All right. Guess we'll get started here. So my name is Peyton Bohnsack. I'm one of the vice presidents. I'm in the biotechnology equity research sector. I'm joined by my colleagues, Divya Rao, Athena Chin, and then our distinguished panelists, from Ardelyx, we have Susan Rodriguez, our Chief Commercial Officer. From Kezar Life Sciences, we've got Chris Kirk, CEO and co-founder, and from Milestone Pharmaceuticals, we've got Joseph Oliveto, CEO. Welcome to the second day of our conference in this Cardio-Renal Corporate panel. We'd like to start off these panels with thematic questions about the overall landscape that the companies are developing in So I guess to start out, I guess on the top of everyone's mind, there have been a lot of recent developments in the cardio-renal space, but one that's really taken a lot of precedence is this, the development of GLP-1 agonist, which we believe kind of has changed the landscape for cardiovascular, renal, and metabolic disease, as obesity is often correlated with many cardio-renal disorders. So I guess the question that we'd like to pose is: how has this changed the development in this space broadly? How much of an impact do you think this will have on prescribing patterns, reimbursement, general patient perception in the, in both the short term and long term, and how does this change your guys' commercial outlook? I guess we'll kick this over to, Susan first. Oh, great. Well, so for the one individual on the panel who has a drug for patients with CKD on dialysis, I think you might think it's, it's, less influential for us, but, from our perspective, it is fantastic the amount of data that's being generated, both with, GLP-1 and SGLT2. I mean, the amount of data generated around the kidney protective effects, I think it's putting a lot of pressure on payers to have to cover these novel drugs for patients with CKD. So I think it's been really transformative in the CKD space and really gives nephrologists, so many new therapies in their treatment armamentarium to manage patients, in CKD before they enter dialysis. So I think it's just been a really phenomenal, impact on patients with CKD in the nephrology space. Yep. What about, you, Chris? Anything to add to that? So for what keys are focus is on, which is inflammatory nephritic diseases like lupus nephritis, the GLP-1 agonists don't have as much of an impact. Where we're dealing with sort of an emerging therapy that's garnering a lot of attention these days is CAR T therapy, which is starting to take hold in terms of mind share within the rheumatology and the nephrology community as we try to develop a more simplified small molecule approach to immunomodulation with Finally, last but not least, what about you? Yeah. Well, I think, you know, for us, we're in the arrhythmia space, and, you know, we see two kind of dynamics happening with the focus on weight loss and diabetes. One being that payers are really needing to figure out how- Right. They're going to handle this onslaught of patients that are coming in with these new technologies that are just absolutely phenomenal. So I'm really just proud to be in the industry when these are happening. But, you know, for our value proposition, dealing with arrhythmias, really the opportunity to save costs by preventing people from being treated in the nursing department in the hospital is a big plus. So we think we could help the system and help them manage budgets. I think from the perspective of the weight loss companies needing to articulate cardiovascular claims now, which is needing to call on cardiovascular calling on cardiologists, it helps us in terms of how we think about getting in, getting access to these patients to these physicians. And again, we think we have a great story that can complement, you know, general health and benefits that come from obesity, weight loss, that they're gonna be espousing, I would say. Great. Okay, good to Divya, for our next one. Yeah, so, just given the wide range of generic options that are available for both, you know, cardio-renal diseases, across the board, how do you feel like you're thinking about, like, go-to-market strategy when, you know, there are other options available out there? How, how are you thinking about highlighting what differentiates your specific therapies over kind of what is now generically available and obviously much cheaper? So maybe we'll start with you, Chris. Sure. So, lupus nephritis is the renal manifestation of a generalized immune dysfunction disorder, lupus disease. Most patients are treated by their rheumatologist, and they're both interested in dealing with their rash, their joints, their fatigue. They're a little less concerned about what's going on in their kidneys because they can't quite feel it, though it will ultimately lead them to end-stage renal disease and need for dialysis and transplant. The available medications to patients with lupus and lupus nephritis are broad-based immunosuppressive agents like CellCept and prolonged corticosteroid. Both of these have high burden to the patient, both, medically and economically, due to lost time at work due to immunosuppression and increased infection risk, changes in risk of diabetes and bone mineral density loss from the prolonged corticosteroid use. Where we see the advantage of zetomipzomib is that it can treat both the lupus and the lupus nephritis, providing a major impact for those patients immediately that they can feel, and then for long term, in what we hope to show, which is protected kidney restoration or kidney function restoration. You want to go, Susan? Oh, sure. Yeah. So I think, you know, for Ardelyx, we're an innovation-centered company, with our focus on discovery, development, and commercialization of first-in-class mechanism drugs. So we're entering into exactly what your question is, established therapeutic areas, but with a high level of remaining unmet need, and actually limited options. So we've demonstrated this in both cases.... for our drug, IBSRELA, for IBS-C, and limited, the treatments were limited to one class of therapy, and if that didn't work, patients had no other option. So, so it's an innovation centered on addressing an unmet need. So we're really not competing with the alternatives. We're really providing a new option where patients didn't have one before. For XPHOZAH, for the treatment of hyperphosphatemia in CKD patients with dialysis, it's a very analogous situation where the as much as everybody is aligned to aggressively treating phosphorus levels to achieve target levels, despite best efforts with the available therapies, they're limited to one class of therapy, binders, which are generically available. And despite best efforts, approximately 70% of patients are unable to maintain their target levels over a six-month period. So, so now those patients where before, despite treatment with binders, are still not at target levels, had no option. XPHOZAH is now a novel mechanism option, the first-in-class phosphate absorption inhibitor. So our go-to-market strategy is really focused on not competing with these generic therapies, but really addressing the unmet need that exists in the space, leveraging the novel mechanism profile of the drug, the favorable clinical data profile of the drug, and our go-to-market strategy, you know, very much centers on assisting offices access the drug through the prior authorization process. So you need to commercialize a drug with that in mind, 'cause implicitly, that will be what the coverage policies will define. So success will be determined by the nephrologist, you know, in this case, XPHOZAH nephrologist, motivated to go through the prior auth process. The fact that the patients meet the criteria because they've been tried on the limited options, and they are not well controlled and are candidates for XPHOZAH, and then enabling the patient to afford the drug. The whole access strategy really centers on how to commercialize a drug successfully through a prior auth process, which is only possible if it's an innovative therapy that addresses an important, recognized unmet need, which is the case for our portfolio at Ardelyx. Do you guys have anything to add now that, with your focus more on the cardiovascular side? Yeah, no. In the world of tachycardias and Milestone's focused on two, in particular, PSVT, paroxysmal supraventricular tachycardia. It's a mouthful. Probably a lot of the audience would not have heard of that, but atrial fibrillation is our second indication, which I'm sure everyone's heard of. And, and in the world of both of those tachycardias, patients