where you would certainly not expect to see it. We continue to dose children and assess the safety and efficacy of this product and we anticipate filing its BLA sometime in 2027. Okay, so hopefully three launches upcoming. How are we going to do it? That's a lot for a small biotech and we think we can employ this decentralized model that we have to continue to scale launches. Those three launches, hopefully if we're lucky with the achondroplasia top line and hopefully launches to come with some of these additional indications that I talked about. Very hearteningly you see a dose responsive improvement in the behavior of these children. very hearteningly you see a dose responsive improvement in the behavior of these children Improvements such as sitting, head control, reaching and grasping, and in certain cases ambulation where you would certainly not expect to see it. improvements such as sitting head control reaching and grasping and in certain cases ambulation where you would certainly not expect to see it We continue to dose children and assess the safety and efficacy of this product and we anticipate filing its BLA sometime in 2027. we continue to dose children and assess the safety and efficacy of this product and we anticipate filing its bla sometime in 2027 Okay, so hopefully three launches upcoming. okay so hopefully three launches upcoming How are we going to do it? how are we going to do it That's a lot for a small biotech and we think we can employ this decentralized model that we have to continue to scale launches. that's a lot for a small biotech and we think we can employ this decentralized model that we have to continue to scale launches Those three launches, hopefully if we're lucky with the achondroplasia top line and hopefully launches to come with some of these additional indications that I talked about. those three launches hopefully if we're lucky with the achondroplasia top line and hopefully launches to come with some of these additional indications that i talked about And what we've done here is we've preserved the affiliate structure so that we have the teams that are close to the physicians in any given therapeutic area, that are close to the patient and patient advocacy groups and that are close to the data really running the launches. But they're doing so in partnership with the wonderful team that Matt Outten and our commercial colleagues have put together, therefore making it such that we don't have to re spend the money to set up the infrastructure. As many of you know, in rare disease, the preponderance of spend is not against FTE or the field force every time, but rather against the back end of market access, patient services, analytics, etc. So we can use that already established expertise and apply it to launch after launch in tandem with the affiliates. And what we've done here is we've preserved the affiliate structure so that we have the teams that are close to the physicians in any given therapeutic area, that are close to the patient and patient advocacy groups and that are close to the data really running the launches. and what we've done here is we've preserved the affiliate structure so that we have the teams that are close to the physicians in any given therapeutic area that are close to the patient and patient advocacy groups and that are close to the data really running the launches But they're doing so in partnership with the wonderful team that Matt Outten and our commercial colleagues have put together, therefore making it such that we don't have to re spend the money to set up the infrastructure. but they're doing so in partnership with the wonderful team that matt outten and our commercial colleagues have put together therefore making it such that we don't have to re spend the money to set up the infrastructure As many of you know, in rare disease, the preponderance of spend is not against FTE or the field force every time, but rather against the back end of market access, patient services, analytics, etc. So we can use that already established expertise and apply it to launch after launch in tandem with the affiliates. as many of you know in rare disease the preponderance of spend is not against fte or the field force every time but rather against the back end of market access patient services analytics etc so we can use that already established expertise and apply it to launch after launch in tandem with the affiliates So that's what we intend to do over these next three launches and hopefully maybe five launches associated with the comments I've made to date. But the question is where else do we want to take this platform in the years to come? That takes me to the final points maybe I'll make on why we believe it is still day one in this era of genetic disease. I won't belabor it because I think many of you in the room know this, but about three years ago I was up here chatting with Anup about this concept of missing heritability. Why is it that so much of what we see in terms of phenotype is not well captured by genetic information? So that's what we intend to do over these next three launches and hopefully maybe five launches associated with the comments I've made to date. so that's what we intend to do over these next three launches and hopefully maybe five launches associated with the comments i've made to date But the question is where else do we want to take this platform in the years to come? but the question is where else do we want to take this platform in the years to come That takes me to the final points maybe I'll make on why we believe it is still day one in this era of genetic disease. that takes me to the final points maybe i'll make on why we believe it is still day one in this era of genetic disease I won't belabor it because I think many of you in the room know this, but about three years ago I was up here chatting with Anup about this concept of missing heritability. i won't belabor it because i think many of you in the room know this but about three years ago i was up here chatting with anup about this concept of missing heritability Why is it that so much of what we see in terms of phenotype is not well captured by genetic information? why is it that so much of what we see in terms of phenotype is not well captured by genetic information And it turns out, as many of you know who have been following the literature, that just an increase in whole genome sequences versus exome sequences, coupled with a higher density of data has allowed us to really fill in the gaps around missing heritability and to begin to really tamp that down. But maybe most excitingly, we're able to start to identify these new variants and then connect them with mechanism, and then connect that mechanism with phenotype. What's allowing us to do that? Obviously advances in long read sequencing, allowing us to identify things like structural variants. And it turns out, as many of you know who have been following the literature, that just an increase in whole genome sequences versus exome sequences, coupled with a higher density of data has allowed us to really fill in the gaps around missing heritability and to begin to really tamp that down. and it turns out as many of you know who have been following the literature that just an increase in whole genome sequences versus exome sequences coupled with a higher density of data has allowed us to really fill in the gaps around missing heritability and to begin to really tamp that down But maybe most excitingly, we're able to start to identify these new variants and then connect them with mechanism, and then connect that mechanism with phenotype. but maybe most excitingly we're able to start to identify these new variants and then connect them with mechanism and then connect that mechanism with phenotype What's allowing us to do that? what's allowing us to do that Obviously advances in long read sequencing, allowing us to identify things like structural variants. obviously advances in long read sequencing allowing us to identify things like structural variants Obviously advances in things like having a pan genome, a better reference against which we can understand variants, the prior and aforementioned increase in data density associated with these databases like UK Biobank and the like, and then really importantly, the ability to interrogate the function of these variants in cell and tissue specific experiments so that we can tease out their function and better design therapeutics that target well described conditions at their source. A fingerprint of all of these advances is simply the pipeline that we see at GondolaBio, a company, as you know, that is a sister company to BridgeBio and a company that you collectively own as investors in BridgeBio. Here you can see 17 different programs in a span of just a year, all pretty early stage, advancing all the way from early stage research to phase II. Obviously advances in things like having a pan genome, a better reference against which we can understand variants, the prior and aforementioned increase in data density associated with these databases like UK Biobank and the like, and then really importantly, the ability to interrogate the function of these variants in cell and tissue specific experiments so that we can tease out their function and better design therapeutics that target well described conditions at their source. obviously advances in things like having a pan genome a better reference against which we can understand variants the prior and aforementioned increase in data density associated with these databases like uk biobank and the like and then really importantly the ability to interrogate the function of these variants in cell and tissue specific experiments so that we can tease out their function and better design therapeutics that target well described conditions at their source A fingerprint of all of these advances is simply the pipeline that we see at Gondola Bio, a company, as you know, that is a sister company to BridgeBio and a company that you collectively own as investors in BridgeBio. a fingerprint of all of these advances is simply the pipeline that we see at gondola bio a company as you know that is a sister company to bridgebio and a company that you collectively own as investors in bridgebio Here you can see 17 different programs in a span of just a year, all pretty early stage, advancing all the way from early stage research to phase II. here you can see 17 different programs in a span of just a year all pretty early stage advancing all the way from early stage research to phase ii But in important areas of high unmet need, investors will be familiar with areas like EPP, ADPKD, Alpha-1 Antitrypsin, CMT1A, neurofibromatosis type 1 and the like. I don't have time to go through all of these programs obviously, but I'd like to touch on one example of again the well described process that we put forward at BridgeBio, which is to take generally small molecules and target these well described conditions at their source. So I want to talk a little bit about our EPP program. Most of you in the room, I think and on the line are familiar with EPP. But for those of you that are not, it is unfortunately a very large unmet need affecting some 20,000-25,000 people between the United States and the EU. So that makes it one of the larger disease states that we work on. But in important areas of high unmet need, investors will be familiar with areas like EPP, ADPKD, Alpha-1 Antitrypsin , CMT1A, neurofibromatosis type 1 and the like. but in important areas of high unmet need investors will be familiar with areas like epp adpkd alpha-1 antitrypsin cmt1a neurofibromatosis type 1 and the like I don't have time to go through all of these programs obviously, but I'd like to touch on one example of again the well described process that we put forward at BridgeBio, which is to take generally small molecules and target these well described conditions at their source. i don't have time to go through all of these programs obviously but i'd like to touch on one example of again the well described process that we put forward at bridgebio which is to take generally small molecules and target these well described conditions at their source So I want to talk a little bit about our EPP program. so i want to talk a little bit about our epp program Most of you in the room, I think and on the line are familiar with EPP. most of you in the room i think and on the line are familiar with epp But for those of you that are not, it is unfortunately a very large unmet need affecting some 20,000-25,000 people between the United States and the EU. but for those of you that are not it is unfortunately a very large unmet need affecting some 20,000-25,000 people between the united states and the eu So that makes it one of the larger disease states that we work on. so that makes it one of the larger disease states that we work on When it does affect people, unfortunately it affects them with deleterious morbidity associated with skin damage and excruciating pain, as well as downstream liver disease. That's the bad news. The good news is that the pathomechanism of this condition has been very well described over the years. What we can see here from the cartoon on the left-hand side of this slide is that this condition uniformly arises from mutations in the heme synthesis pathway, most commonly through mutations in ferrochelatase. And what that does is it promotes the production of a compound called PP9, which then is present in the plasma, the skin and the bile at too high a concentration. And because PP9 is photosensitive, it drives the phototoxicity and pain that I just mentioned. Now there are many different ways to go after this condition. When it does affect people, unfortunately it affects them with deleterious morbidity associated with skin damage and excruciating pain, as well as downstream liver disease. when it does affect people unfortunately it affects them with deleterious morbidity associated with skin damage and excruciating pain as well as downstream liver disease That's the bad news. that's the bad news The good news is that the pathomechanism of this condition has been very well described over the years. the good news is that the pathomechanism of this condition has been very well described over the years What we can see here from the cartoon on the left-hand side of this slide is that this condition uniformly arises from mutations in the heme synthesis pathway, most commonly through mutations in ferrochelatase. what we can see here from the cartoon on the left-hand side of this slide is that this condition uniformly arises from mutations in the heme synthesis pathway most commonly through mutations in ferrochelatase And what that does is it promotes the production of a compound called PP9, which then is present in the plasma, the skin and the bile at too high a concentration. and what that does is it promotes the production of a compound called pp9 which then is present in the plasma the skin and the bile at too high a concentration And because PP9 is photosensitive, it drives the phototoxicity and pain that I just mentioned. and because pp9 is photosensitive it drives the phototoxicity and pain that i just mentioned Now there are many different ways to go after this condition. now there are many different ways to go after this condition There are non causal ways to go after it, like using tanning agents. That has been the approach of Clinuvel, Mitsubishi Tanabe. And then there are different ways to target this causal pathway. Certainly Disc Medicine has one where they try to inhibit the intake of glycine. And we looked at that product and we started to ask ourselves, how do we improve upon it? The intake of glycine and its inhibition takes a very long time to provide PP9 reduction. It's not able to provide PP9 reduction to the marked levels that would be required to take people back down to, let's say, quote, a normal range of PP9. And you can't do it safely. As you know, GlyT1 inhibition, which is associated with glycine intake, comes from the schizophrenia field and is associated in EPP trials alone with high levels, almost 50% of dizziness and other AES. There are non causal ways to go after it, like using tanning agents. there are non causal ways to go after it like using tanning agents That has been the approach of Clinuvel, Mitsubishi Tanabe. that has been the approach of clinuvel mitsubishi tanabe And then there are different ways to target this causal pathway. and then there are different ways to target this causal pathway Certainly Disc Medicine has one where they try to inhibit the intake of glycine. certainly disc medicine has one where they try to inhibit the intake of glycine And we looked at that product and we started to ask ourselves, how do we improve upon it? and we looked at that product and we started to ask ourselves how do we improve upon it The intake of glycine and its inhibition takes a very long time to provide PP9 reduction. the intake of glycine and its inhibition takes a very long time to provide pp9 reduction It's not able to provide PP9 reduction to the marked levels that would be required to take people back down to, let's say, quote, a normal range of PP9. it's not able to provide pp9 reduction to the marked levels that would be required to take people back down to let's say quote a normal range of pp9 And you can't do it safely. and you can't do it safely As you know, GlyT1 inhibition, which is associated with glycine intake, comes from the schizophrenia field and is associated in EPP trials alone with high levels, almost 50% of dizziness and other AES. as you know glyt1 inhibition which is associated with glycine intake comes from the schizophrenia field and is associated in epp trials alone with high levels almost 50% of dizziness and other aes We asked ourselves, how else might we target this well described condition at its source, but do so avoiding some of those handicaps? What we decided on in collaboration with Dr. Ma at University of Pittsburgh was to inhibit the egress of PP9 from the red blood cell by inhibiting potently its solitary transporter, which is ABCG2. We have designed a compound by the name of Port-77, which is an orally bioavailable, highly potent inhibitor of ABCG2 that in cellular models, animal models and the like, has provided best in class efficacy and a beautifully safe profile that allows us to turn down levels of PP9 in the plasma and importantly and uniquely PP9 levels in the bile, staving off both the phototoxicity and pain that patients suffer from, but also the downstream liver disease. We asked ourselves, how else might we target this well described condition at its source, but do so avoiding some of those handicaps? we asked ourselves how else might we target this well described condition at its source but do so avoiding some of those handicaps What we decided on in collaboration with Dr. Ma at University of Pittsburgh was to inhibit the egress of PP9 from the red blood cell by inhibiting potently its solitary transporter, which is ABCG2. what we decided on in collaboration with dr ma at university of pittsburgh was to inhibit the egress of pp9 from the red blood cell by inhibiting potently its solitary transporter which is abcg2 We have designed a compound by the name of Port-77, which is an orally bioavailable, highly potent inhibitor of ABCG2 that in cellular models, animal models and the like, has provided best in class efficacy and a beautifully safe profile that allows us to turn down levels of PP9 in the plasma and importantly and uniquely PP9 levels in the bile, staving off both the phototoxicity and pain that patients suffer from, but also the downstream liver disease. we have designed a compound by the name of port-77 which is an orally bioavailable highly potent inhibitor of abcg2 that in cellular models animal models and the like has provided best in class efficacy and a beautifully safe profile that allows us to turn down levels of pp9 in the plasma and importantly and uniquely pp9 levels in the bile staving off both the phototoxicity and pain that patients suffer from but also the downstream liver disease So I'll just go right to the point here, which are the results of our phase II-A trial which we recently just generated about a month ago. And here you can see the design of our gateway trial effectively to interrogate two different doses of Port-77 and to look at the change in plasma PP9 as compared to baseline and a run-in placebo. We also obviously wanted to interrogate PK safety and tolerability. So what did we find? Firstly and hearteningly we found a profound impact in terms of the diminishment of PP9 in the plasma. This has not been seen before. 75% reduction in PP9 levels. So I'll just go right to the point here, which are the results of our phase II-A trial which we recently just generated about a month ago. so i'll just go right to the point here which are the results of our phase ii-a trial which we recently just generated about a month ago And here you can see the design of our gateway trial effectively to interrogate two different doses of Port- 77 and to look at the change in plasma PP9 as compared to baseline and a run- in placebo. and here you can see the design of our gateway trial effectively to interrogate two different doses of port- 77 and to look at the change in plasma pp9 as compared to baseline and a run- in placebo We also obviously wanted to interrogate PK safety and tolerability. we also obviously wanted to interrogate pk safety and tolerability So what did we find? so what did we find Firstly and hearteningly we found a profound impact in terms of the diminishment of PP9 in the plasma. firstly and hearteningly we found a profound impact in terms of the diminishment of pp9 in the plasma This has not been seen before. 75% reduction in PP9 levels. this has not been seen before 75% reduction in pp9 levels And even more importantly, because every minute matters for the patients that we serve, we were able to take action in a matter of hours as opposed to weeks from Disc Medicine's drug, and within days we reached steady state at 75% reduction. So the marked efficacy associated with this compound is unique in this space. But perhaps even more encouraging to me was the next slide. I have sat on many clinical trials and I rarely get this level of consistency from a phase II-A. Here you can see all 12 patients and I'll just take your eye to the dark blue lines here. Every single patient dosed with high-dose Port-77 experienced a reduction in PP9 levels. Maybe the smallest reduction observed was 57% and again the mean was 75%. And even more importantly, because every minute matters for the patients that we serve, we were able to take action in a matter of hours as opposed to weeks from Disc Medicine's drug, and within days we reached steady state at 75% reduction. and even more importantly because every minute matters for the patients that we serve we were able to take action in a matter of hours as opposed to weeks from disc medicine's drug and within days we reached steady state at 75% reduction So the marked efficacy associated with this compound is unique in this space. so the marked efficacy associated with this compound is unique in this space But perhaps even more encouraging to me was the next slide. but perhaps even more encouraging to me was the next slide I have sat on many clinical trials and I rarely get this level of consistency from a phase II-A. i have sat on many clinical trials and i rarely get this level of consistency from a phase ii-a Here you can see all 12 patients and I'll just take your eye to the dark blue lines here. here you can see all 12 patients and i'll just take your eye to the dark blue lines here Every single patient dosed with high-dose Port- 77 experienced a reduction in PP9 levels. every single patient dosed with high-dose port- 77 experienced a reduction in pp9 levels Maybe the smallest reduction observed was 57% and again the mean was 75%. maybe the smallest reduction observed was 57% and again the mean was 75% So not only do we see profound reductions in PP9 levels, not only do we see relatively quick reductions in PP9 levels, we see very consistent action from this drug across the patient population. And importantly we are doing it safely. You can see a numeric imbalance in actually favor of the treatment as compared to placebo in most of these rows. This is importantly different than the other molecules in this space. Okay, so what I hope I've convinced you of in a few brief slides, and we will certainly be elaborating on this more in talks to come, is that we have a ABCG2 inhibitor that applied in its application to EPP, allows for potential best in class PP9 reduction. So not only do we see profound reductions in PP9 levels, not only do we see relatively quick reductions in PP9 levels, we see very consistent action from this drug across the patient population. so not only do we see profound reductions in pp9 levels not only do we see relatively quick reductions in pp9 levels we see very consistent action from this drug across the patient population And importantly we are doing it safely. and importantly we are doing it safely You can see a numeric imbalance in actually favor of the treatment as compared to placebo in most of these rows. you can see a numeric imbalance in actually favor of the treatment as compared to placebo in most of these rows This is importantly different than the other molecules in this space. this is importantly different than the other molecules in this space Okay, so what I hope I've convinced you of in a few brief slides, and we will certainly be elaborating on this more in talks to come, is that we have a ABCG2 inhibitor that applied in its application to EPP, allows for potential best in class PP9 reduction. okay so what i hope i've convinced you of in a few brief slides and we will certainly be elaborating on this more in talks to come is that we have a abcg2 inhibitor that applied in its application to epp allows for potential best in class pp9 reduction It has a dual mechanism that targets all aspects of the condition, has a clean safety profile, and that we're able to see it and that reduction within hours, not days to weeks. This is just one snapshot of all of the progress that you as investors own across the ecosystem of BridgeBio. We've got BridgeBio and its late-stage franchises. We certainly have early-stage research ongoing as I highlighted with the Depleter program. There are other programs in that same vein at BridgeBio. We have all of what's happening at GondolaBio, and indeed you are substantial owners of BridgeBio Oncology Therapeutics, where the CEO of that effort, Eli Wallace, will be talking a bit later today about some of the exciting updates against its franchises as well. So lots going on, lots to do for the patients that we serve. It has a dual mechanism that targets all aspects of the condition, has a clean safety profile, and that we're able to see it and that reduction within hours, not days to weeks. it has a dual mechanism that targets all aspects of the condition has a clean safety profile and that we're able to see it and that reduction within hours not days to weeks This is just one snapshot of all of the progress that you as investors own across the ecosystem of BridgeBio. this is just one snapshot of all of the progress that you as investors own across the ecosystem of bridgebio We've got BridgeBio and its late-stage franchises. we've got bridgebio and its late-stage franchises We certainly have early-stage research ongoing as I highlighted with the Depleter program. we certainly have early-stage research ongoing as i highlighted with the depleter program There are other programs in that same vein at BridgeBio. there are other programs in that same vein at bridgebio We have all of what's happening at Gondola Bio, and indeed you are substantial owners of BridgeBio Oncology Therapeutics, where the CEO of that effort, Eli Wallace, will be talking a bit later today about some of the exciting updates against its franchises as well. we have all of what's happening at gondola bio and indeed you are substantial owners of bridgebio oncology therapeutics where the ceo of that effort eli wallace will be talking a bit later today about some of the exciting updates against its franchises as well So lots going on, lots to do for the patients that we serve. so lots going on lots to do for the patients that we serve This is just a summary of all of the issues that I've covered today. Commercial momentum, late stage development momentum, early stage research and development momentum, all portending, I hope, in partnership with you all in this room, the ability to serve many more patients in the years to come. It wouldn't be a JPM slide if I didn't end on the comment that we are well financed to undertake all of these activities in the coming years and that all collectively these activities will create a steady drumbeat, hopefully, of advances for both the patients that we serve and investors in and around the stock. With that, I will thank you all for your attention. If we have time, I'll take a question or two. This is just a summary of all of the issues that I've covered today. this is just a summary of all of the issues that i've covered today Commercial momentum, late stage development momentum, early stage research and development momentum, all portending, I hope, in partnership with you all in this room, the ability to serve many more patients in the years to come. commercial momentum late stage development momentum early stage research and development momentum all portending i hope in partnership with you all in this room the ability to serve many more patients in the years to come It wouldn't be a JPM slide if I didn't end on the comment that we are well financed to undertake all of these activities in the coming years and that all collectively these activities will create a steady drumbeat, hopefully, of advances for both the patients that we serve and investors in and around the stock. it wouldn't be a jpm slide if i didn't end on the comment that we are well financed to undertake all of these activities in the coming years and that all collectively these activities will create a steady drumbeat hopefully of advances for both the patients that we serve and investors in and around the stock With that, I will thank you all for your attention. with that i will thank you all for your attention If we have time, I'll take a question or two. if we have time i'll take a question or two

