to the third annual H.C. Wainwright Virtual Kidney Conference. My name is Ed Arce. I'm one of the senior biotech analysts here at H.C. Wainwright, and I'm very pleased to have our next presenter. John Butler is the CEO of Akebia Therapeutics, and he has a presentation ready to go. So John, please take it away. Ed, thank you very much, and thanks to you and to Wainwright for the invitation. And thanks for holding this third Kidney Day. It's great to see a focus on the innovation that's happening in kidney disease, and it's great to see how much innovation is actually happening in kidney disease today. You know, as someone who's been working in this space for 30-plus years, I think this is one of the most interesting times that we've ever had and, you know, wonderful opportunities to help patients who have kidney disease. You know, I'm proud of the fact that Akebia is right on the forefront there as well, particularly with our newest product, Vafseo, for the anemia of chronic kidney disease for patients on dialysis, and I look forward to giving you an update on that. Just remind everyone that I'm making forward-looking statements, so please refer to our SEC filings for more information. But Akebia is really a very unique company. We are a commercial company already in the kidney disease space with Auryxia, a product that did $170 million in revenue last year. We expect modest growth from the product this year. But that's the platform on which we're launching our newest product, and the product that really is, I think, driving the future value of the company, and that's Vafseo. And Vafseo is approved for the anemia of chronic kidney disease in adults who've been receiving dialysis at least three months. This is a billion-dollar market opportunity. This was a much larger market opportunity. Prices have come down in the space, but it's still a very significant opportunity, and a place where we believe Vafseo and Akebia can make a real difference for patients. So, you know, what is the... what are the areas of differentiation for Vafseo? Well, again, this is a hypoxia-inducible factor prolyl hydroxylase inhibitor or a HIF activator. The science behind Vafseo is Nobel Prize-winning science. The biology of HIF, of hypoxia-inducible factor, is incredibly interesting, and we think has applicability well beyond even the anemia of chronic kidney disease. But this is why physicians are really excited about the product and about the pathway, that this is a very different way of managing their patients. First and foremost, it's a once-a-day oral tablet. That's unique versus the super physiologic injectable ESAs that people have been using for the last 30 years. Most importantly, though, it is with this pathway, you're activating a much more normal physiologic response to hypoxia or low oxygen levels than you are with giving this large dose of a protein. You're using the body to stimulate endogenous production of EPO, erythropoietin, to treat anemia. Additionally, you're inhibiting hepcidin, which allows iron to be utilized more effectively. It's just a much more natural physiologic response to hypoxia and anemia, and we're excited to bring it forward for patients in the U.S. Now, the drug's been on the market for three years in Japan for both dialysis patients and non-dialysis patients. You know, that's an important market that we'll talk about a bit later in the presentation. Where, obviously, the U.S. market is a huge driver of value. We're very excited that our partner, Medice, has now launched the product in Germany and in Europe, and will continue to introduce it in more European countries as they secure pricing. Last week, we announced our wholesale acquisition cost of about $1,278 for a month's supply at the starting dose. That's an important number. Now, in dialysis, every patient is contracted, so, you know, no one will be paying the WAC price. But, you know, as we considered the WAC pricing, we really had to think about expanding the product's use into the non-dialysis market, and the value that we'd be bringing there, and that was absolutely central to our decision-making around our cost. And as I talk more about contracting and dialysis, we'll talk more about the cost. Let me just give a sense of the market that we're launching into in the U.S., and as I said, this is a billion-dollar market opportunity. There's about 540,000 prevalent dialysis patients. 90% of them are treated for anemia, and, you know, that anemia payment is part of the bundled payment. So we're gonna talk a lot about the reimbursement dynamics in dialysis, which are clearly unique. But the way we think about the market opportunity is that you've got about 90% of those 540,000 patients, so roughly 500,000 patients. The price per patient per year now is in the $2,000-$2,500 range, maybe a little bit north for higher-dose patients, but you know, that's about a billion-dollar market opportunity. So a very significant opportunity for us to launch into. And we are launching today. So we had approval in March. We're not making the product available until January, and that's because you know, that's something that people really focused on. It's because of these unique reimbursement dynamics in dialysis. We have this Transitional Drug Add-on Payment Adjustment. or TDAPA payment that we have to secure from CMS, and it takes six months for that to, you know, for them to go through their internal process. So that means the drug will be available on January, or the beginning of January. And, what's great for us is that it gives us the opportunity to set the stage for that product introduction. And clearly, our positioning of the product is that Vafseo can be a new oral standard of care. How do we get there? You know, this is something that doesn't happen overnight in a competitive market, and there's really three legs to the stool that we have to do well over the next, now it's less than six months, and certainly beyond, to make the product all that it can