get very rapid heart rates. They feel it, and interestingly enough, the generics that are used are IV forms, but they're actually costly because they come with trips to the emergency department, the cost of the emergency department, and in the case of PSVT, probably about a third of those patients wind up getting into the hospital, taking, if you want to call it, an inexpensive, generic emergency department visit from $1,500-$ 10,000 you know, $10,000-$ 15,000 for overnight stays in the hospital. In the case of AFib, it gets worse, more elderly population. If you're taking a trip to the emergency department, AFib will drive you in there, but there's just a caution and the need for oversight that will keep you in there, right? So actually, generics in the world of our world of tachycardias are expensive, right? There's no reason, and doctors are trying very hard to treat their patients at home, and, they use whatever's available. They'll use oral drugs off-label because they want to get something, and they're just really fighting very hard to have their patients cared for in a more comfortable way and a way that is not as costly to the system, but also to the patient and to the doctor. The doctor's getting these calls when they show up at the emergency room. They have other life-threatening conditions to worry about, you know, so they're inundated with calls. Patients are hit with big bills in the emergency department, depending on their insurance coverage. So our approach is, if we can deliver our technology, which is a very potent calcium channel blocker, that's a nasal spray, and you can do that safely at home, then you can resolve the tachycardia quickly or bring down the heart rate and allow the patient to feel better, they'll hopefully not go to the emergency department. In our studies, 40% fewer emergency department utilizations as a result of using our drug compared to placebo. So we feel that it's actually less expensive to use the innovative drug in our particular area. Does take a little bit of a mind shift, but the beauty-- the other kind of benefit of our technology is a calcium channel blocker. So physicians, patients are already used to getting those in IV form in the emergency department, just really bringing it to the at-home setting. Relatively simple story, but a big piece of it is the pharmacoeconomic piece of just using care efficiently. Got it. So the Cardio- Renal Division at the FDA has seen shifts in regulatory policy on registrational endpoints. Specifically, biomarkers have seen mixed success for supporting registration, and demonstrating functional clinical benefit. An example would be mortality with outcome measures isn't usually feasible for a typical one to three year timeframe. What kind of strategies are you able to kind of pursue to get around this? And how do companies like you guys decide whether to approach a development strategy based on clinical endpoints, biomarkers, or the use of placebo/standard of care comparators? Maybe we'll start with Susan. Yeah. So it's good to start with me because we are on the successful end of a biomarker-centered development and approval program. So, XPHOZAH was approved on the basis of, phosphorus levels as the biomarker. So I think it really is a fantastic example on how biomarkers can enable, you know, the development of innovation and bringing this innovation to market, you know, to patients who really have a high level of need for novel mechanism therapies. Prior to the submission of XPHOZAH, there had been other drugs approved on the basis of the phosphorus reduction biomarker. So, you know, so we really were fortunate to be able to pursue that path, and, and the result is the drug is now approved, and patients who didn't have an option before, who, weren't adequately managed on binders, now have a novel mechanism option. ... Thank you. Chris? So, we actually are not with the cardiorenal group. We're part of DPARP, so the rheumatology division. Mm. We had a choice to make- Mm. When we were developing zetomipzomib, because as a selective inhibitor of the immunoproteasome with broad immunomodulatory activity, we didn't want to restrict ourselves just to renal outcomes in lupus patients. We wanted to be able to treat all of the lupus and other rheumatic diseases, so we went to the rheumatology division. That said, there are two drugs that are approved in LN. One is voclosporin, a calcineurin inhibitor, that made its way through to approval with cardiorenal, and utilized in essence a surrogate endpoint, achieving a complete renal response in LN patients, getting their UPCR to below 0.5, so dramatic proteinuria reduction, maintaining normal GFR, and keeping a low steroid dose. Similarly, Benlysta or belimumab, which already had a label in lupus through DPARP, achieved a similar success in LN, utilizing a similar endpoint, though it took them a two-year study to get there. So both divisions sort of accept the same endpoints. LN doesn't have an FDA guidance around it as to what will be required for ultimate approval, though we do feel it will be two randomized studies with those proteinuria endpoints, along with maintaining a low steroid dose in those patients. Athena, I'll be a little contrarian. Biomarkers scare the hell out of me with cardiorenal. I why? I, you know, I, you know, went through cardiorenal. Now, this is my second time. I was with a company called Chelsea Therapeutics, where we- Mm. We were in an area of neurogenic orthostatic hypotension, so trying to reduce blood pressure in a subset of Parkinson's patients. And we got approved based on a surrogate endpoint, contingent upon showing, you know, post-marketing studies, and our competitor never showed post-marketing study success. So the agency was left in a real quandary about what to do with the, with the drug. They, they actually wanted to pull it off the market. This was our- Mm ... competitor's product, and there was an outcry from the community because it was a very useful drug. FDA listened to the physicians and to the patients and left it on. But it really leaves them in a tough spot for how to handle. Mm ... when the biomarkers don't exactly work out the way they're supposed to post-market. Mm-hmm. In this company, I love the fact that we're working on tachycardias. I love the fact that- Mm ... you break the tachycardia, you know? Forget about biomarkers. Forget about surrogates. It's just measurable. It's very simple. Mm-hmm. It's not simple to do, but it's simple to measure, and that's- Mm-hmm ... a great benefit of, of where we are now. So I could sleep a lot better at night—not having to worry about this, but— Mm-hmm ... let's stay informed just how you guys are doing. Thanks, Joe. Back to you, Peyton. Yeah, I guess maybe to follow that up, since some of you guys have had experience with different divisions in the FDA, do you see that there's a difference between the cardiorenal division when it comes to, like, flexibility compared to, like, say, rheumatology or gastroenterology? Mm-hmm. Mm-hmm. Yeah, across my career, I've been across three or four different divisions, and I've been in cardiorenal now probably for the last 10 or 15 years, so I'll stick to those guys. It's hard to compare, but you know, I really think cardiorenal is very practical thinkers. I think there are certain areas where the rules of the road are the rules of road, and you know that going in, and I really value that from cardiorenal. In areas, you know, where- Mm ... it does take a little scientific thinking. To me, they're very practical about how they think about things, and I think they're one of the, in general, better divisions for that in terms of practicality and thinking about the patient first. Anything to add on that? So, you know, I cut my teeth working in the oncology division in the discovery and development of Kyprolis, first at Proteolix and later at Onyx and Amgen. And so when we started down the path of working with the rheumatology group, we were expecting a conservative group, but they've proven themselves to be one that's, like all FDA divisions, looking for therapies that provide an adequate risk-benefit analysis for the patients that they're trying to treat. And this has been true with our work in lupus and lupus nephritis with the rheumatology group. It's been, although early days, also true with the gastroenterology and metabolic group for our autoimmune hepatitis study, which we call PORTOLA. They're data driven, and provide good guidance for us as we think about drug development across a continuum of autoimmune disorders. Yeah, I would just say, I think it's less