Speaker 5: Neil, your presentation was so robust, I do not have any questions. Thank you. Neil, your presentation was so robust, I do not have any questions. neil your presentation was so robust i do not have any questions Thank you. thank you

Speaker 3: Thank you, Anup. Thank you, Anup. thank you anup

Speaker 5: I see the strategy. Great job. I see the strategy. i see the strategy Great job. great job

Speaker 4: [inaudible] [inaudible] [inaudible] Welcome everyone to the 44th annual J.P. Morgan Healthcare Conference. My name is Tess Romero and I'm one of the senior biotech analysts here at J.P. Morgan. Our next presenting company is Xenon Pharmaceuticals. And presenting on behalf of the company we have President and CEO Ian Mortimer. Ian, over to you. Welcome everyone to the 44th annual J.P. welcome everyone to the 44th annual j.p Morgan Healthcare Conference. morgan healthcare conference My name is Tess Romero and I'm one of the senior biotech analysts here at J.P. my name is tess romero and i'm one of the senior biotech analysts here at j.p Morgan. morgan Our next presenting company is Xenon Pharmaceuticals. our next presenting company is xenon pharmaceuticals And presenting on behalf of the company we have President and CEO Ian Mortimer. and presenting on behalf of the company we have president and ceo ian mortimer Ian, over to you. ian over to you

Speaker 2: Thank you, Tess. Good morning everyone. Great to be here. Kick off the year at JPMorgan and a really big update for Xenon. It's been a very important and impressive year over the last 12 months and now we're right on the doorstep of our first phase III clinical data, so we'll go through that today. I'm joined by some of my colleagues here. To my immediate left, Chris Kenney, our Chief Medical Officer. And to his left, Darren Cline, our Chief Commercial Officer. And Tucker Kelly, our CFO is here as well. Tucker and Darren are newer members of the team, have joined over the last 12 months. Both have significant experience in forward integration into a commercial organization, which is our strategic goal, so really nice to have them as part of the Xenon team here at JPMorgan this year. Thank you, Tess. thank you tess Good morning everyone. good morning everyone Great to be here. great to be here Kick off the year at JP Morgan and a really big update for Xenon. kick off the year at jp morgan and a really big update for xenon It's been a very important and impressive year over the last 12 months and now we're right on the doorstep of our first phase III clinical data, so we'll go through that today. it's been a very important and impressive year over the last 12 months and now we're right on the doorstep of our first phase iii clinical data so we'll go through that today I'm joined by some of my colleagues here. i'm joined by some of my colleagues here To my immediate left, Chris Kenney, our Chief Medical Officer. to my immediate left chris kenney our chief medical officer And to his left, Darren Cline, our Chief Commercial Officer. and to his left darren cline our chief commercial officer And Tucker Kelly, our CFO is here as well. and tucker kelly our cfo is here as well Tucker and Darren are newer members of the team, have joined over the last 12 months. tucker and darren are newer members of the team have joined over the last 12 months Both have significant experience in forward integration into a commercial organization, which is our strategic goal, so really nice to have them as part of the Xenon team here at JP Morgan t his year. both have significant experience in forward integration into a commercial organization which is our strategic goal so really nice to have them as part of the xenon team here at jp morgan t his year I will be making some forward-looking statements. So I do refer you to all of our risk factors that are filed with the SEC. So let's get started. Today we're going to spend time talking about our lead molecule, azetukalner, both in epilepsy and in psychiatry. This is the most advanced potassium channel modulator in late-stage clinical development today. And really the only Kv program that is unblinded clinical data and over 800 patient years of both efficacy and safety data. So I'll go through a number of those points throughout the presentation. We also have a really nice emerging earlier-stage pipeline that I'm going to spend some time on. We've got two phase I molecules right now that eventually will be developed in the pain space. I will be making some forward-looking statements. i will be making some forward-looking statements So I do refer you to all of our risk factors that are filed with the SEC. so i do refer you to all of our risk factors that are filed with the sec So let's get started. so let's get started Today we're going to spend time talking about our lead molecule, azetukalner, both in epilepsy and in psychiatry. today we're going to spend time talking about our lead molecule azetukalner both in epilepsy and in psychiatry This is the most advanced potassium channel modulator in late-stage clinical development today. this is the most advanced potassium channel modulator in late-stage clinical development today And really the only Kv program that is unblinded clinical data and over 800 patient years of both efficacy and safety data. and really the only kv program that is unblinded clinical data and over 800 patient years of both efficacy and safety data So I'll go through a number of those points throughout the presentation. so i'll go through a number of those points throughout the presentation We also have a really nice emerging earlier-stage pipeline that I'm going to spend some time on. we also have a really nice emerging earlier-stage pipeline that i'm going to spend some time on We've got two phase I molecules right now that eventually will be developed in the pain space. we've got two phase i molecules right now that eventually will be developed in the pain space I'm going to actually show a little bit of data and updates on one of those programs this morning. If we look at our pipeline, there's really three key areas of today's presentation. I'm going to talk most of the presentation on our lead molecule, which is azetukalner. We have six ongoing double-blind phase III clinical trials for azk. That's what we call the shortened version of azetukalner, three in epilepsy and three in neuropsychiatry. Today we'll spend time on the epilepsy program, we'll spend time on the psychiatry program. Then as I mentioned, the third thing is to give an update on some of our earlier-stage molecules that have transitioned now into human clinical development. I'm going to actually show a little bit of data and updates on one of those programs this morning. i'm going to actually show a little bit of data and updates on one of those programs this morning If we look at our pipeline, there's really three key areas of today's presentation. if we look at our pipeline there's really three key areas of today's presentation I'm going to talk most of the presentation on our lead molecule, which is azetukalner. i'm going to talk most of the presentation on our lead molecule which is azetukalner We have six ongoing double-blind phase III clinical trials for azk. we have six ongoing double-blind phase iii clinical trials for azk That's what we call the shortened version of azetukalner, three in epilepsy and three in neuropsychiatry. that's what we call the shortened version of azetukalner three in epilepsy and three in neuropsychiatry Today we'll spend time on the epilepsy program, we'll spend time on the psychiatry program. today we'll spend time on the epilepsy program we'll spend time on the psychiatry program Then as I mentioned, the third thing is to give an update on some of our earlier-stage molecules that have transitioned now into human clinical development. then as i mentioned the third thing is to give an update on some of our earlier-stage molecules that have transitioned now into human clinical development If we start with the azetukalner, just more broadly, before I get into the epilepsy program, the feedback we're getting from physicians, both in the psychiatry space as well as in the epilepsy space, is there's high anticipation for a drug with a novel mechanism. There are no potassium channel modulators available either in epilepsy or in psychiatry. The other feedback we get are really the attributes of the drug. This drug is easy to administer, it's a QD drug. Once a day, daily dose and no titration. A lot of neurology drugs and drugs in the CNS, you have to start low and go slow. You're on a therapeutic dose on day one for azetukalner. We also have no meaningful DDIs, so we don't have to make adjustments to other background medications. The drug is backed by a significant amount of clinical data already. If we start with the azetukalner, just more broadly, before I get into the epilepsy program, the feedback we're getting from physicians, both in the psychiatry space as well as in the epilepsy space, is there's high anticipation for a drug with a novel mechanism. if we start with the azetukalner just more broadly before i get into the epilepsy program the feedback we're getting from physicians both in the psychiatry space as well as in the epilepsy space is there's high anticipation for a drug with a novel mechanism There are no potassium channel modulators available either in epilepsy or in psychiatry. there are no potassium channel modulators available either in epilepsy or in psychiatry The other feedback we get are really the attributes of the drug. the other feedback we get are really the attributes of the drug This drug is easy to administer, it's a QD drug. this drug is easy to administer it's a qd drug Once a day, daily dose and no titration. once a day daily dose and no titration A lot of neurology drugs and drugs in the CNS, you have to start low and go slow. a lot of neurology drugs and drugs in the cns you have to start low and go slow You're on a therapeutic dose on day one for azetukalner. you're on a therapeutic dose on day one for azetukalner We also have no meaningful DDIs, so we don't have to make adjustments to other background medications. we also have no meaningful ddis so we don't have to make adjustments to other background medications The drug is backed by a significant amount of clinical data a lready. the drug is backed by a significant amount of clinical data a lready As I mentioned, we have over 800 patient years just in patients with focal onset seizures. We have some patients that have been dosed for more than five years now. So I'll go through both the clinical data as well as the safety profile of the drug. Both in efficacy or both in epilepsy as well as in neuropsychiatry. So let's start on the epilepsy side. So if we just take a quick look at the epilepsy market. So epilepsy is actually more common than I think many people recognize. It's the fourth most common neurological condition. You have a one in 26 lifetime risk of developing epilepsy. Epilepsy, if you look at the right, it's a breakdown of the different epilepsy subtypes. There's about three million Americans that have epilepsy. The most common form is focal onset seizures, or about 60% of the market. As I mentioned, we have over 800 patient years just in patients with focal onset seizures. as i mentioned we have over 800 patient years just in patients with focal onset seizures We have some patients that have been dosed for more than five years now. we have some patients that have been dosed for more than five years now So I'll go through both the clinical data as well as the safety profile of the drug. so i'll go through both the clinical data as well as the safety profile of the drug Both in efficacy or both in epilepsy as well as in neuropsychiatry. both in efficacy or both in epilepsy as well as in neuropsychiatry So let's start on the epilepsy side. so let's start on the epilepsy side So if we just take a quick look at the epilepsy market. so if we just take a quick look at the epilepsy market So epilepsy is actually more common than I think many people recognize. so epilepsy is actually more common than i think many people recognize It's the fourth most common neurological condition. it's the fourth most common neurological condition You have a one in 26 lifetime risk of developing epilepsy. you have a one in 26 lifetime risk of developing epilepsy Epilepsy, if you look at the right, it's a breakdown of the different epilepsy subtypes. epilepsy if you look at the right it's a breakdown of the different epilepsy subtypes There's about three million Americans that have epilepsy. there's about three million americans that have epilepsy The most common form is focal onset seizures, or about 60% of the market. the most common form is focal onset seizures or about 60% of the market In terms of the generalized epilepsy market, the most common form of generalized epilepsy are these patients with primary generalized tonic-clonic seizures. And for azetukalner, as you'll see throughout the presentation, we're developing the drug both in FOS as well as in PGTCS, so the most common forms of epilepsy. What we find when we do all of our primary and secondary market research is about half of the patients are not getting good treatment today. So there are many drugs available to treat epilepsy. We recognize that this is a novel mechanism. And about half of the patients are still requiring better therapy, either because of efficacy or because of side effects. So the total addressable market that we think for a branded ASM in the conditions that we're developing is about a million patients in the U.S. In terms of the generalized epilepsy market, the most common form of generalized epilepsy are these patients with primary generalized tonic-clonic seizures. in terms of the generalized epilepsy market the most common form of generalized epilepsy are these patients with primary generalized tonic-clonic seizures And for azetukalner, as you'll see throughout the presentation, we're developing the drug both in FOS as well as in PGTCS, s o the most common forms of epilepsy. W hat we find when we do all of our primary and secondary market research is about half of the patients are not getting good treatment today. and for azetukalner as you'll see throughout the presentation we're developing the drug both in fos as well as in pgtcs, s o the most common forms of epilepsy. w hat we find when we do all of our primary and secondary market research is about half of the patients are not getting good treatment today So there are many drugs available to treat epilepsy. so there are many drugs available to treat epilepsy We recognize that this is a novel mechanism. we recognize that this is a novel mechanism And about half of the patients are still requiring better therapy, either because of efficacy or because of side effects. and about half of the patients are still requiring better therapy either because of efficacy or because of side effects So the total addressable market that we think for a branded ASM in the conditions that we're developing is about a million patients in the U.S. so the total addressable market that we think for a branded asm in the conditions that we're developing is about a million patients in the u.s Our excitement and our confidence in epilepsy really is off of our phase II-B trial that we unblinded in 2021, really underpinning our key leadership position in the epilepsy space. This was our X-TOLE study. This was a study where we randomized 325 subjects. It was a four-arm study, three active doses and placebo. Now we're following those patients in open-label extension. I'll go through both the double-blind data as well as the OLE data in today's presentation. If we first look at the efficacy data that we unblinded, there's two different graphs on this slide. On the left is what we call the MPC. This is looking at the percent reduction in seizures. This is the key primary endpoint for FDA. On the right is a responder analysis. Our excitement and our confidence in epilepsy really is off of our phase II-B trial that we unblinded in 2021, really underpinning our key leadership position in the epilepsy space. our excitement and our confidence in epilepsy really is off of our phase ii-b trial that we unblinded in 2021 really underpinning our key leadership position in the epilepsy space This was our X-TOLE study. this was our x-tole study This was a study where we randomized 325 subjects. this was a study where we randomized 325 subjects It was a four-arm study, three active doses and placebo. it was a four-arm study three active doses and placebo Now we're following those patients in open-label extension. now we're following those patients in open-label extension I'll go through both the double-blind data as well as the OLE data in today's presentation. i'll go through both the double-blind data as well as the ole data in today's presentation If we first look at the efficacy data that we unblinded, there's two different graphs on this slide. if we first look at the efficacy data that we unblinded there's two different graphs on this slide On the left is what we call the MPC. on the left is what we call the mpc This is looking at the percent reduction in seizures. this is looking at the percent reduction in seizures This is the key primary endpoint for FDA. this is the key primary endpoint for fda On the right is a responder analysis. on the right is a responder analysis So this is the percent of patients that have at least a 50% reduction in their seizure burden when we compare the double-blind period to the baseline period, and that's the key primary endpoint for European health regulators. I'm just going to focus on the left for a second, but you can see it on both graphs. There's a clear dose-response. So as we move from 10 mg to 20 mg to 25 mg, you get a deepening of the seizure reduction and the response. You'll also notice that we had p-values of less than 0.05 at all seizure reduction endpoints all doses and obviously even more significant p-values as you move up in dose. If we just look at the 25 mg dose on the left, that was the 52.8% reduction in seizures. And we placebo can adjust that. So this is the percent of patients that have at least a 50% reduction in their seizure burden when we compare the double-blind period to the baseline period, and that's the key primary endpoint for European health regulators. so this is the percent of patients that have at least a 50% reduction in their seizure burden when we compare the double-blind period to the baseline period and that's the key primary endpoint for european health regulators I'm just going to focus on the left for a second, but you can see it on both graphs. i'm just going to focus on the left for a second but you can see it on both graphs There's a clear dose-response. there's a clear dose-response So as we move from 10 mg to 20 mg to 25 mg, you get a deepening of the seizure reduction and the response. so as we move from 10 mg to 20 mg to 25 mg you get a deepening of the seizure reduction and the response You'll also notice that we had p- values of less than 0.05 at all seizure reduction endpoints all doses and obviously even more significant p- values as you move up in dose. you'll also notice that we had p- values of less than 0.05 at all seizure reduction endpoints all doses and obviously even more significant p- values as you move up in dose If we just look at the 25 mg dose on the left, that was the 52.8% reduction in seizures. if we just look at the 25 mg dose on the left that was the 52.8% reduction in seizures And we placebo can adjust that. and we placebo can adjust that The high dose minus placebo, that placebo-adjusted MPC. This is the greatest reduction in seizures ever seen in an FOS study that's been unblinded. In a patient population that has been the most severe or most refractory that's ever been tested based on our review of the literature. We look at that severity of patients based on three different measures. We look at the number of drugs that these patients have failed, the number of background medications they are coming on to study, as well as their baseline seizure burden. The median patient in our phase II program had failed six drugs. They were on three background medications and they had 13 and a half seizures per 28 days. Quite a severe population. The high dose minus placebo, that placebo-adjusted MPC. the high dose minus placebo that placebo-adjusted mpc This is the greatest reduction in seizures ever seen in an FOS study that's been unblinded. I n a patient population that has been the most severe or most refractory that's ever been tested b ased on our review of the literature. W e look at that severity of patients based on three different measures. this is the greatest reduction in seizures ever seen in an fos study that's been unblinded. i n a patient population that has been the most severe or most refractory that's ever been tested b ased on our review of the literature. w e look at that severity of patients based on three different measures We look at the number of drugs that these patients have failed, the number of background medications they are coming on to study, as well as their baseline seizure burden. we look at the number of drugs that these patients have failed the number of background medications they are coming on to study as well as their baseline seizure burden The median patient in our phase II program had failed six drugs. the median patient in our phase ii program had failed six drugs They were on three background medications and they had 13 and a half seizures per 28 days. they were on three background medications and they had 13 and a half seizures per 28 days Quite a severe population. quite a severe population Another thing that we looked at in the phase II program and we're going to look at in phase III is also the rapidity of onset, so this is a similar analysis to the last slide. The last slide was on a monthly basis. This is looking at the data on a weekly basis, so what you'll see on the left graph, it's again, we're looking at both the reduction in seizures as well as the responder analysis, but just focusing on the left graph for a minute, you'll see quite a deep response at week one, so all doses were statistically significant or less than 0.05 at week one, so not only do we see a deepening of response over time, but you see a rapidity of onset. Another thing that we looked at in the phase II program and we're going to look at in phase III is also the rapidity of onset, so this is a similar analysis to the last slide. another thing that we looked at in the phase ii program and we're going to look at in phase iii is also the rapidity of onset so this is a similar analysis to the last slide The last slide was on a monthly basis. the last slide was on a monthly basis This is looking at the data on a weekly basis, so what you'll see on the left graph, it's again, we're looking at both the reduction in seizures as well as the responder analysis, but just focusing on the left graph for a minute, you'll see quite a deep response at week one, so all doses were statistically significant or less than 0.05 at week one, so not only do we see a deepening of response over time, but you see a rapidity of onset. this is looking at the data on a weekly basis so what you'll see on the left graph it's again we're looking at both the reduction in seizures as well as the responder analysis but just focusing on the left graph for a minute you'll see quite a deep response at week one so all doses were statistically significant or less than 0.05 at week one so not only do we see a deepening of response over time but you see a rapidity of onset For these patients that are having breakthrough seizure, for them to have an immediate seizure reduction within days or within the first week of being on drug is really important for these patients. As I mentioned, we continue to follow these patients in open label extension. What started as a one-year OLE has been extended to a three-, five-, and now a seven-year open-label extension. We have a huge amount of both efficacy and safety data in the long term. At the American Epilepsy Society meeting every December, we mature these data and we show these data to the epilepsy community and get feedback. This is the 48-month data that we presented last month at the AES meeting. A couple of key messages from this slide. One, overall, we're getting over a 90% reduction in seizure burden for the population. For these patients that are having breakthrough seizure, for them to have an immediate seizure reduction within days or within the first week of being on drug is really important for these patients. for these patients that are having breakthrough seizure for them to have an immediate seizure reduction within days or within the first week of being on drug is really important for these patients As I mentioned, we continue to follow these patients in open label extension. as i mentioned we continue to follow these patients in open label extension What started as a one-year OLE has been extended to a three-, five-, and now a seven-year open- label extension. what started as a one-year ole has been extended to a three- five- and now a seven-year open- label extension We have a huge amount of both efficacy and safety data in the long term. we have a huge amount of both efficacy and safety data in the long term At the American Epilepsy Society meeting every December, we mature these data and we show these data to the epilepsy community and get feedback. at the american epilepsy society meeting every december we mature these data and we show these data to the epilepsy community and get feedback This is the 48-month data that we presented last month at the AES meeting. this is the 48-month data that we presented last month at the aes meeting A couple of key messages from this slide. a couple of key messages from this slide One, overall, we're getting over a 90% reduction in seizure burden for the population. one overall we're getting over a 90% reduction in seizure burden for the population As I mentioned, this was a very severe and refractory population. We actually, if we look at those patients that were on fewer background medications, either one or two background ASMs, you have 100% reduction in seizure burden for these patients. They're not having any seizures at all. It's quite remarkable when we look at the overall. What's otherwise interesting to notice is not only do we get a reduction immediately, as we talked about at week one, but it looks like that response is deepening over time. Looks like there's a deepening of the response a few months into the open label, and then again as we look out about 12 months or so. We've also been looking at seizure freedom. As I mentioned, this was a very severe and refractory population. as i mentioned this was a very severe and refractory population We actually, if we look at those patients that were on fewer background medications, either one or two background ASMs, you have 100% reduction in seizure burden for these patients. we actually if we look at those patients that were on fewer background medications either one or two background asms you have 100% reduction in seizure burden for these patients They're not having any seizures at all. they're not having any seizures at all It's quite remarkable when we look at the overall. it's quite remarkable when we look at the overall What's otherwise interesting to notice is not only do we get a reduction immediately, as we talked about at week one, but it looks like that response is deepening over time. what's otherwise interesting to notice is not only do we get a reduction immediately as we talked about at week one but it looks like that response is deepening over time Looks like there's a deepening of the response a few months into the open label, and then again as we look out about 12 months or so. looks like there's a deepening of the response a few months into the open label and then again as we look out about 12 months or so We've also been looking at seizure freedom. we've also been looking at seizure freedom I wouldn't say there's a consensus definition for seizure freedom, but overall, when we talk to epileptologists and neurologists, patients being seizure free for 12 months is incredibly important. This provides patients independence because in most jurisdictions, if you have no seizures over a 12-month period, you can drive again. We're looking at all of the patients in our open label that have been dosed for 48 months and what you'll see, about two in five patients, or just under 40% have had 12 months of seizure freedom. So if you remember, these patients were having a seizure every other day. And now we're getting these long periods of seizure freedom with the medicine. And what we're hearing back from physicians, their patients are gaining more independence, they're working more, they're having more social interactions. I wouldn't say there's a consensus definition for seizure freedom, but overall, when we talk to epileptologists and neurologists, patients being seizure free for 12 months is incredibly important. i wouldn't say there's a consensus definition for seizure freedom but overall when we talk to epileptologists and neurologists patients being seizure free for 12 months is incredibly important This provides patients independence because in most jurisdictions, if you have no seizures over a 12-month period, you can drive again. this provides patients independence because in most jurisdictions if you have no seizures over a 12-month period you can drive again We're looking at all of the patients in our open label that have been dosed for 48 months and what you'll see, about two in five patients, or just under 40% have had 12 months of seizure freedom. we're looking at all of the patients in our open label that have been dosed for 48 months and what you'll see about two in five patients or just under 40% have had 12 months of seizure freedom So if you remember, these patients were having a seizure every other day. so if you remember these patients were having a seizure every other day And now we're getting these long periods of seizure freedom with the medicine. and now we're getting these long periods of seizure freedom with the medicine And what we're hearing back from physicians, their patients are gaining more independence, they're working more, they're having more social interactions. and what we're hearing back from physicians their patients are gaining more independence they're working more they're having more social interactions Not shown on this graph, but if you look at our AES data from last month, we also looked at those patients that had a breakthrough seizure. And this was an analysis that we don't believe ever has been done before. So people can have a breakthrough seizure for a number of different reasons. It could be a missed medication, it could be a change, something in their lives. And what we found is that if you have a breakthrough seizure on azetukalner, you can regain seizure freedom for long periods of time and the majority of patients can regain seizure freedom for six or more months. So I think that's really important as we start to think about this drug in the real world. Not shown on this graph, b ut if you look at our AES data from last month, we also looked at those patients that had a breakthrough seizure. not shown on this graph, b ut if you look at our aes data from last month we also looked at those patients that had a breakthrough seizure And this was an analysis that we don't believe ever has been done before. and this was an analysis that we don't believe ever has been done before So people can have a breakthrough seizure for a number of different reasons. so people can have a breakthrough seizure for a number of different reasons It could be a missed medication, it could be a change, something in their lives. it could be a missed medication it could be a change something in their lives And what we found is that if you have a breakthrough seizure on azetukalner, you can regain seizure freedom for long periods of time and the majority of patients can regain seizure freedom for six or more months. and what we found is that if you have a breakthrough seizure on azetukalner you can regain seizure freedom for long periods of time and the majority of patients can regain seizure freedom for six or more months So I think that's really important as we start to think about this drug in the real world. so i think that's really important as we start to think about this drug in the real world Patients are not going to necessarily be seizure free forever, but if they have a breakthrough seizure they should remain on therapy and they can do well over longer periods of time. So what I've really shown over the last number of slides is a huge amount of efficacy data overall for azetukalner in epilepsy. When we look at safety and tolerability, this drug is very active in the CNS and it has an adverse event profile that you would expect for a drug that's consistent with other ASMs and consistent with a drug that's active in the central nervous system. So we do see treatment-emergent adverse events, things like dizziness and somnolence, many of these in a dose-dependent manner. But overall the safety profile is something that we're very comfortable with and the feedback we've had from treating physicians as well. Patients are not going to necessarily be seizure free forever, but if they have a breakthrough seizure they should remain on therapy and they can do well over longer periods of time. patients are not going to necessarily be seizure free forever but if they have a breakthrough seizure they should remain on therapy and they can do well over longer periods of time So what I've really shown over the last number of slides is a huge amount of efficacy data overall for azetukalner in epilepsy. so what i've really shown over the last number of slides is a huge amount of efficacy data overall for azetukalner in epilepsy When we look at safety and tolerability, this drug is very active in the CNS and it has an adverse event profile that you would expect for a drug that's consistent with other ASMs and consistent with a drug that's active in the central nervous system. when we look at safety and tolerability this drug is very active in the cns and it has an adverse event profile that you would expect for a drug that's consistent with other asms and consistent with a drug that's active in the central nervous system So we do see treatment-emergent adverse events, things like dizziness and somnolence, many of these in a dose-dependent manner. so we do see treatment-emergent adverse events things like dizziness and somnolence many of these in a dose-dependent manner But overall the safety profile is something that we're very comfortable with and the feedback we've had from treating physicians as well. but overall the safety profile is something that we're very comfortable with and the feedback we've had from treating physicians as well Also nice to know is that we're not seeing new adverse events in open label extension. As we mentioned, we now have patients that have been on the