to do with the actual division and more about the condition itself- Mm ... how well navigated it is, the clarity of the endpoint, how measurable the endpoint is. Mm-hmm. So good for you. That's one regulatory risk - you can take off the table. You know, and, and really making sure to work in partnership when you're designing the clinical program. Great. So we're gonna ask, switch over to some company-specific questions going round robin. We're gonna do this in alphabetical order of the name of the company, so let's start with Susan again. Great. So in January, you guys recently announced that you were gonna double your peak sales projections for IBSRELA, which is, you know, indicated for IBS-C. What gave you the confidence in doing that? And I know you were instrumental in helping launch this. Mm-hmm. Can you maybe give us just, like, a little bit of background about why you chose to launch in this, and then how you moved forward to actually doubling these numbers and- Yeah, thank you, Peyton. Excellent. So, you know, we were very confident when we launched IBSRELA as a first-in-class mechanism drug, that there, you know, there was really an established unmet need in this space. And even though a lot of doctors write for IBS-C, half of this prescription volume is actually concentrated in 9,000 HCPs. So we know the HCPs that are seeing these patients and have already cycled through the limited options, which is one class of therapy, GCC agonist. And our research clearly showed, physicians said, once we use a GCC agonist, they repeatedly said about a third of their patients have persistent symptoms and they consider to be inadequately managed, which they also reported is not surprising because they see IBS-C as a condition of multifactorial pathophysiology. Therefore, it's not surprising that one mechanism of therapy isn't going to be enough to cover the full needs of the patient. So in our go-to-market strategy, we very much contemplated that we were focused on these high-writing HCPs to address this very well recognized unmet need to be the next alternative after the patient cycles through the GCC agonist. And so that was our go-to-market approach, and we actually had experienced really early success. You've seen consistent, persistent growth and uptake of IBSRELA across this target HCP base. So the patients are there every day. The coverage policies define a path to access that says the decision has to submit the prior auth to attest to the fact that the patient had been tried on a GCC agonist and needed a novel mechanism approach. So, with our early success on the nice coverage policies in terms of path to access, our committed patient services program and specialty distribution focus to support offices with the prior, and to support patient affordability, we saw a consistent and persistent uptake of IBSRELA. And that is at a price point that we established that reflects the value proposition of IBSRELA, that it's unopposed. For the patients where GCC agonists don't work, there is no other alternative. So, we did establish a novel price point in the space as well. So with all of this moving forward, a critical learning, as the quarters passed of launch, showing persistent, consistent growth, is the extent to which the space is highly promotion sensitive. So we find that when a doctor sees a rep, they start writing IBSRELA. The more frequently they see the rep, the more they write IBSRELA. And what we're finding is because of their early, favorable clinical experience and access experience, doctors are now beginning to expand their view of patients who could be candidates for IBSRELA. So, you know, our success now is actually changing, disrupting the marketplace, changing the way the physician looks at IBS-C now that they have this expanded treatment armamentarium. So with the view of the potential IBSRELA has to penetrate the space because of the patients that are in those offices today, we believed it was important to let the community know that we see the potential to achieve a 10% market share position as achievable, which with, you know, it's a 5 million script market about growing 5% a year with annual price increases, you know, is really what takes you to make IBSRELA a billion-dollar product. And so we're investing, you know, in our promotion, seeing that it's promotion sensitive, to make sure we realize the full potential for IBSRELA. Yeah. I think, yeah, we're definitely optimistic about it. I'm glad that it's been taken up so well. Moving on to kind of like the other side of the business, which is the XPHOZAH for hyperphosphatemia. Mm-hmm. I guess, what, metrics do you plan on providing going forward? I know you gave a lot for IBSRELA, and then could you basically outline how the IBSRELA launch prepared you for the XPHOZAH launch as well? Okay, great. So in terms of metrics, it'll be very similar to what we provided for IBSRELA, which is we'll provide our revenue numbers that are linked to the bottles that we sell into our distributors, and we'll give you details around our gross to net profile as well. So in time, you know, that will be the metrics we will provide for XPHOZAH. In terms of IBSRELA preparing us for XPHOZAH, I mean, as I mentioned before, just in the core of the company is innovation-centered, first-in-class mechanism drugs, high unmet need, established therapeutic areas, you know, with limited options. So both products really are parallel in that regard. So our leadership team really has a very strong capability around how do you introduce a novel mechanism therapy to... How do you make sure to work with doctors to let them for them to realize that now what was an unmet need, where they had no option, now there's a new option, and to really expand their thinking on how they're treating a condition and incorporate a novel mechanism product. So all that know-how, which obviously requires strong scientific go-to-market messaging, strong clinical data program, engaging with the opinion leader community, you know, you're disrupting the way a condition is being treated. And in parallel to that, you're engaging with payers to make sure that there is a path to access defined, and then your engagement with the office and patients to make sure that the prior auth gets submitted and that the patient can afford your drug. So all of those capabilities really, really fuel the growth of both IBSRELA and XPHOZAH. With all that said, so there's all those synergies on our go-to-market approach and capability, but actually, focus on the physicians prescribing these therapies is very singular, very dedicated. So we have a dedicated sales force focused on the HCPs that are high prescribing for IBS-C, for IBSRELA, and we have a separate dedicated sales team calling on the nephrology call point for XPHOZAH. So that's where specialization and dedication is really critical, and then, you know, fueled by the synergies of our commercial go-to-market strategies. Great. I'll kick it over to Divya. Mm-hmm. So I'll turn it to Kezar. Zetomipzomib, obviously, Kezar's lead asset, and full data from the MISSION trial was presented, I guess, late 2022. Can you kind of walk through the data? And then I think most importantly, I think one of the questions that investors always ask us is about, obviously, it's not placebo-controlled. How are you confident that- ... you know, specifically in LN, where you have high placebo rates, how are you confident that the numbers that you saw with Zeto are real, and they're compelling enough to move into a potentially registration trial? Yeah. So we embarked on the MISSION study with zetomipzomib during the height of the COVID pandemic, when patients were not showing up to clinic, particularly those patients with autoimmune disorders. And so we made a calculated decision. The endpoint in LN studies is proteinuria changes, and that's a pretty hard and fast objective endpoint. And so knowing that this was a proof of concept study to tell us, did we have a drug in LN to bring into larger randomized trials, it was worth running an open label study to get data in a timely fashion and then go talk to regulators. So we chose to treat patients whose lupus nephritis had been inadequately treated with their standard of care, mycophenolate and prednisone, daily prednisone usage. A large number of patients had had calcineurin inhibitors and other active therapy in LN. A lot of patients had had experimental biologics like rituximab treatment in their past. From those 21 patients that were enrolled to six months of therapy, 95% of the response-eligible patients achieved at least a 50% reduction