drug for more than five years and we have the safety profile in open label extension is consistent with the safety profile that we see in the double blind period. All of these data have given us a huge amount of confidence to go into a large phase III program. This phase III program was started a few years ago after an end of phase II meeting with FDA in focal onset seizures. We're running two phase III clinical trials in parallel. They're exactly the same. X-TOLE2 and X-TOLE3, two active doses of the drug versus placebo. Each study was targeted to randomize 360 subjects. For X-TOLE2 we have completed randomization. Also nice to know is that we're not seeing new adverse events in open label extension. also nice to know is that we're not seeing new adverse events in open label extension As we mentioned, we now have patients that have been on the drug for more than five years and we have the safety profile in open label extension is consistent with the safety profile that we see in the double blind period. as we mentioned we now have patients that have been on the drug for more than five years and we have the safety profile in open label extension is consistent with the safety profile that we see in the double blind period All of these data have given us a huge amount of confidence to go into a large phase III program. all of these data have given us a huge amount of confidence to go into a large phase iii program This phase III program was started a few years ago after an end of phase II meeting with FDA in focal onset seizures. this phase iii program was started a few years ago after an end of phase ii meeting with fda in focal onset seizures We're running two phase III clinical trials in parallel. we're running two phase iii clinical trials in parallel They're exactly the same. they're exactly the same X-TOLE 2 and X-TOLE 3, two active doses of the drug versus placebo. x-tole 2 and x-tole 3 two active doses of the drug versus placebo Each study was targeted to randomize 360 subjects. each study was targeted to randomize 360 subjects For X-TOLE 2 we have completed randomization. for x-tole 2 we have completed randomization We've randomized 380 subjects. Randomizations were complete last fall. The last few patients are just going through their final follow-up visits. We'll be analyzing the data and as we guided this morning we'll have our first phase III clinical readout in March of this year. X-TOLE3 is a little bit behind but we did have an important announcement this morning as well. We've completed an ethnobridging study, a phase I study in Japanese subjects, and we had last fall a meeting with the PMDA, the Japanese health regulator, and we're now including Japanese subjects into X-TOLE3, so of the 360 subjects, 60 of them will be Japanese subjects, and what's really important here is we're not going to have to run separate phase III clinical trials in Japan. We can incorporate that into the global phase III program into X-TOLE3. We've randomized 380 subjects. we've randomized 380 subjects Randomizations were complete last fall. randomizations were complete last fall The last few patients are just going through their final follow-up visits. the last few patients are just going through their final follow-up visits We'll be analyzing the data and as we guided this morning we'll have our first phase III clinical readout in March of this year. we'll be analyzing the data and as we guided this morning we'll have our first phase iii clinical readout in march of this year X-TOLE3 is a little bit behind but we did have an important announcement this morning as well. x-tole3 is a little bit behind but we did have an important announcement this morning as well We've completed an ethnobridging study, a phase I study in Japanese subjects, and we had last fall a meeting with the PMDA, the Japanese health regulator, and we're now including Japanese subjects into X-TOLE3, so of the 360 subjects, 60 of them will be Japanese subjects, and what's really important here is we're not going to have to run separate phase III clinical trials in Japan. we've completed an ethnobridging study a phase i study in japanese subjects and we had last fall a meeting with the pmda the japanese health regulator and we're now including japanese subjects into x-tole3 so of the 360 subjects 60 of them will be japanese subjects and what's really important here is we're not going to have to run separate phase iii clinical trials in japan We can incorporate that into the global phase III program into X-TOLE3. we can incorporate that into the global phase iii program into x-tole3 The non-Japanese subject enrollment will be completed this year. That was another update and milestone we announced this morning. And then we'll incorporate Japanese sites and Japanese subjects into X-TOLE3 as well. As I mentioned, we're continuing to do work outside of FOS and we have an ongoing phase III clinical trial in primary generalized tonic-clonic seizures. What's a little bit different on this approach versus what other companies have done in epilepsy is we're running this study in parallel with our FOS study. Very common. You choose your high dose to randomize versus placebo. This says 25 mg versus placebo. Sample size of about 160. These studies do take a little bit longer than the FOS study. So the study continues to recruit and randomize patients. The non-Japanese subject enrollment will be completed this year. the non-japanese subject enrollment will be completed this year That was another update and milestone we announced this morning. that was another update and milestone we announced this morning And then we'll incorporate Japanese sites and Japanese subjects into X-TOLE3 as well. and then we'll incorporate japanese sites and japanese subjects into x-tole3 as well As I mentioned, we're continuing to do work outside of FOS and we have an ongoing phase III clinical trial in primary generalized tonic-clonic seizures. as i mentioned we're continuing to do work outside of fos and we have an ongoing phase iii clinical trial in primary generalized tonic-clonic seizures What's a little bit different on this approach versus what other companies have done in epilepsy is we're running this study in parallel with our FOS study. what's a little bit different on this approach versus what other companies have done in epilepsy is we're running this study in parallel with our fos study Very common. very common You choose your high dose to randomize versus placebo. you choose your high dose to randomize versus placebo This says 25 mg versus placebo. this says 25 mg versus placebo Sample size of about 160. sample size of about 160 These studies do take a little bit longer than the FOS study. these studies do take a little bit longer than the fos study So the study continues to recruit and randomize patients. so the study continues to recruit and randomize patients So that's the update on epilepsy. Really exciting, exciting time to be on the doorstep of unblinding our first phase III clinical trial with top line data as I mentioned in March of this year. So if we now expand the azetukalner opportunity outside of epilepsy and give an update in neuropsychiatry, we ran a smaller phase II study. This was really more signal finding, what we would call a proof of concept study in MDD. So a smaller study that unblinded in the fall of 2023, we were looking at two active doses of the drug, 10 mg and 20 mg versus placebo. Key primary endpoint was a clinical scale of depression called the MADRS scale. This drug works in the reward circuitry in the brain. So that's the update on epilepsy. so that's the update on epilepsy Really exciting, exciting time to be on the doorstep of unblinding our first phase III clinical trial with top line data a s I mentioned in March of this year. really exciting exciting time to be on the doorstep of unblinding our first phase iii clinical trial with top line data a s i mentioned in march of this year So if we now expand the azetukalner opportunity outside of epilepsy and give an update in neuropsychiatry, we ran a smaller phase II study. so if we now expand the azetukalner opportunity outside of epilepsy and give an update in neuropsychiatry we ran a smaller phase ii study This was really more signal finding, what we would call a proof of concept study in MDD. this was really more signal finding what we would call a proof of concept study in mdd So a smaller study that unblinded in the fall of 2023, we were looking at two active doses of the drug, 10 mg and 20 mg versus placebo. so a smaller study that unblinded in the fall of 2023 we were looking at two active doses of the drug 10 mg and 20 mg versus placebo Key primary endpoint was a clinical scale of depression called the MADRS scale. key primary endpoint was a clinical scale of depression called the madrs scale This drug works in the reward circuitry in the brain. this drug works in the reward circuitry in the brain One of the, based on the preclinical data and some other clinical data that was generated, we've also been looking at a scale of anhedonia and this scale is called the SHAPS scale. I'll walk through the data from the phase II study, which supports us moving into the large phase III program in major depressive disorder that we have ongoing. If we look at the MADRS, this was the primary endpoint. A couple of key points from this slide, one, you see a clear dose response. The 10 mg arm outperformed placebo and the 20 mg arm outperformed the 10 mg arm at every time point. What you'll actually see, again, very consistent with epilepsy, you see that rapid response immediately. This is really important in depression. One of the, based on the preclinical data and some other clinical data that was generated, we've also been looking at a scale of anhedonia and this scale is called the SHAPS scale. one of the based on the preclinical data and some other clinical data that was generated we've also been looking at a scale of anhedonia and this scale is called the shaps scale I'll walk through the data from the phase II study, which supports us moving into the large phase III program in major depressive disorder that we have ongoing. i'll walk through the data from the phase ii study which supports us moving into the large phase iii program in major depressive disorder that we have ongoing If we look at the MADRS, this was the primary endpoint. if we look at the madrs this was the primary endpoint A couple of key points from this slide, one, you see a clear dose response. a couple of key points from this slide one you see a clear dose response The 10 mg arm outperformed placebo and the 20 mg arm outperformed the 10 mg arm at every time point. the 10 mg arm outperformed placebo and the 20 mg arm outperformed the 10 mg arm at every time point What you'll actually see, again, very consistent with epilepsy, you see that rapid response immediately. what you'll actually see again very consistent with epilepsy you see that rapid response immediately This is really important in depression. this is really important in depression Many of the drugs that are used to treat depression right now take weeks if not months to show an effect. So to be able to have early onset of efficacy is important. We were able to show that in this study as well. We had about a three-point separation on MADRS between the top dose of 20 mg versus placebo. So a little bit of a high placebo rate in this study and a p-value based on sample size of 0.135. Interesting. We looked at a different scale of depression, which is called the HAMD-17 scale. And we also had a three-point separation, but a p-value less than 0.05. And the reason that was based on variability. So what we saw when we looked at HAMD-17 is we saw less variability in that endpoint compared to the MADRS scale. Many of the drugs that are used to treat depression right now take weeks if not months to show an effect. many of the drugs that are used to treat depression right now take weeks if not months to show an effect So to be able to have early onset of efficacy is important. so to be able to have early onset of efficacy is important We were able to show that in this study as well. we were able to show that in this study as well We had about a three-point separation on MADRS between the top dose of 20 mg versus placebo. we had about a three-point separation on madrs between the top dose of 20 mg versus placebo So a little bit of a high placebo rate in this study and a p- value based on sample size of 0.135. so a little bit of a high placebo rate in this study and a p- value based on sample size of 0.135 Interesting. interesting We looked at a different scale of depression, which is called the HAMD-17 scale. we looked at a different scale of depression which is called the hamd-17 scale And we also had a three-point separation, but a p- value less than 0.05. and we also had a three-point separation but a p- value less than 0.05 And the reason that was based on variability. and the reason that was based on variability So what we saw when we looked at HAMD-17 is we saw less variability in that endpoint compared to the MADRS scale. so what we saw when we looked at hamd-17 is we saw less variability in that endpoint compared to the madrs scale And so now in phase III, we're looking at HAMD-17 as the primary endpoint. As I mentioned, we looked at a clinical scale of anhedonia called the SHAPS scale, again very similar. We saw a clear dose response and separation between the two active doses in placebo. About a 2.5 point difference between active and placebo at the high dose and also a p-value of less than 0.05. When we looked at the safety and tolerability data in depression, this was actually quite surprising to us. It looks like the tolerability profile is a little bit softer in the depression patients versus the epilepsy patients. Obviously this is a cross trial comparison, but overall it was quite a benign adverse event profile in depression. And importantly, when we think about depression, we didn't see any notable weight gain and no notable sexual dysfunction and we do see that with some of the current standard of care. And so now in phase III, we're looking at HAMD- 17 as the primary endpoint. and so now in phase iii we're looking at hamd- 17 as the primary endpoint As I mentioned, we looked at a clinical scale of anhedonia called the SHAPS scale, a gain very similar. as i mentioned we looked at a clinical scale of anhedonia called the shaps scale, a gain very similar We saw a clear dose response and separation between the two active doses in placebo. we saw a clear dose response and separation between the two active doses in placebo About a 2.5 point difference between active and placebo at the high dose and also a p- value of less than 0.05. about a 2.5 point difference between active and placebo at the high dose and also a p- value of less than 0.05 When we looked at the safety and tolerability data in depression, this was actually quite surprising to us. when we looked at the safety and tolerability data in depression this was actually quite surprising to us It looks like the tolerability profile is a little bit softer in the depression patients versus the epilepsy patients. it looks like the tolerability profile is a little bit softer in the depression patients versus the epilepsy patients Obviously this is a cross trial comparison, but overall it was quite a benign adverse event profile in depression. obviously this is a cross trial comparison but overall it was quite a benign adverse event profile in depression And importantly, when we think about depression , we didn't see any notable weight gain and no notable sexual dysfunction and w e do see that with some of the current standard of care. and importantly when we think about depression we didn't see any notable weight gain and no notable sexual dysfunction and w e do see that with some of the current standard of care When we think about our approach in psychiatry, a novel mechanism, rapidity of onset and having a different adverse event profile is the feedback that we're receiving from the psychiatry community is really important in the advancement of this new medicine. We now are in a large phase III program in major depressive disorder. Two ongoing phase III clinical trials, currently X-NOVA 2 and X-NOVA 3. A significant number of differences that we made between the phase II program and phase III, obviously a huge increase in sample size, one to one randomization using HAMD-17 as the primary endpoint, as well as we're looking at patients that are a little bit more severe coming into study. That cutoff of patients to get into study as a more severe depressed population. When we think about our approach in psychiatry, a novel mechanism, rapidity of onset and having a different adverse event profile is the feedback that we're receiving from the psychiatry community is really important in the advancement of this new medicine. when we think about our approach in psychiatry a novel mechanism rapidity of onset and having a different adverse event profile is the feedback that we're receiving from the psychiatry community is really important in the advancement of this new medicine We now are in a large phase III program in major depressive disorder. we now are in a large phase iii program in major depressive disorder Two ongoing phase III clinical trials, currently X-NOVA 2 and X-NOVA 3. two ongoing phase iii clinical trials currently x-nova 2 and x-nova 3 A significant number of differences that we made between the phase II program and phase III, obviously a huge increase in sample size, one to one randomization using HAMD-17 as the primary endpoint, as well as we're looking at patients that are a little bit more severe coming into study. a significant number of differences that we made between the phase ii program and phase iii obviously a huge increase in sample size one to one randomization using hamd-17 as the primary endpoint as well as we're looking at patients that are a little bit more severe coming into study That cutoff of patients to get into study as a more severe depressed population. that cutoff of patients to get into study as a more severe depressed population We also announced this morning, execution on these studies have been going really well and we'll have X-NOVA 2 data in the first half of next year. We've expanded in neuropsychiatry beyond major depressive disorder, also into bipolar depression. Really significant unmet medical need in bipolar depression. Fewer mechanisms and fewer drugs available for these patients. So we started a study mid year last year called the X-CEED study where we're looking at patients with both bipolar I and bipolar II. We're looking at scales of clinical depression as measured by MADRS single dose of 20 milligrams versus placebo. So as I mentioned, we also wanted to give an update. Obviously a huge amount of the focus for investors is on azetukalner, both in epilepsy as well in psychiatry. But we've made some great progress on the early stage portfolio and I wanted to provide an update this morning. We also announced this morning, execution on these studies have been going really well and we'll have X-NOVA 2 data in the first half of next year. we also announced this morning execution on these studies have been going really well and we'll have x-nova 2 data in the first half of next year We've expanded in neuropsychiatry beyond major depressive disorder, also into bipolar depression. we've expanded in neuropsychiatry beyond major depressive disorder also into bipolar depression Really significant unmet medical need in bipolar depression. really significant unmet medical need in bipolar depression Fewer mechanisms and fewer drugs available for these patients. fewer mechanisms and fewer drugs available for these patients So we started a study mid year last year called the X-CEED study where we're looking at patients with both bipolar I and bipolar II. so we started a study mid year last year called the x-ceed study where we're looking at patients with both bipolar i and bipolar ii We're looking at scales of clinical depression as measured by MADRS single dose of 20 milligrams versus placebo. we're looking at scales of clinical depression as measured by madrs single dose of 20 milligrams versus placebo So as I mentioned, we also wanted to give an update. so as i mentioned we also wanted to give an update Obviously a huge amount of the focus for investors is on azetukalner, both in epilepsy as well in psychiatry. obviously a huge amount of the focus for investors is on azetukalner both in epilepsy as well in psychiatry But we've made some great progress on the early stage portfolio and I wanted to provide an update this morning. but we've made some great progress on the early stage portfolio and i wanted to provide an update this morning I'm going to focus on our Nav1.7 program. We do have a second program that's targeting a potassium channel called Kv7 that's also in a phase I clinical trial. Today, in the interest of time, we're going to focus on our Nav1.7 program. The genetics of Nav1.7 are absolutely remarkable. Xenon led some of this work. About 20, 25 years ago, the history of the company started as a genetics company. These patients in a gene called SCN9A which encodes for a protein called Nav1.7. If you're complete loss of function for Nav1.7 or even a partial loss of function of about 75%-85% loss of function, these patients feel no pain. They feel no pain regardless of noxious stimuli. There's also gain of function in the channel. If you have too much activity in Nav1.7 you feel non precipitated severe pain. I'm going to focus on our Nav1.7 program. i'm going to focus on our nav1.7 program We do have a second program that's targeting a potassium channel called Kv7 that's also in a phase I clinical trial. we do have a second program that's targeting a potassium channel called kv7 that's also in a phase i clinical trial Today, in the interest of time, we're going to focus on our Nav1.7 program. today in the interest of time we're going to focus on our nav1.7 program The genetics of Nav1.7 are absolutely remarkable. the genetics of nav1.7 are absolutely remarkable Xenon led some of this work. xenon led some of this work About 20, 25 years ago, the history of the company started as a genetics company. about 20 25 years ago the history of the company started as a genetics company These patients in a gene called SCN9A which encodes for a protein called Nav1.7. these patients in a gene called scn9a which encodes for a protein called nav1.7 If you're complete loss of function for Nav1.7 or even a partial loss of function of about 75%-85% loss of function, these patients feel no pain. if you're complete loss of function for nav1.7 or even a partial loss of function of about 75%-85% loss of function these patients feel no pain They feel no pain regardless of noxious stimuli. they feel no pain regardless of noxious stimuli There's also gain of function in the channel. there's also gain of function in the channel If you have too much activity in Nav1.7 you feel non precipitated severe pain. if you have too much activity in nav1.7 you feel non precipitated severe pain There's a genetic condition called inherited erythromelalgia where these people have extreme pain in their extremities. It was an absolutely remarkable genetic target when it was identified about 25 years ago. For years pharma, almost every of the large pharma companies were trying to drug this target. It's proven to be very challenging to target from a chemistry point of view. I think we've really made a breakthrough over the last couple of years. Some of the challenges with the first, what we would call kind of the first and second generation molecules against Nav1.7, we didn't have the potency and selectivity, so they didn't have isoform subselectivity on the sodium channels. We need to selectively hit Nav1.7 while not hitting the other isoforms. There's a genetic condition called inherited erythromelalgia where these people have extreme pain in their extremities. there's a genetic condition called inherited erythromelalgia where these people have extreme pain in their extremities It was an absolutely remarkable genetic target when it was identified about 25 years ago. it was an absolutely remarkable genetic target when it was identified about 25 years ago For years pharma, almost every of the large pharma companies were trying to drug this target. for years pharma almost every of the large pharma companies were trying to drug this target It's proven to be very challenging to target from a chemistry point of view. it's proven to be very challenging to target from a chemistry point of view I think we've really made a breakthrough over the last couple of years. i think we've really made a breakthrough over the last couple of years Some of the challenges with the first, what we would call kind of the first and second generation molecules against Nav1.7, we didn't have the potency and selectivity, so they didn't have isoform subselectivity on the sodium channels. some of the challenges with the first what we would call kind of the first and second generation molecules against nav1.7 we didn't have the potency and selectivity so they didn't have isoform subselectivity on the sodium channels We need to selectively hit Nav1.7 w hile not hitting the other isoforms. we need to selectively hit nav1.7 w hile not hitting the other isoforms Many of the drugs also had significant protein binding, so they didn't have enough free fraction to interact with the target. And many of them were restricted to the peripheral nervous system, so they didn't act centrally. And if we want to mimic the human genetics, which is what we're trying to do as a novel analgesic, we believe we have to mimic where the target is, which is both in the peripheral nervous system as well in the central nervous system. So what we've been saying is that our lead molecule, XEN1701, which is now in a phase I clinical trial, has a profile that addresses all of these limitations and has a profile that's never been tested in a human clinical trial previously. Many of the drugs also had significant protein binding, so they didn't have enough free fraction to interact with the target. many of the drugs also had significant protein binding so they didn't have enough free fraction to interact with the target And many of them were restricted to the peripheral nervous system, so they didn't act centrally. and many of them were restricted to the peripheral nervous system so they didn't act centrally And if we want to mimic the human genetics, which is what we're trying to do as a novel analgesic, we believe we have to mimic where the target is, which is both in the peripheral nervous system as well in the central nervous system. and if we want to mimic the human genetics which is what we're trying to do as a novel analgesic we believe we have to mimic where the target is which is both in the peripheral nervous system as well in the central nervous system So what we've been saying is that our lead molecule, XEN1701, which is now in a phase I clinical trial, has a profile that addresses all of these limitations and has a profile that's never been tested in a human clinical trial previously. so what we've been saying is that our lead molecule xen1701 which is now in a phase i clinical trial has a profile that addresses all of these limitations and has a profile that's never been tested in a human clinical trial previously Here's just a little bit of the early preclinical data. What you'll see on the left part of the slide on the graph is that we have molecules, and specifically 1701, but other molecules in other chemistries that are order of magnitude is more potent than the previous drugs that were targeting Nav1.7, shown here as both a Pfizer molecule as well as a Genentech molecule, which was actually our drug in collaboration with Genentech. We had a large collaboration with Genentech, Roche for many years. So we have significant increases in potency and significant increases in selectivity as well. What the right graph shows is that we need to get into the brain. So if you can get into the brain and you can have free drug in the brain, that can drive efficacy. So that's important for the profile overall. Here's just a little bit of the early preclinical data. here's just a little bit of the early preclinical data What you'll see on the left part of the slide on the graph is that we have molecules, and specifically 1701, but other molecules in other chemistries that are order of magnitude is more potent than the previous drugs that were targeting Nav1.7, shown here as both a Pfizer molecule as well as a Genentech molecule, which was actually our drug in collaboration with Genentech. what you'll see on the left part of the slide on the graph is that we have molecules and specifically 1701 but other molecules in other chemistries that are order of magnitude is more potent than the previous drugs that were targeting nav1.7 shown here as both a pfizer molecule as well as a genentech molecule which was actually our drug in collaboration with genentech We had a large collaboration with Genentech, Roche for many years. we had a large collaboration with genentech roche for many years So we have significant increases in potency and significant increases in selectivity as well. so we have significant increases in potency and significant increases in selectivity as well What the right graph shows is that we need to get into the brain. what the right graph shows is that we need to get into the brain So if you can get into the brain and you can have free drug in the brain, that can drive efficacy. so if you can get into the brain and you can have free drug in the brain that can drive efficacy So that's important for the profile overall. so that's important for the profile overall What we announced this morning, which I think is incredibly exciting, we're partway through the phase I clinical trial, but we've already reached exposures in the SAD portion of the study that are above concentrations predicted to mimic the human genetics. We don't believe that something like this has ever been seen in a healthy volunteer study. We will wrap up these phase I studies later this year and we're excited to get into a proof of concept study, probably something like bunionectomy before the end of 2026. In addition to the work on azetukalner, really nice progress on the early stage pipeline as well. Just to wrap up in milestones before we hit Q&A, as I said, it's been a really important year of execution for Xenon across a number of our clinical trials. What we announced this morning, which I think is incredibly exciting, we're partway through the phase I clinical trial, but we've already reached exposures in the SAD portion of the study that are above concentrations predicted to mimic the human genetics. what we announced this morning which i think is incredibly exciting we're partway through the phase i clinical trial but we've already reached exposures in the sad portion of the study that are above concentrations predicted to mimic the human genetics We don't believe that something like this has ever been seen in a healthy volunteer study. we don't believe that something like this has ever been seen in a healthy volunteer study We will wrap up these phase I studies later this year and we're excited to get into a proof of concept study, probably something like bunionectomy before the end of 2026. we will wrap up these phase i studies later this year and we're excited to get into a proof of concept study probably something like bunionectomy before the end of 2026 In addition to the work on azetukalner, really nice progress on the early stage pipeline as well. in addition to the work on azetukalner really nice progress on the early stage pipeline as well Just to wrap up in milestones before we hit Q&A, as I said, it's been a really important year of execution for Xenon across a number of our clinical trials. just to wrap up in milestones before we hit q&a as i said it's been a really important year of execution for xenon across a number of our clinical trials We have six ongoing phase III clinical trials for azetukalner in both epilepsy and in psychiatry. The first of those is going to read out in March of this year, which is our X-TOLE2 study in focal onset seizures. That'll be followed by a number of clinical readouts in the coming quarters and coming years, both in epilepsy and in psychiatry. And we have a really nice maturing early stage portfolio and pipeline as well and some really nice progress on our Nav1.7 program. So thanks very much. An exciting year for Xenon coming up. And Tess, I'll pass it back to you for Q&A. We have six ongoing phase III clinical trials for azetukalner in both epilepsy and in psychiatry. we have six ongoing phase iii clinical trials for azetukalner in both epilepsy and in psychiatry The first of those is going to read out in March of this year, which is our X-TOLE2 study in focal onset seizures. the first of those is going to read out in march of this year which is our x-tole2 study in focal onset seizures That'll be followed by a number of clinical readouts in the coming quarters and coming years, both in epilepsy and in psychiatry. that'll be followed by a number of clinical readouts in the coming quarters and coming years both in epilepsy and in psychiatry And we have a really nice maturing early stage portfolio and pipeline as well and some really nice progress on our Nav1.7 program. and we have a really nice maturing early stage portfolio and pipeline as well and some really nice progress on our nav1.7 program So thanks very much. so thanks very much An exciting year for Xenon coming up. an exciting year for xenon coming up And Tess, I'll pass it back to you for Q&A. and tess i'll pass it back to you for q&a

Speaker 4: Okay, thank you, Ian. So I thought I'd actually start our conversation with a little bit of a bigger picture strategic question for you. Just around how you think about investment and balancing it across azetukalner and epilepsy, but also neuropsychiatry and maximizing the value there, but also expanding some of your pipeline? Okay, thank you, Ian. okay thank you ian So I thought I'd actually start our conversation with a little bit of a bigger picture strategic question for you. so i thought i'd actually start our conversation with a little bit of a bigger picture strategic question for you Just around how you think about investment and balancing it across azetukalner and epilepsy, but also neuropsychiatry and maximizing the value there, but also expanding some of your pipeline? just around how you think about investment and balancing it across azetukalner and epilepsy but also neuropsychiatry and maximizing the value there but also expanding some of your pipeline

Speaker 2: Yeah, I think it's a great question. A couple of comments. One, we've been really clear on what our strategic objective is. We want to be a fully integrated biopharma company. We want to discover, develop and commercialize our own molecules. We have deep expertise, I didn't mention this at the beginning. In drugging ion channels in the CNS. We've been doing this for many, many years. I think that expertise is world class. So obviously a huge amount of focus is on azetukalner. That's where the vast majority of our effort is, the vast majority of our spend is. Yeah, I think it's a great question. yeah i think it's a great question A couple of comments. a couple of comments One, we've been really clear on what our strategic objective is. one we've been really clear on what our strategic objective is We want to be a fully integrated biopharma company. we want to be a fully integrated biopharma company We want to discover, develop and commercialize our own molecules. we want to discover develop and commercialize our own molecules We have deep expertise, I didn't mention this at the beginning. we have deep expertise i didn't mention this at the beginning In drugging ion channels in the CNS. in drugging ion channels in the cns We've been doing this for many, many years. we've been doing this for many many years I think that expertise is world class. i think that expertise is world class So obviously a huge amount of focus is on azetukalner. so obviously a huge amount of focus is on azetukalner That's where the vast majority of our effort is, the vast majority of our spend is. that's where the vast majority of our effort is the vast majority of our spend is And not only are we going to have our phase III X-TOLE2 readout in March of this year, that'll be followed by a new drug application in the second half of this year and put us in a position to get our very first drug approved. But as you mentioned, we really want to build a world-class company, which means we have to think about the portfolio. That's both the expansion of azetukalner into psychiatry, but also the early stage portfolio. And as I mentioned, two molecules transition in the phase I clinical trial last year and you'll see more molecules transition from our labs into human clinical development over the coming years. And not only are we going to have our phase III X-TOLE 2 readout in March of this year, that'll be followed by a new drug application in the second half of this year and put us in a position to get our very first drug approved. and not only are we going to have our phase iii x-tole 2 readout in march of this year that'll be followed by a new drug application in the second half of this year and put us in a position to get our very first drug approved But as you mentioned, we really want to build a world-class company, which means we have to think about the portfolio. but as you mentioned we really want to build a world-class company which means we have to think about the portfolio That's both the expansion of azetukalner into psychiatry, but also the early stage portfolio. that's both the expansion of azetukalner into psychiatry but also the early stage portfolio And as I mentioned, two molecules transition in the phase I clinical trial last year and you'll see more molecules transition from our labs into human clinical development over the coming years. and as i mentioned two molecules transition in the phase i clinical trial last year and you'll see more molecules transition from our labs into human clinical development over the coming years