in their proteinuria. That's clinically meaningful. A further 35% achieved what's called a complete renal response. That means their UPCR got to 0.5 or less. That's what will help you prevent end-stage renal disease and need for kidney transplant. Their steroid dose went down to 10 mg or less, and their GFR either didn't worsen or normalized over time. It was really compelling data to us in large part because we didn't have to give the patients what's called induction therapy, high-dose IV corticosteroids, which do a really great job of walloping the inflammation. They also do a really great job of inducing frank immunosuppression in these patients. And during COVID, we were concerned about that. So this novel approach, which quite frankly represents a more real-world way that lupus nephritis patients are treated, was compelling to us. It was a challenge to the investment community because, of course, they don't have a way to compare this to other trials. Mycophenolate mofetil and a calcineurin inhibitor, two large randomized trials with 35-ish% complete renal response rate, so about the same as us. Benlysta, a two-year trial that got to about 32%-33% complete renal response rate. So again, we're in that ballpark, but without placebo control, it's hard to know. In LN studies, with that in IV steroid usage, you can expect 20% of the patients to achieve a complete renal response and about half of the patients to have some form of overall response. So our 35% CR rate and our 95% overall response rate, we feel, is compelling. And of course, more importantly for us, it enabled us to go talk to the FDA and EMA, have a discussion about what trial design should look like for the next study in LN, and bring that to patients, which, of course, is a randomized trial, which will give us and everyone else very much unequivocal understanding of how good of a drug Zeto actually is in this space. Based on that data from the phase II, and I guess also with your conversation with physicians, how do you see Zeto filling in or fitting in or fitting into the current paradigm, treatment paradigm in LN? So, I spend these days a lot of time talking to physicians. You know, when we started Kezar almost nine years ago, lupus was an area of very little drug development work, and LN even less so. Now there are tons of entrants, whether it's lifecycle management of drugs like Rinvoq and Sotyktu, emergence of CAR-T therapy coming from oncology into the LN space, or further development of drugs that have already been approved in lupus, like Saphnelo from AstraZeneca. So, for the physicians, they have a lot of choices, and what they're looking for for their patients, first and foremost, rapid responses, particularly in LN. You want to get that proteinuria under control. You want to get those steroid doses down to as low as possible. Can this be done both conveniently and without immunosuppression? We have data, both randomized and in open label, to show that Zeto has very little risk for immunosuppression. And then finally, and as I mentioned in the beginning, it's predominantly rheumatologists who are treating LN patients, about two-thirds of LN patients being treated by rheumatologists, and they want to treat the lupus. They want that rash to go away. They want their joints to feel better. They want their fatigue to go away. So you need a drug to treat all of the lupus, not just the kidney, and we've seen that with Zeto in spades. Rash gets better, fatigue scores get better, global assessments get better, serologic markers get better. It's not just a drug for the kidney, it's a drug for lupus. and we're developing it that way with key secondary endpoints around non-renal lupus measures in our ongoing PALISADE studies. So, Joe, on your lead asset, etripamil for PSVT, you submitted the NDA last October but received an RTF in December 2023, with the FDA asking for clarification on the adverse event timings between the clinical trial, device recordings, and patient-reported weekly visits. So I know you held a Type A meeting recently to discuss resolving these issues. Could you just remind us, what did the FDA request prior to the upcoming resubmission for your NDA? And then I have some follow-ups after that. Yeah, sure, Athena. You're exactly right. We received the RTF from the FDA right before Christmas, and it was a very specific request, just to orient the audience to it. It was around, you know, the timing of adverse events. So no questions as to the safety, but when you're dealing with this 60-day review period, it's not about-... It's more about do you have all the pieces or does the FDA have all the pieces to make the review complete? And they had questions and were obviously confused about the idea of when patients reported the exact time of an adverse event. Sounds like a simple issue. In our world, time is very important to us. We go down to the second, because that's our primary endpoint. But when you ask a patient to come back a week later from having an event and report their adverse events, they might not remember down to the minute. So it's very logical as to why there's questions of timing and the exactness of reporting an AE time compared to your primary endpoint is different, but the FDA needed some clarification on that. We did that. We had the Type A meeting just last Monday. We announced the release of a path forward, which is basically that upon understanding this, the FDA was comfortable that they could complete the review on safety. As a result of this, they actually dug into the safety a little bit, so we feel like we're a little ahead of the game now. The path forward, specifically for us, which we'll get done and we committed to resubmitting next quarter, is, you know, really just supplementing our NDA with a little bit of a different view as to what treatment emergent is, so a time window around when patients report their adverse event. So it's a relatively simple thing to do for us, and we'll also provide them some updated ECG formats. Very technical item, but they learned that their formatting of how they want ECGs don't give them all the info that they really will need for their analysis. So we'll do that as well. So really technical things that will just get done expeditiously and get it in, and allow the rest of the review to happen. Just to be clear, there was no kind of reanalysis that was required or reconciliation of your adverse event? No, it's just a supplement to go into, to help the statisticians do their work around treatment emergence. Got it. Yeah. What does that review timeline look like after you resubmit the NDA? Yeah, we're in a standard review cycle, so, we guide investors that, you know, just as an easy rule of thumb, think about it as 12 months from the submission. So if we submit in Q2- Mm-hmm. Of this year, we'll be looking at a PDUFA in Q2 of next year. Could come in a little quicker, especially given the FDA's already completed this 60-day review. There's a question as to whether they would need all 60 again. Mm-hmm. But for conservatism, we're not into the full 12 months from submission. Understood. Thank you. Yeah. Okay. So moving back, we're gonna just do now one question in round robin style. So I guess one of the major outstanding questions that we usually get is, what is Ardelyx strategy? Is it, oral-only drugs are included in the ESRD bundle? So inclusion is currently set to occur on January 1st, 2025, and there has been, you know, some precedent that this has been delayed previously. And there is also a bill, H.R. 5074, that has been introduced that would delay it until 2033. Mm-hmm. I guess three main points on this is, how likely do you think is that the oral drugs will be included in the bundle, given the previous precedents, and the current political climate around pricing and access? How does this change your internal peak sales estimates and number of patients, suppose it is included or not included? And then finally, I guess, how are you thinking about the timing for a TDAPA payment, and what is the overall timeline for that? Okay, great. I'll try to remember all those questions. Thank you for talking about your, your challenge and how you're overcoming it. So let me just take a step back for those in the audience who may or may not have all that background. So ultimately, as you noted, including phosphorus-reducing agents on the Medicare side of the business as part of a ESRD bundle, has been delayed three times historically, and it's up based on bills that are passed through Congress, and there's another one waiting that would delay it to 2033. So that's really the