Speaker 4: So we know now that top-line results from the phase III X-TOLE2 trial are expected in March. And you know, quite frankly I feel like we've been talking about this trial and expectations for a long time, but I'll just ask it to be complete here. What would you consider a win in terms of efficacy and safety here and how could the longer treatment duration, 12 weeks versus eight weeks in X-TOLE impact the results? So we know now that top-line results from the phase III X-TOLE2 trial are expected in March. so we know now that top-line results from the phase iii x-tole2 trial are expected in march And you know, quite frankly I feel like we've been talking about this trial and expectations for a long time, but I'll just ask it to be complete here. and you know quite frankly i feel like we've been talking about this trial and expectations for a long time but i'll just ask it to be complete here What would you consider a win in terms of efficacy and safety here and how could the longer treatment duration, 12 weeks versus eight weeks in X-TOLE impact the results? what would you consider a win in terms of efficacy and safety here and how could the longer treatment duration 12 weeks versus eight weeks in x-tole impact the results

Speaker 2: Sure, I'm happy to start and make a few comments, but I think Chris should provide his perspective, and then I want Darren to weigh in as well as we think about just the overall profile and the importance of that from a commercial perspective. So you've asked a couple of questions in there. One of the principles that we had at Xenon, given the great success we had in our phase II-B X-TOLE study, is that X-TOLE2 and X-TOLE3 should be very similar studies, and so if you look at the inclusion and exclusion criteria, the phase III program is exactly the same as the phase II program. You did mention one difference, and one difference is that the double blind period is 12 weeks in phase III, it was eight weeks in phase II. Sure, I'm happy to start and make a few comments, but I think Chris should provide his perspective, and then I want Darren to weigh in as well as we think about just the overall profile and the importance of that from a commercial perspective. sure i'm happy to start and make a few comments but i think chris should provide his perspective and then i want darren to weigh in as well as we think about just the overall profile and the importance of that from a commercial perspective So you've asked a couple of questions in there. so you've asked a couple of questions in there One of the principles that we had at Xenon, given the great success we had in our phase II-B X-TOLE study, is that X-TOLE 2 and X-TOLE 3 should be very similar studies, and so if you look at the inclusion and exclusion criteria, the phase III program is exactly the same as the phase II program. one of the principles that we had at xenon given the great success we had in our phase ii-b x-tole study is that x-tole 2 and x-tole 3 should be very similar studies and so if you look at the inclusion and exclusion criteria the phase iii program is exactly the same as the phase ii program You did mention one difference, and one difference is that the double blind period is 12 weeks i n phase III, it was eight weeks i n phase II. you did mention one difference, and one difference is that the double blind period is 12 weeks i n phase iii it was eight weeks i n phase ii When we look at the open label data, it actually looks like those patients continue to have a deeper response over time. So I think moving from eight weeks to 12 weeks, we're very comfortable with the 12-week double blind period overall. In terms of just kind of managing expectations going into data, obviously that's a question we get a lot. I think you did really nice work, Tess, in your preview for Xenon coming into the conference and coming into our X-TOLE2 data, so I would encourage people to look at the analysis that you've provided. You know, I think at the highest level, obviously this study needs to be positive, it needs to be statistically significant, which will put us in a position to file a new drug application later this year. W hen we look at the open label data, it actually looks like those patients continue to have a deeper response over time. w hen we look at the open label data it actually looks like those patients continue to have a deeper response over time So I think moving from eight weeks to 12 weeks, we're very comfortable with the 12-week double blind period overall. I n terms of just kind of managing expectations going into data, o bviously that's a question we get a lot. so i think moving from eight weeks to 12 weeks we're very comfortable with the 12-week double blind period overall. i n terms of just kind of managing expectations going into data, o bviously that's a question we get a lot I think you did really nice work, Tess, in your preview for Xenon coming into the conference and coming into our X-TOLE 2 data, s o I would encourage people to look at the analysis that you've provided. i think you did really nice work tess in your preview for xenon coming into the conference and coming into our x-tole 2 data, s o i would encourage people to look at the analysis that you've provided You know, I think at the highest level, obviously this study needs to be positive, it needs to be statistically significant, which will put us in a position to file a new drug application later this year. you know i think at the highest level obviously this study needs to be positive it needs to be statistically significant which will put us in a position to file a new drug application later this year Obviously, every study is a little bit different. We have already commented that the patient population in phase III looks very similar to phase II and the open-label extension rollover rate in phase III is very similar to phase II. So that gives us a lot of confidence going into it, and I think I also always want to remind people that the X-TOLE study will be on-label. Right. That study's already been complete with the best placebo adjusted efficacy ever seen in a focal onset seizure study, and so this is really a study that'll add to that and be part of the new drug application. Chris? Obviously, every study is a little bit different. obviously every study is a little bit different We have already commented that the patient population in phase III looks very similar to phase II and the open-label extension rollover rate in phase III is very similar to phase II. we have already commented that the patient population in phase iii looks very similar to phase ii and the open-label extension rollover rate in phase iii is very similar to phase ii So that gives us a lot of confidence going into it, and I think I also always want to remind people that the X-TOLE study will be on-label. so that gives us a lot of confidence going into it and i think i also always want to remind people that the x-tole study will be on-label Right. right That study's already been complete with the best placebo adjusted efficacy ever seen in a focal onset seizure study, and so this is really a study that'll add to that and be part of the new drug application. that study's already been complete with the best placebo adjusted efficacy ever seen in a focal onset seizure study and so this is really a study that'll add to that and be part of the new drug application Chris? chris