good news. And what's important to consider there is that this bill was sponsored by Buddy Carter. It has bicameral, bipartisan support. The entire kidney community is in support of this bill. They believe that adding phosphorus-reducing agents into a bundle payment system for Medicare is bad for patients. It's bad treatment for patients. So every stakeholder across the nephrology community is behind this bill and delaying adding these, these drugs to a bundle payment system. We have no opposition to it. There's no one opposed to it. So in terms of your the, how you led your question on the probability it will pass, you know, I cannot answer that. So I think we all understand, you know, the situation right now in Washington. So, but the good news is, everyone's behind it. They say it's bad medicine, and the bill is waiting. It has all the support it needs, and there's a lot of energy behind making sure patients have access to innovation around phosphorus-lowering therapies and the importance of patients having access to XPHOZAH. So, so we have to wait and see how that progresses. Again, I think it's important to set context because we've launched—you know, we've launched XPHOZAH shortly after approval in November. You know, we're off to a very nice early start with uptake from the nephrology community. Our research showed that there was high awareness, interest, intent to adopt, and our experience on the market has shown exactly that. We have coverage policies emerging from all payer segments that define a path to access for XPHOZAH based on the really very consistent with its indication, which is patients inadequately managed on binders, then would have access to XPHOZAH, so inadequately responding or intolerant. So, we have nice coverage policies, path to access. Nephrologists are adopting the drug across all payer segments, and so our mix right now of XPHOZAH prescriptions, as of today, which is still very early in the launch, is 55% Medicare and 45% non-Medicare. So your question, you know, specifically is, you know, a headwind that we're gonna need to navigate around that Medicare subset of the business. Should the bundle not be delayed, despite everybody's best efforts and support and the fact that it's bad medicine, it does move into this transition period where it moves on the Medicare side, XPHOZAH from a Part D pharmacy benefit drug to a Part B drug, and then through the transition period, it's paid, based on ASP. So that's the period where CMS, the rationale is that they use that period to collect data on utilization, and then that it's based on that utilization over the transition period, that they then calculate the rate that will be added to the bundle to cover phosphorus lowering therapy. So, it's really unprecedented for oral, chronic oral medications that were historically paid through pharmacy benefit to move into this kind of a system. Every other drug that has gone through this process is an infused drug as part of the dialysis procedure. So this is chronic therapy, taken daily, that actually can't be taken at the time of the dialysis procedure. So exactly how this will work in that transition, during TDAPA is, is really very hard to predict. You know, as an innovation-focused company, we will be, you know, quite dedicated, very persistent in doing everything we can to make sure that all patients who need XPHOZAH will have access to XPHOZAH. Great! Kicking it over to Divya. You mentioned the PALISADE study that you're running, which is one of potentially two registrational trials. Can you talk a little bit about the trial design, you know, how that design came up with... How you came up with that with the regulators, and then when we could see potential initial data from that trial? So as I mentioned, the MISSION study was an open-label trial in patients with active proliferative lupus nephritis, otherwise known as Class III or IV disease. Patients weren't required to undergo the standard care, which is IV pulse steroids, followed by immunosuppression, usually with mycophenolate or CellCept, for six months and then evaluation. We were so compelled by the data, that we went to the FDA to say: We don't believe IV induction therapy is needed. And in fact, only a few of the patients had even had prior induction therapy in the past, and they had responded well to Zetomipzomib, when they did receive it, as part of the trial. That negotiation with the FDA was a challenging one, but ultimately, the FDA said, "You need to offer patients, per guideline, this IV induction therapy." So we set up PALISADE to study two different dose levels of Zetomipzomib versus placebo. One year of treatment, which is standard in the field. Patients will be stratified as to whether they receive or don't receive IV induction therapy. Everybody gets CellCept and oral corticosteroid prednisone doses in the 40-60 range to start off with. Everyone will have a rapid tapering of their steroid dose. We'll be monitoring proteinuria every month. The key endpoints, the primary endpoint is after nine months of therapy, but other key secondary endpoints are at six months and one year, to sort of meet with the treatment guidelines. This is a 279-patient study enrolling globally. We, like others, expect heavy enrollment in Latin America and the Asia-Pacific region. We anticipate a study readout in mid-2026. I know you mentioned this a couple of times before, but based on your conversation with regulators, I guess how necessary is that second trial? Do you think that if PALISADE was positive, do you think that there's any flexibility with regulators that you might have in just running one trial for a potential approval? Yeah, I'm not going to go down the path of reading lines of the FDA. That usually gets you in trouble. Mm-hmm. The precedent says, one of the two following things to get a drug approved in lupus nephritis: two large, randomized, well-controlled studies, PALISADE would count as one of them, and a follow-on study wouldn't have to test multiple dose levels, most likely just a single dose level of Zeto versus placebo. The other way is the Benlysta route, which is to get a label in lupus and then run a single confirmatory study in lupus nephritis. We're focusing on the LN development. So our anticipation is that following PALISADE, there'll be some form of confirmatory registration study in LN, or maybe we might be so bold as to consider a combination of lupus and lupus nephritis. Mm. Joe, let's take a step back and just think about the larger PSVT commercial opportunity. Can you remind us where etripamil will fit upon potential approval, what the market size is, and what percentage of PSVT patients would be eligible for this therapy? Yeah, no, PSVT is probably the biggest indication no one's heard of. There's actually two million patients in the U.S. today living with PSVT, and it's, it's just a... It's kinda disheartening, but classic example of the drugs that are used there, of drugs that don't work, quite honestly. There's one procedure that works. It's called an ablation. Cardiac physiologists will go in and burn a portion of the patient's heart to sever these pathways. But really, the learning for Milestone, very early in our development, was that the vast majority of patients, some 80% or 90%, do not opt for that. It's a relatively successful procedure, but it is scary. It is heart surgery for, or heart procedure for people that are generally otherwise healthy, and we've seen this over and over again in the claims data. So where, what's available for them other than that, which is the 80% of the market, if you will? Well, you can go to the emergency department, and if you're in an episode and get a drug called adenosine, then it stops your heart. It literally stops your heart. Flatlines you. It's only for a few seconds, but, you know, it's tough. I mean, I've never had it, but I hear hundreds of patients tell me about this experience. What I'm sure everyone in the audience has dealt with is going to the emergency department, and, it's only gotten worse after COVID, right? You do not want to go there. And then put on top of that, that someone's gonna stop your heart for a little bit. It's, it's not a good experience. So it's a lot of these patients are faced with, "What do I do when I get an episode?" Your heart's going 200 beats a minute, you feel it, you feel sweating, you feel anxious, you feel nausea, you know, these types of things. You can't carry on with your day, but then you have, "Do I go get my heart stopped? And by the way, that's gonna take a few hours, and then maybe they'll admit me," et cetera, et cetera. "What do I do with my kids? What do I do with my job?" This is what goes through their mind. Other options available are all off-label. They'll try oral drugs, you know, to reduce the number of episodes. About two-thirds of patients will try that. Two-thirds of patients in our trial are on those oral drugs. They still have episodes. The last resort is the doctor will ask them to pop a pill, 'cause they wanna do something for them. There's no reason the pill should actually work, but they wanna give them something. So we really feel for these patients. Milestone's been a very patient-driven organization from its inception. We've spoken to thousands of these patients. We know them. We feel them. We say we love them. We really are holding the flag for them. And where an etripamil could. And by the way, so there's two million patients. About 40%-60%, so half the market, are patients that are having episodes burdensome enough, frequent enough to really where we can help them. The ones that are having it every week, they really should get an ablation. Mm. The ones that are having it once a year don't get benefit from a CARDAMYST, 'cause it's a little bit of an insurance policy. They could feel comfortable to go on their trips and not have to worry about where the local emergency department is. But really, the 40%-60% that have it, we call it about a dozen times a year, with episodes that are bothersome enough. Half of the time, five times a year are really our sweet spot. And when we think about that market, that's hundreds of thousands of patients at peak that are candidates and would be using a CARDAMYST. And, you know, we feel that it's a great foray into this market because a CARDAMYST is well thought of in the sense that, unlike a new mechanism, they're very comfortable with calcium channel blockers. Mm-hmm. They've been around for decades. So we feel physicians have a relatively low bar to try it, right? "As long as it's safe, I know calcium channel blockers, and I have reasonable efficacy, I'm gonna try it because I have nothing else available for my patient," is the way they're talking about it. The payers, a very key stakeholder here, like the idea of not having patients show up at the emergency department 'cause it's a gateway for more costs, and it's an inefficient use of their dollars. Unlike most drugs, most drugs are just additive to the cost burden, right? So we feel like we have a benefit there. Again, we've spoken to maybe hundreds of payers so far. And lastly, coming back to where kind of true north is for us, the patients are really waiting for this. When we had the hiccup with the FDA before Christmas, we heard from patients. "What should we do? Should we call FDA?" They're waiting for this, and right now they're kind of walking on eggshells, waiting for when their next event's gonna occur, and are they going to get that blood... you know, that heart-stopping medication at the emergency department, or am I gonna try to wait these out for five or six hours? Not pleasant, going 200 beats a minute. Mm-hmm. You know, they describe it as feeling like they've run a marathon, which when you are beating 200 beats a minute and you're in it five hours, it's the number of beats that you'd probably take to run a marathon. Mm-hmm. It's understandable. Yeah. Wow. We really are patient-driven. We think etripamil fills that gap between ablation, which 20% handle, and the other 80% that are just trying to manage it episode by episode. So for the 40%-50% Mm-hmm ... of the two million people- Mm-hmm ... who would be eligible, what is the ideal patient who should be taking etripamil? Are these, like, younger folks- Mm-hmm ... athletes, people who are going to school? Are they parents? Yes, yes, yes. It is a pretty heterogeneous condition. It starts... We find mainly younger women as the first groups- Interesting ... that come, often for unknown reasons, around the time of their first pregnancy- Mm ... is a, is a popular group. So unlike many other cardiovascular conditions, it is, it skews younger, right? Okay. So, a little bit more commercial payer for us when we go out and launch this. Yeah. So that's an advantage for us. But I think for us, when we look at that population that is so heterogeneous, what we do see is, when I talk about two million patients, they're experienced patients with PSVT. They know they have it, and they're dealing with it already. So for us, it's more identifying the patient that has that burden high enough- Mm-hmm ... that's not too high that they should get an ablation, but that, you know, half of them - half the population that's getting five or six really bad ones, that they really need to, to intervene. And, like, an easy target, if you will, for educating a doctor is: Has anyone gone to the emergency department in the last couple of years? They're a patient that's had burdensome enough events to overcome the burden of, you know, going, spending two, three, four hours, and getting your heart stopped. So for us, that's a very clear target at launch. Mm-hmm. But if it's safe, and we don't price it in a way that causes angst, we think it's really gonna mushroom out to a lot of people that really wanna have peace of mind and use it three or four times a year. Last follow-up before I pass it back to Peyton. Mm-hmm. What is the status of commercial prep for potential approval? Yeah. We're. Again, the benefit of this market is, while it is a paradigm shift, it's not changing much. There's no new entrants coming. We're there. As I mentioned, we got calls from patients. We got physician calls: "What's happening? When's it gonna be ready?" So we've been out with all of our major studies are published. Right. We've been out in front of KOLs with medical affairs, and we're in the process of figuring out our go-to strategy. We're interacting with payers now in a more tangible way, and the last step will be really how we wanna launch it. We'll adopt the same approach that you are with regard to let's get it in the hands of the doctors and the patients to have them have a good experience. We think good experiences at the outset- Mm-hmm. will lead to a very easy understanding of the market. Right now, it's, we understand investors can't see other comps, so it's gonna be a little bit of a show-me story. Mm-hmm. But we think we got a very targeted approach that will, will come out to the investment community once we file and start talking about our stepwise approach: get coverage, follow coverage, get good experiences, and then build our promotional efforts as that happens. Got it. Thank you. Yeah. That's actually a really nice transition to what I was gonna ask. So when you're building out the XPHOZAH launch, how much sampling are you planning on doing? How much free drug product? And then also kind of looking more at the IBSRELA launch, I know you have mentioned that you will increase sampling efforts. How much do we expect those to go up, and how often do you think that the PAP will be used, and will we see seasonality in these efforts? Yeah. So overall, for both first-in-class mechanism drugs, we have a comprehensive patient services system. So the way the patient services works is that when the physician orders the drug, it immediately goes through the prior auth process, and it's processed in efforts to optimize a revenue script. So where it's a PA is approved, and it's affordable for a commercial patient, we have a co-pay program that covers the full cost of the co-pay, so making sure to employ that. So ultimately, just a physician prescribes the drug, and we have an optimized approach to generate a revenue script. It's a seamless process that if for some reason along that path, either because a PA is denied or because it's accepted, but they still can't afford it, and that's typically 'cause it's not a commercial patient, and they can't afford the copay, and we can't offset it, that patient can apply for patient assistance, and if they're eligible, receive the drug at no cost. So it's a seamless process. It's not a separate form, a separate standalone process. So you can imagine from a physician perspective, they prescribe the drug, and they see the patient come back on the drug. They don't know if it's a revenue patient or a patient that's on patient assistance, but ultimately, it really does achieve our objective of making sure that, you know, we optimize revenue scripts, we optimize, you know, the extent to which a patient who's prescribed a drug and needs a drug has access to the drug, and then circles back to actually create this reinforcing perception of access for the doctor, so