Speaker 6: I think you covered it. I think you covered it. i think you covered it

Speaker 2: Darren, do you want to provide just your perspective on the overall profile? Darren, do you want to provide just your perspective on the overall profile? darren do you want to provide just your perspective on the overall profile

Speaker 1: Yeah, I think, you know, when you think of the X-TOLE data, it really has set the precedent. And when you think about the prescribing epileptologist, general neurologist, the novel mechanism of AZK is really going to be transformative in there. It's just not another sodium channel blocker. And so commercially we already know, based on our market research, our discussions most recently at AES, there's a tremendous amount of excitement for, as Ian outlined, the attributes of azetukalner and particularly with the general neurologist, they view this as a really easy therapy to incorporate into their practice. And so I think with the backdrop of the clinical data, the safety and tolerability, we're pretty excited to get this to physicians and their patients. Yeah, I think, you know, when you think of the X-TOLE data, it really has set the precedent. yeah i think you know when you think of the x-tole data it really has set the precedent And when you think about the prescribing epileptologist, general neurologist, the novel mechanism of AZK is really going to be transformative in there. and when you think about the prescribing epileptologist general neurologist the novel mechanism of azk is really going to be transformative in there It's just not another sodium channel blocker. it's just not another sodium channel blocker And so commercially we already know, based on our market research, our discussions most recently at AES, there's a tremendous amount of excitement for, as Ian outlined, the attributes of azetukalner and particularly with the general neurologist, they view this as a really easy therapy to incorporate into their practice. and so commercially we already know based on our market research our discussions most recently at aes there's a tremendous amount of excitement for as ian outlined the attributes of azetukalner and particularly with the general neurologist they view this as a really easy therapy to incorporate into their practice And so I think with the backdrop of the clinical data, the safety and tolerability, we're pretty excited to get this to physicians and their patients. and so i think with the backdrop of the clinical data the safety and tolerability we're pretty excited to get this to physicians and their patients

Speaker 4: Okay. And I did get this question this morning. I thought it was kind of a good one. Have there been any protocol amendments to X-TOLE2 or X-TOLE3? Okay. okay And I did get this question this morning. and i did get this question this morning I thought it was kind of a good one. i thought it was kind of a good one Have there been any protocol amendments to X-TOLE 2 or X-TOLE3 ? have there been any protocol amendments to x-tole 2 or x-tole3

Speaker 2: Chris? Chris? chris

Speaker 6: Yeah, there have been some amendments, but nothing that has. I mean, to Ian's point, basically the spirit of X-TOLE2 was to maintain consistent with X-TOLE. And so if you look at the major sort of inclusion and exclusion criteria, you look at the baseline characteristics, you look at the geographical spread, specifically percentage of patients from the U.S., we're seeing a great deal of consistency. So there isn't anything within any of the differences between those protocols that we think are substantive and would drive a difference in efficacy. Yeah, there have been some amendments, but nothing that has. yeah there have been some amendments but nothing that has I mean, to Ian's point, basically the spirit of X-TOLE2 was to maintain consistent with X-TOLE. i mean to ian's point basically the spirit of x-tole2 was to maintain consistent with x-tole And so if you look at the major sort of inclusion and exclusion criteria, you look at the baseline characteristics, you look at the geographical spread, specifically percentage of patients from the U.S., we're seeing a great deal of consistency. and so if you look at the major sort of inclusion and exclusion criteria you look at the baseline characteristics you look at the geographical spread specifically percentage of patients from the u.s we're seeing a great deal of consistency So there isn't anything within any of the differences between those protocols that we think are substantive and would drive a difference in efficacy. so there isn't anything within any of the differences between those protocols that we think are substantive and would drive a difference in efficacy

Speaker 4: With all that in mind, what keeps you up at night on this study? With all that in mind, what keeps you up at night on this study? with all that in mind what keeps you up at night on this study

Speaker 2: I can start and then Chris can add, you know, look, every clinical trial, you know, we're enrolling a large number of patients dispersed throughout a number of clinical sites. But I think, you know, what gives us great confidence is we have the most experience of running epilepsy studies over the last decade. And so I think both internally in our team, we have epileptologists and psychiatrists that work at Xenon that have a huge amount of experience. We've run the largest, you know, the largest study ever run in FOS that's been unblinded. So I think we have tremendous confidence. So I wouldn't say that there's anything that we're really concerned about as we think about the epilepsy work. I can start and then Chris can add, you know, look, every clinical trial, you know, we're enrolling a large number of patients dispersed throughout a number of clinical sites. i can start and then chris can add you know look every clinical trial you know we're enrolling a large number of patients dispersed throughout a number of clinical sites But I think, you know, what gives us great confidence is we have the most experience of running epilepsy studies over the last decade. but i think you know what gives us great confidence is we have the most experience of running epilepsy studies over the last decade And so I think both internally in our team, we have epileptologists and psychiatrists that work at Xenon that have a huge amount of experience. and so i think both internally in our team we have epileptologists and psychiatrists that work at xenon that have a huge amount of experience We've run the largest, you know, the largest study ever run in FOS that's been unblinded. we've run the largest you know the largest study ever run in fos that's been unblinded So I think we have tremendous confidence. so i think we have tremendous confidence So I wouldn't say that there's anything that we're really concerned about as we think about the epilepsy work. so i wouldn't say that there's anything that we're really concerned about as we think about the epilepsy work Obviously, with psychiatry, we're always these studies in terms of execution is critically important as we spend a lot of time working with the sites and making sure that we're getting the right patients into a psychiatry study. So that's something that we spend a lot of time thinking about as well, and then as we think about the early stage portfolio, it's really the excitement of where we could take this. I think if we have a novel analgesic and non-opioid mechanism with the profile of our Nav1.7 program, I mean, the opportunity to have an oral non-opioid chronic pain drug is incredible, and so there's a lot of excitement and thinking internally about how do we develop that in the most efficient way? Chris? Obviously, with psychiatry, we're always these studies in terms of execution is critically important as we spend a lot of time working with the sites and making sure that we're getting the right patients into a psychiatry study. obviously with psychiatry we're always these studies in terms of execution is critically important as we spend a lot of time working with the sites and making sure that we're getting the right patients into a psychiatry study So that's something that we spend a lot of time thinking about as well, and then as we think about the early stage portfolio, it's really the excitement of where we could take this. so that's something that we spend a lot of time thinking about as well and then as we think about the early stage portfolio it's really the excitement of where we could take this I think if we have a novel analgesic and non-opioid mechanism with the profile of our Nav1.7 program, I mean, the opportunity to have an oral non-opioid chronic pain drug is incredible, and so there's a lot of excitement and thinking internally about how do we develop that in the most efficient way? i think if we have a novel analgesic and non-opioid mechanism with the profile of our nav1.7 program i mean the opportunity to have an oral non-opioid chronic pain drug is incredible and so there's a lot of excitement and thinking internally about how do we develop that in the most efficient way Chris? chris

Speaker 6: Yeah, I mean, I think we're in as good a shape as we possibly could be for all the reasons that Ian and I have mentioned so far, so I'm sleeping well. Yeah, I mean, I think we're in as good a shape as we possibly could be for all the reasons that Ian and I have mentioned so far, so I'm sleeping well. yeah i mean i think we're in as good a shape as we possibly could be for all the reasons that ian and i have mentioned so far so i'm sleeping well

Speaker 4: Okay. And you know, as maybe this is a zoom ahead question here. So beg your pardon, but how should we think about the marketing message here? And is there any kind of key differences that you expect there could be between epileptologists and general neurologists? Okay. okay And you know, as maybe this is a zoom ahead question here. and you know as maybe this is a zoom ahead question here So beg your pardon, but how should we think about the marketing message here? so beg your pardon but how should we think about the marketing message here And is there any kind of key differences that you expect there could be between epileptologists and general neurologists? and is there any kind of key differences that you expect there could be between epileptologists and general neurologists

Speaker 1: Yeah, you know, traditionally with anti-seizure medications, typically the epileptologist or the early adoption, which is not surprising. Right. Everybody, every patient they see in their practice every day are patients with seizures and typically refractory seizures. Right. So they're getting referred to the epileptologist because of the severity of their disease. And then the general neurology community, they are typically a more late adopter. And remember, when we are approved and launched, it'll be an eight-year gap between the last time a branded ASM was approved. And so there's been this kind of period of really nothing new for the general neurologist. And so from the last branded medication that was approved, you know, the general neurologists are really finding that medication difficult because of the ability to have to titrate both up with the medication and down on other ASMs and other issues. Yeah, you know, traditionally with anti-seizure medications, typically the epileptologist or the early adoption, which is not surprising. yeah you know traditionally with anti-seizure medications typically the epileptologist or the early adoption which is not surprising Right. right Everybody, every patient they see in their practice every day are patients with seizures and typically refractory seizures. everybody every patient they see in their practice every day are patients with seizures and typically refractory seizures Right. right So they're getting referred to the epileptologist because of the severity of their disease. so they're getting referred to the epileptologist because of the severity of their disease And then the general neurology community, they are typically a more late adopter. and then the general neurology community they are typically a more late adopter And remember, when we are approved and launched, it'll be an eight-year gap between the last time a branded ASM was approved. and remember when we are approved and launched it'll be an eight-year gap between the last time a branded asm was approved And so there's been this kind of period of really nothing new for the general neurologist. and so there's been this kind of period of really nothing new for the general neurologist And so from the last branded medication that was approved, you know, the general neurologists are really finding that medication difficult because of the ability to have to titrate both up with the medication and down on other ASMs and other issues. and so from the last branded medication that was approved you know the general neurologists are really finding that medication difficult because of the ability to have to titrate both up with the medication and down on other asms and other issues Again, back to my earlier comment. I think with azetukalner, it's very clear that the ease of use, and then you're talking about kind of what will make a difference here. And I think because of the daily dosing, the novel mechanism, no drug-drug interactions, titrated dose right out of the gate. Tremendously excited to bring this to the general neurologist. So they're able to incorporate this into the patients that they're currently managing, keep getting them to get seizure control, potentially seizure freedom and not have to refer and be able to manage that. And again, all our market research suggests that this is the perfect medication for them to do that. And so I think the messaging for us is going to be around the attributes that we're able to to really see in X-TOLE and what we anticipate, an X-TOLE2. Again, back to my earlier comment. again back to my earlier comment I think with azetukalner , it's very clear that the ease of use, and then you're talking about kind of what will make a difference here. i think with azetukalner it's very clear that the ease of use and then you're talking about kind of what will make a difference here And I think because of the daily dosing, the novel mechanism, no drug-drug interactions, titrated dose right out of the gate. and i think because of the daily dosing the novel mechanism no drug-drug interactions titrated dose right out of the gate Tremendously excited to bring this to the general neurologist. tremendously excited to bring this to the general neurologist So they're able to incorporate this into the patients that they're currently managing, keep getting them to get seizure control, potentially seizure freedom and not have to refer and be able to manage that. so they're able to incorporate this into the patients that they're currently managing keep getting them to get seizure control potentially seizure freedom and not have to refer and be able to manage that And again, all our market research suggests that this is the perfect medication for them to do that. and again all our market research suggests that this is the perfect medication for them to do that And so I think the messaging for us is going to be around the attributes that we're able to to really see in X-TOLE and what we anticipate, an X-TOLE 2. and so i think the messaging for us is going to be around the attributes that we're able to to really see in x-tole and what we anticipate an x-tole 2

Speaker 4: Any other learnings of like what the keys to success are for a branded epilepsy launch and what Xenon may be doing differently or similarly to others? Any other learnings of like what the keys to success are for a branded epilepsy launch and what Xenon may be doing differently or similarly to others? any other learnings of like what the keys to success are for a branded epilepsy launch and what xenon may be doing differently or similarly to others

Speaker 1: Yeah, there's several. I think as I think about commercial success, there are a few different areas. One is it's all centers on the data. Right. So we feel confident there and then it's about how. How do you think about patient identification, the treating physicians and really think about those epileptologists, the general neurologists and also the advanced practice APPs that are in the community that are more and more getting involved in patient management. So we look at where do we think about taking the AZK message depending on where the patients are. So that's the key and then those key messages and what have you. But then there's other key stakeholders involved. Obviously the payer, that landscape is, you know, can underestimate how important that is. Yeah, there's several. yeah there's several I think as I think about commercial success, there are a few different areas. i think as i think about commercial success there are a few different areas One is it's all centers on the data. one is it's all centers on the data Right. right So we feel confident there and then it's about how. so we feel confident there and then it's about how How do you think about patient identification, the treating physicians and really think about those epileptologists, the general neurologists and also the advanced practice APPs that are in the community that are more and more getting involved in patient management. how do you think about patient identification the treating physicians and really think about those epileptologists the general neurologists and also the advanced practice apps that are in the community that are more and more getting involved in patient management So we look at where do we think about taking the AZK message depending on where the patients are. so we look at where do we think about taking the azk message depending on where the patients are So that's the key and then those key messages and what have you. so that's the key and then those key messages and what have you But then there's other key stakeholders involved. but then there's other key stakeholders involved Obviously the payer, that landscape is, you know, can underestimate how important that is. obviously the payer, that landscape is you know can underestimate how important that is And again, I think the ability for us, which we'll start executing on post data late this year, is that engagement with payers. Right. Again, that kind of gap between the last launch to be able to bring them up to speed on the current practice of treating epilepsy patients, seizure patients, and really understanding and letting them understand still what is a tremendous unmet medical need. And so making sure that upon launch that we could have as quick an update as possible. The other component is, you know, that patient experience I think is critical to a successful launch. How do you set up your distribution, your patient support, all those services that really make what I say, you want that patient to have that outstanding experience early on. All those things hinge around. And again, I think the ability for us, which we'll start executing on post data late this year, is that engagement with payers. and again i think the ability for us which we'll start executing on post data late this year is that engagement with payers Right. right Again, that kind of gap between the last launch to be able to bring them up to speed on the current practice of treating epilepsy patients, seizure patients, and really understanding and letting them understand still what is a tremendous unmet medical need. again that kind of gap between the last launch to be able to bring them up to speed on the current practice of treating epilepsy patients seizure patients and really understanding and letting them understand still what is a tremendous unmet medical need And so making sure that upon launch that we could have as quick an update as possible. and so making sure that upon launch that we could have as quick an update as possible The other component is, you know, that patient experience I think is critical to a successful launch. the other component is you know that patient experience i think is critical to a successful launch How do you set up your distribution, your patient support, all those services that really make what I say, you want that patient to have that outstanding experience early on. how do you set up your distribution your patient support all those services that really make what i say you want that patient to have that outstanding experience early on All those things hinge around. all those things hinge around The last thing that I think is absolutely critical is the team that you build. And I think that when I think of a commercial team that we're starting to build, really a lot of deep, deep epilepsy experience both across all facets. Sales, marketing on the payer side. And then I believe one thing about epilepsy and it's a lot of people, if you think about sales representatives, people in the field, MSLs, they commit their careers to epilepsy. And so I think we'll be able to attract the top talent that will want to come with this new medication with the impressive efficacy, the opportunity to bring something new and novel to their customers. And so I think those are the things that I think about that make this a successful launch. The last thing that I think is absolutely critical is the team that you build. the last thing that i think is absolutely critical is the team that you build And I think that when I think of a commercial team that we're starting to build, really a lot of deep, deep epilepsy experience both across all facets. and i think that when i think of a commercial team that we're starting to build really a lot of deep deep epilepsy experience both across all facets Sales, marketing on the payer side. sales marketing on the payer side And then I believe one thing about epilepsy and it's a lot of people, if you think about sales representatives, people in the field, MSLs, they commit their careers to epilepsy. and then i believe one thing about epilepsy and it's a lot of people if you think about sales representatives people in the field msls they commit their careers to epilepsy And so I think we'll be able to attract the top talent that will want to come with this new medication with the impressive efficacy, the opportunity to bring something new and novel to their customers. and so i think we'll be able to attract the top talent that will want to come with this new medication with the impressive efficacy the opportunity to bring something new and novel to their customers And so I think those are the things that I think about that make this a successful launch. and so i think those are the things that i think about that make this a successful launch

Speaker 2: Maybe I could just add, on the talent side, azetukalner based on the profile so far has the opportunity to be a generational asset. Right. The profile is different than we have seen in so long in the epilepsy space. And the team to execute is critically important. You know, Darren joining as chief commercial officer involved in the launch of Epidiolex, the most successful epilepsy launch ever. Darren has already added to his team in terms of head of market access, head of sales and marketing who has probably some of the deepest epilepsy experience over the last two decades. And Chris, on the medical side, we've had MSLs in the field for the last 18 months. So we have already invested in building relationships in the epilepsy community for Xenon as a trusted partner, and is azetukalner a trusted brand. Maybe I could just add, on the talent side, azetukalner based on the profile so far has the opportunity to be a generational asset. maybe i could just add on the talent side azetukalner based on the profile so far has the opportunity to be a generational asset Right. right The profile is different than we have seen in so long in the epilepsy space. the profile is different than we have seen in so long in the epilepsy space And the team to execute is critically important. and the team to execute is critically important You know, Darren joining as chief commercial officer involved in the launch of Epidiolex, the most successful epilepsy launch ever. you know darren joining as chief commercial officer involved in the launch of epidiolex the most successful epilepsy launch ever Darren has already added to his team in terms of head of market access, head of sales and marketing who has probably some of the deepest epilepsy experience over the last two decades. darren has already added to his team in terms of head of market access head of sales and marketing who has probably some of the deepest epilepsy experience over the last two decades And Chris, on the medical side, we've had MSLs in the field for the last 18 months. and chris on the medical side we've had msls in the field for the last 18 months So we have already invested in building relationships in the epilepsy community for Xenon as a trusted partner, a nd is azetukalner a trusted brand. so we have already invested in building relationships in the epilepsy community for xenon as a trusted partner, a nd is azetukalner a trusted brand I think our data disclosure and our relationships and information and scientific sharing with the community has been incredibly well received. We had over 50 employees at the American Epilepsy Society meeting and there's a real buzz around Xenon in the epilepsy community. I think our data disclosure and our relationships and information and scientific sharing with the community has been incredibly well received. i think our data disclosure and our relationships and information and scientific sharing with the community has been incredibly well received We had over 50 employees at the American Epilepsy Society meeting and there's a real buzz around Xenon in the epilepsy community. we had over 50 employees at the american epilepsy society meeting and there's a real buzz around xenon in the epilepsy community

Speaker 1: Well said. Well said. well said

Speaker 6: Tess, will you indulge me with one thing? So just real quick. You know, Ian talked a lot about how well patients are doing in our open label extension study in epilepsy. It's really quite impressive. If you take a look at how they're doing compared to the double blind period, over 90% of them had a 50% reduction in seizures. A lot of the data we show starts at the baseline of the open label. So if one were to compare the phase III open label studies, and one comparison you were looking at the beginning of the double blind and the other you were looking at the beginning of the open label, it would be a comparison that would be tough to make. So I just want to point that out. Thanks. Tess, will you indulge me with one thing? tess will you indulge me with one thing So just real quick. so just real quick You know, Ian talked a lot about how well patients are doing in our open label extension study in epilepsy. you know ian talked a lot about how well patients are doing in our open label extension study in epilepsy It's really quite impressive. it's really quite impressive If you take a look at how they're doing compared to the double blind period, over 90% of them had a 50% reduction in seizures. if you take a look at how they're doing compared to the double blind period over 90% of them had a 50% reduction in seizures A lot of the data we show starts at the baseline of the open label. a lot of the data we show starts at the baseline of the open label So if one were to compare the phase III open label studies, and one comparison you were looking at the beginning of the double blind and the other you were looking at the beginning of the open label, it would be a comparison that would be tough to make. so if one were to compare the phase iii open label studies and one comparison you were looking at the beginning of the double blind and the other you were looking at the beginning of the open label it would be a comparison that would be tough to make So I just want to point that out. so i just want to point that out Thanks. thanks

Speaker 4: Thinking through the expansion potential of azetukalner here, you know, how does the next three to five years look for Xenon if you are successful in both epilepsy and neuropsych versus just epilepsy? Thinking through the expansion potential of azetukalner here, you know, how does the next three to five years look for Xenon if you are successful in both epilepsy and neuropsych versus just epilepsy? thinking through the expansion potential of azetukalner here you know how does the next three to five years look for xenon if you are successful in both epilepsy and neuropsych versus just epilepsy

Speaker 2: Sure. Darren, do you want to talk about kind of the launch first in epilepsy and then as we'd expand? And actually maybe even before that, Chris, one of the things that we haven't talked about today that I think is important is maybe talking about the comorbidities in epilepsy as well, and that we're looking at endpoints of depression and anxiety in our epilepsy studies. That's probably a nice segue to psychiatry. Sure. sure Darren, do you want to talk about kind of the launch first in epilepsy and then as we'd expand? A nd actually maybe even before that, Chris, one of the things that we haven't talked about today that I think is important is maybe talking about the comorbidities in epilepsy as well, and that we're looking at endpoints of depression and anxiety in our epilepsy studies. darren do you want to talk about kind of the launch first in epilepsy and then as we'd expand? a nd actually maybe even before that chris one of the things that we haven't talked about today that i think is important is maybe talking about the comorbidities in epilepsy as well and that we're looking at endpoints of depression and anxiety in our epilepsy studies That's probably a nice segue to psychiatry. that's probably a nice segue to psychiatry

Speaker 6: Sure. We haven't shared the baseline characteristics of X-TOLE2 just yet, but we're expecting them to be quite similar to X-TOLE. Depression, anxiety, migraine, headaches are all very common comorbidities. We're expecting to be able to gather that data in the ongoing phase III program. Sure. sure We haven't shared the baseline characteristics of X-TOLE 2 just yet, but we're expecting them to be quite similar to X-TOLE. we haven't shared the baseline characteristics of x-tole 2 just yet but we're expecting them to be quite similar to x-tole Depression, anxiety, migraine, headaches are all very common comorbidities. depression anxiety migraine headaches are all very common comorbidities We're expecting to be able to gather that data in the ongoing phase III program. we're expecting to be able to gather that data in the ongoing phase iii program

Speaker 1: Yeah, I think, you know, obviously epilepsy is the focal seizure launch is the initial focus. But if we were being so fortunate to have great data in MDD, that's a tremendous opportunity and we would pivot to, you know, building out that psychiatry business. And again, Ian pointed it out today, tremendous unmet need. A lot of patients that suffer with MDD that could be helped by the novel mechanism, the rapid onset and really, really favorable safety profile. So, yeah, tremendous. That would be. That'd be a nice outcome. Yeah, I think, you know, obviously epilepsy is the focal seizure launch is the initial focus. yeah i think you know obviously epilepsy is the focal seizure launch is the initial focus But if we were being so fortunate to have great data in MDD, that's a tremendous opportunity and we would pivot to, you know, building out that psychiatry business. but if we were being so fortunate to have great data in mdd that's a tremendous opportunity and we would pivot to you know building out that psychiatry business And again, Ian pointed it out today, tremendous unmet need. and again ian pointed it out today tremendous unmet need A lot of patients that suffer with MDD that could be helped by the novel mechanism, the rapid onset and really, really favorable safety profile. a lot of patients that suffer with mdd that could be helped by the novel mechanism the rapid onset and really really favorable safety profile So, yeah, tremendous. so yeah tremendous That would be. that would be That'd be a nice outcome. that'd be a nice outcome

Speaker 4: Just last question for me here is just on formulation. Are you exploring any other formulations of azetukalner? Just last question for me here is just on formulation. just last question for me here is just on formulation Are you exploring any other formulations of azetukalner? are you exploring any other formulations of azetukalner

Speaker 2: Are you specifically thinking about intravenous? Yeah. Yeah. So often in epilepsy, we think about kind of two parts of life cycle management. One is on the pediatric side and one is on the IV side. So, yes, all of that work is ongoing. We have agreed upon pediatric development plans with FDA as well with EMA. So over time, we will get into younger and younger patients. Obviously, adolescents can take a pill, but as you get into younger patients, you need a specific pediatric formulation. So a lot of that work has already taken place, and we'll get into younger patients over time. The other thing, often that the epilepsy community is asking for is whether you have an IV formulation. So as patients come into the hospital that they may start on an IV formulation and then they leave the hospital with an oral formulation. Are you specifically thinking about intravenous? are you specifically thinking about intravenous Yeah. yeah Yeah. yeah So often in epilepsy, we think about kind of two parts of life cycle management. so often in epilepsy we think about kind of two parts of life cycle management One is on the pediatric side and one is on the IV side. one is on the pediatric side and one is on the iv side So, yes, all of that work is ongoing. so yes all of that work is ongoing We have agreed upon pediatric development plans with FDA as well with EMA. we have agreed upon pediatric development plans with fda as well with ema So over time, we will get into younger and younger patients. so over time we will get into younger and younger patients Obviously, adolescents can take a pill, but as you get into younger patients, you need a specific pediatric formulation. obviously adolescents can take a pill but as you get into younger patients you need a specific pediatric formulation So a lot of that work has already taken place, and we'll get into younger patients over time. so a lot of that work has already taken place and we'll get into younger patients over time The other thing, often that the epilepsy community is asking for is whether you have an IV formulation. the other thing often that the epilepsy community is asking for is whether you have an iv formulation So as patients come into the hospital that they may start on an IV formulation and then they leave the hospital with an oral formulation. so as patients come into the hospital that they may start on an iv formulation and then they leave the hospital with an oral formulation So that works ongoing as well. So that works ongoing as well. so that works ongoing as well

Speaker 4: Great. Thank you. Great. great Thank you. thank you

Speaker 6: Thank you. Thank you. thank you

Speaker 2: Thanks, Tess. Thanks, Tess. thanks tess

Speaker 1: Thanks. Thanks. thanks