they continue to be motivated to go through that administrative step of submitting the prior auth. So that's really the go-to-market focus, and the samples are really used to just initiate therapy while the PA process is ongoing. So you know, increasing samples is really just focused on increasing the number of patients that they start with a prescription. So, so for XPHOZAH, clearly now in nephrology, they're... To some extent, not all offices accept samples as much as in the IBS-C space, but clearly, we're seeing that, you know, physicians like to start the patient on a sample just to get them started while the script is processing through the administrative PA process. We haven't spoken about necessarily the mix of patient assistance to revenue patients. I think the more important point is the strategic focus on the ease of the program, the seamlessness of it, and the reinforcing perception of access. For IBSRELA, we have—and now that we have quarters of experience on the market with IBSRELA, we did note that Symphony captures non-revenue scripts. So, you know, we gave you a heads up just to that it wouldn't necessarily link directly to our revenue reporting, whereas IQVIA does not include non-revenue scripts. For XPHOZAH, it's too soon to tell. We really, it's too soon to say anything about the audits and their projection methodologies and how closely perhaps they'll link to what our revenue will be. Yeah, and I guess kind of follow-up question on that, in terms of like prior authorization, approval rates, are you seeing a difference between IBSRELA and XPHOZAH? And if you could maybe kind of give us a hint about what the percents are. Yeah, no, I can't, but, you know, they both are good. They're both good because executionally, we need to focus on the doctor writing the drug for the patient that needs it. So they implicitly meet the criteria, which in both therapeutic spaces, we're calling on the doctors where those patients are there, and we make sure that they write it for patients who meet the criteria. So in both cases, really the prior auth approval rates are favorable. Over to Divya. Kezar obviously is running a phase II-A trial of Zydos in AIH. Can you talk a little bit about what AIH is, what the unmet need looks like there, and then why you think Zydus made sense to kind of evaluate in that indication? Yeah. So let's start with the disease. Autoimmune hepatitis is one of the most poorly understood autoimmune disorders, despite tons of drug development in the AI space in general. Around 100,000-200,000 patients in the U.S. These are patients who have elevated liver enzymes, usually elevated immunoglobulins, and on a biopsy, heavy immune cell infiltration into their liver, both T and B cells. And then the liver actually has its own unique form of antigen-presenting cell called a Kupffer cell. These cells are overactive in the livers of these patients, helping drive this continual inflammation that ultimately results in cirrhosis and then eventually high risk for hepatocellular carcinoma. Treatment options to date, much like many other heterogeneous autoimmune disorders, high-dose corticosteroids and immunosuppression. It's a common and unfortunately altogether unsuccessful theme of the treatment for these patients. Physicians are very quick to put these patients on high-dose steroids to try to get their liver enzymes down. They want to rapidly taper them, of course, because long-term steroid use is not so good. As soon as they drop the steroid dose and put them on a weak immunosuppressive agent like azathioprine, usually their liver enzymes pop right up. So you've got about a third of the patients who, when they are initially treated, don't respond to high-dose steroid at all, and another third of patients who, upon steroid tapering, relapse in their disease. Now, this makes up the bulk of the population in our Portola study, but AIH is much broader than that. It has an overlap with other inflammatory liver disorders like PBC. It also is a comorbidity with other autoimmune disorders like lupus and Sjögren's syndrome. And so we believe that this trial, Portola, 24 patients being enrolled, randomized treatment for six months, another six months of open-label extension, will show us unequivocally we have the ability to help the doctors lower the steroid dose in these patients, get their liver enzymes under control, get their immunoglobulin under control, and with long-term open-label extension data, show that we're leading to less risk of cirrhosis and hopefully in a substudy of post-biopsy, a reduction in the inflammation. We plan to take those data to the FDA once the trial reads out. Primary analysis, middle of 2025, open-label extension data about six to eight months after that, to the FDA to talk about registration in AIH, and we think we would likely expand into a larger AIH population and perhaps even consider some of the other autoimmune liver disorders as well. Can you just talk a little bit about the site activation, how that's going, before that mid-2025 readout? Yeah, we chose very explicitly to work with U.S. tertiary centers for AIH. We wanted to make sure we were enrolling the right patients, that we had KOL engagement from the get-go. Because there's no drug approvals in this space, only Bardess has an anti-BAFF agent in phase III, we wanted to make sure we had a group of physicians that could go to the FDA to talk about how to get a drug approved in this space because these patients need one. So this is a U.S.-only trial, 24 sites. I've been incredibly pleased with the investigator engagement. They're very excited about the novel mechanism of Veto. They really love that it lacks immunosuppression, that it works quickly, that it has broad-based immunomodulatory activity. We don't give guidance on when trials or how trials are enrolling mid-trial, but we're still on track since from the beginning of the mid-2025 readout. Joe, moving on to your AFib program, can you discuss the market opportunity for AFib and how it compares to PSVT? What is unmet need, and how does etripamil compare to standard care agents? Yeah. So, I'd mentioned before, PSVT is probably what most people have not heard about. Mm-hmm. I'm sure everyone's heard about Atrial Fibrillation. We got Kareem Abdul-Jabbar doing commercials about it, et cetera. In today's world, there's about five million AFib patients compared to two million- Mm-hmm ... PSVT patients, so to, you know, doubling, if you will. The interesting thing about AFib is with the aging population, and other, risk factors that are all around us, this is doubling by what we think of our peak year sales by 2030 to about $10 million-$12 million, depending on what literature you believe. So, it just is an epidemic that's hitting us in the healthcare system. So, the top of the funnel is a lot bigger, right, to, for patients to care for e tripamil role here is, very similar to PSVT in the sense that, again, IV calcium channel blockers are approved and used in this indication, but you have to go to the emergency department for them. And, here, ablations are not that, successful, like PSVT. So, there's a lot of patients that are opting for ablations and opting for second ablations and third ablations and dealing with their AFib over decades, quite honestly. So, the role of e tripamil in AFib is like other calcium channel blockers. You reduce rate, okay? And in the world of managing AFib, there's rhythm, and there's rate control, and rhythm is where you get them out of AFib, the patient out of AFib, back to normal, normal heart rate and normal rhythm. But there's a population of AFib patients that stay in AFib, and you just manage the rate. So the interesting is, whether you're in rhythm control or rate control, the standard of care is to bring down rate first. So even if you convert them back to normal heart sinus rhythm, you have to bring rate down first. So they're often charged with giving rate agents first, whether you convert them to rhythm or just keep the rate down. The role of e tripamil is simply to do that, or actually, CARDAMYST is gonna be a brand name. But let's give them some CARDAMYST, get them down quickly in the at-home setting, not have to bring them to the emergency department, and then you can manage them with either other rate agents, like oral agents down the road, or rhythm agents that are like anti-arrhythmic drugs that'll bring them back to normal rhythm or even cardiovert them back, which is the defibrillator paddles that bring them back. So not a good journey for all of those patients, but the key is to get them down quickly and get them comfortable and allow their AV node to be protected when you bring them over to the normal rhythm or continuing rate control. So for us, we produced some really great phase II data in November of last year, we presented at AHA, and when we compared our rates to what you would see in, like, an IV diltiazem label, which was a 20% reduction, we saw a 35% reduction or beats per minute reduction in rate. Right? So comparing, basically allowing us in a phase II trial, so again, not phase III label yet, but being able to show a level of heart rate reduction that you see with the existing IV, but be able to do it in the at-home setting, again, the value prop is pretty simple. Why have a patient go to the emergency department when you can manage this at home, get them comfortable, and give them the rest of the cascade, which are orals, allow them to do that and just avoid this trip to the emergency department? So the value prop is exactly the same. The treating physician group, exactly the same, unlike you guys having to go to two different groups. Uh-huh. It's exactly the same. It's cardiologists- Right ... and electrophysiologists. So for us, we feel it's a great second indication. It's a bigger second indication. Probably about when you put it all together, two to three times the size- Mm-hmm ... of the PSVT opportunity comes in your second indication, so we're really anxious to get in front of the FDA and get guidance on what our phase III study will look like. It's an sNDA pathway, so you go on the back of the lead indication, and we're hoping to do that soon so that we can figure out how to start the study as soon as possible. Just a quick follow-up on that- Mm-hmm ... is for KOLs, is it more important to show less than 100 beats per minute reduction or at least 20% reduction from baseline? Yeah. I mean, they follow the guidelines, which is 20 beats per minute, right? Mm-hmm. They, in their minds, know that getting that down on, for a patient will be helpful. Whether you're going from 150 to 130, you're still elevated, but you're- Mm-hmm ... you're more comfortable, right? Okay. So, a 35 beat per minute drop is really quite compelling to the KOLs, and that's with the single dose of CARDAMYST. We'll be coming to market with two doses for PSVT. So the idea of, for those patients that don't respond and get that at least 20 beat per minute drop, right? We have another chance to get them down lower, which we'll be able to test in phase III. So chance for the profile to get a little better is, is worth thinking about it. Understood. Yeah. Thank you. All right. Maybe in the last couple of minutes that we've got here, let's ask the question, what you're most excited for in the next year for your company, and then also what you're looking forward to in just the space and company in general in the next 10 years. We can start with Susan. In the next 10 years? Yeah, the pre-question was five years. So, okay, so the, you know, over the next coming year, I mean, it's really an exciting time for Ardelyx because we will continue to expand penetration with IBSRELA. I mean, we definitely have a winning go-to-market strategy. We have a nice runway throughout the patent life for IBSRELA. There is no other product in development today in phase II or III that will launch into the space. So as I had characterized earlier, there's limited options, and for those that don't work, one class, IBSRELA is the choice, and we have a lot of, you know, we have many patients who are out there who are candidates for IBSRELA, and we're excited to continue to grow persistently and consistently as we've spoken to, and particularly given our added investment in the space. So that's very exciting. And to now have, you know, now to be a company that has two products in our portfolio and another launch uptake, and to see with XPHOZAH, that we're off to such a great start. And the, you know, impact that it's having on patients when doctors are telling us that, you know, patients that they had done, you know, despite their best efforts with binders, aren't able to hit target levels. And the doctors are responding that, you know, they really see XPHOZAH as such a flexible drug because they are... For patients who are outside of target range or inadequately managed, they're adding it to their existing regimen and seeing nice results. They're finding they can cut back on the binder regimen, which is great, and in some cases, they're just eliminating the binder regimen and using XPHOZAH alone. So given its novel mechanism approach, it really has a lot of versatility in the physician's treatment armamentarium. So this is gonna be a great year as we see this continued uptake of IBSRELA and successful launch of XPHOZAH. So over a five or 10-year period, you can imagine hitting our, you know, peak potential for IBSRELA and in our billion-dollar mark, as we spoke to. And for XPHOZAH, over time, you know, we could clearly see there are well-accepted global guidelines that set target phosphorus levels, and right now, it's well documented that around 70% of patients aren't able to maintain or achieve these levels. So I see over a period of time, this is gonna be really exciting with the availability of a phosphate absorption inhibitor now, novel mechanism XPHOZAH, that, you know, so many more patients are gonna be able to... You know, it's my hope, we're talking this 10-year vision. Mm-hmm. You know, our goal commercially is more and more patients have access to XPHOZAH, that maybe, you know, more patients can be within target levels. And actually, what many people don't realize, since we're talking a five or 10-year timeframe, is that the global guidelines actually recommend that patients should really, you should try to get it as close to normal levels as possible. And that's so challenging with the current options that the clinical standard is actually not normal levels. It's 5.5, but the normal level is 4.5. So let's hope over time, as with, you know, alternative mechanism drugs available, that not only will more patients be in that target range of 5.5, but perhaps we can start to get closer to that global guideline level of 4.5 and disrupt both of these therapeutic areas for the good of patient. ... Great. Just maybe moving on to Chris and real quickly? Sure. So, over the next two-2.5 years, we've got three data readouts. Most near term is a part of the Kezar story that we haven't talked about, which is our protein secretion inhibitor, KZR-261, currently in dose escalation in refractory solid tumors. We're really excited for this novel mechanism to read out later this year. We have the two trials with ZTO. 2025 will be the autoimmune hepatitis readout, 2026, the LN readout really will, in a randomized fashion, speak to potency of a drug, a message we've been saying about ZTO from the very beginning of the company. From there, we hope to be launching into registration-enabling studies in AIH and LN, hopefully also in lupus as well, to supplement what we're doing in lupus nephritis. So, for a 10-year vision, as the person on this panel who's sort of farthest back in the development pathway, I'm excited to get to the point where, you know, providing the value proposition to payers and patients is gonna be something we're gonna do across a broad number of autoimmune disorders, and very excited to be seeing them in that next stage of the journey. That's probably why you changed it to 10 years. Yeah. We like perfect. Good. And of course, last but not least. Yeah, so Milestone, 10 years. I'll tell you what, next year at this time, I expect to be negotiating a label with the FDA and being ready to promote the drug, and that's. There's nothing more exciting than having an NDA approved and being able to actually give it to the patient. Mm-hmm. I envy you, and I aspire to be like you. Yeah. Thank you. And we're gonna be there. Mm-hmm. So, you know, we next year will be, you know, on the precipice of being a commercial organization, being able to launch this drug, and get it to patients. And, you know, over 10 years, I expect to hear, like, "Can you believe the way we used to manage PSVT and AFib- Mm-hmm -and the antiquated ways that we did it? and, you know, we're gonna, we're gonna just change how the landscape and how the paradigm is managed. And I think, we hope it applies then to other, other areas, right? Not only, you know, helping the patient, but helping the system as well. So we really do expect this to be a major mover, and I think we're gonna surprise a lot of people when we go out and launch it. All right. Thank you guys very much. Thank you so much.