be. First and foremost, like with every other product launch, you have to drive demand from prescribers. You know, the physicians prescribe the drug, the dialysis providers contract the drug. You've got to be able to work with both, but you can have the best contract in the world, but if physicians don't want to use the product, it won't be used. So first and foremost, we have to drive that demand. But again, you can have all the demand in the world, but if you don't have an effective contracting strategy with dialysis, if you don't have the product available, you know, broadly, then, you're not gonna be successful as well. So we'll talk about enabling a broad, effective contracting process, with the dialysis providers. And the third leg of the stool is the medical leg of the stool. We have to continue to invest in the product. We have to continue to demonstrate additional benefits of Vafseo for patients. And, you know, this plays a number of different roles. I mean, as we continue to think about being standard of care and, you know, having more and more physicians adopt, you need to give them more reasons to believe, and that's driving data. In the early days, this also puts the drug in the hands of potentially hundreds of potential prescribers. And while they, you know, while you're, you know, you're creating the opportunity to get interesting new data, you're also giving people the opportunity to try the drug. What we find is that when people see this physiologic response and the gradual response to the drug and keeping patients within the target range, they really like using Vafseo, and it's easier for them, and better, they feel better for their patients. That's a very important component as well. As we think about driving physician adoption, first and foremost, this is about positioning this product differently. Both ESAs and Vafseo increase hemoglobin levels. That's what they do. But how they do it is and the consequence of that is what's really the difference-maker here. Where, you know, you think about injectable ESAs, you're giving these super physiologic doses of EPO. You see this spike in EPO levels that then come down over time. And that's what's caused significant concern. You see cycling of hemoglobins, excursions above target range, the things that physicians really worry about and spend a tremendous amount of time managing. With Vafseo, as you see on the graph on the left, frankly, in our clinical studies, you almost have trouble measuring the change in EPO levels. It's so, it's so gradual and so small. So you see this, you give the product once a day orally. It's got an 8-hour half-life. You get into the cell, you stabilize HIF. You see this modest increase in EPO. You get out of the cell, it goes back down to baseline again, and you do that once a day. And that's a more physiologic response. That's the same diurnal EPO response that you and I have if our kidneys are functioning. So what does that mean for, for patients and physicians? Well, it means you're maintaining EPO levels within the physiologic range. You're increasing the hemoglobin, but you're doing it in a predictable and a controlled manner. What does that mean? It means you have fewer hemoglobin excursions above the target range and fewer dose adjustments than ESAs. We saw that clearly in a number of our studies, and that makes it easier for the physicians to use as well. So, you know, all of these concerns about how quickly hemoglobin's rising, and, you know, staying within the range, those are things that are safety concerns for physicians. So they spend a lot of time in that process. Increasing hemoglobin gradually, keeping it within the range, having fewer dose adjustments, make their lives easier. And, you shouldn't underestimate how important that is for physicians to wanna use a product as well. And of course, you've got this oral dosing, which eases patient management, particularly within the home dialysis setting. So how have things been moving since launch? It's still very early days, but the market research is very encouraging from our perspective. About 85% of nephrologists that we spoke to had an awareness of the HIF class without you know being prompted on that. So awareness of the class is very, very high. More than half of them say they plan to prescribe a HIF. From my perspective, before our sales force has really gotten out there and started promoting significantly, that's a great position to be in. You know, this research was done the beginning of June, and our approval was at the end of March, and our unaided awareness of the brand, Vafseo, has grown by 60% in that two months. So, you know, great movement from that perspective. Not where we want it to be yet, but again, we have the balance of the year to make sure that physicians know Vafseo when they think about a HIF. And we asked them as part of this research, what do you need? And you know, what are the unmet needs in anemia management? Here's a compilation of their verbatims, but they need a drug that can be orally administered, particularly in their home patient population, that allows the body to physiologically produce EPO, that maintains a stable hemoglobin with fewer fluctuations, that requires minimal dose titrations, that avoids overshoots of hemoglobin levels. These are all of the things, all of the areas where we're positioning Vafseo and what we've demonstrated in our clinical studies. We think we're right in the sweet spot of what physicians want. And, you know, we think that bodes well for their willingness to trial and adopt Vafseo for their dialysis patients. Part of that research, you also ask them about where they plan to use the product. And, you know, when you wanna become standard of care, if you're in a competitive market, that doesn't happen overnight, right? Physicians have to think about, "Where are the areas I wanna adopt the product? Where will I use it first?" And once they become comfortable there, they continue to expand their use. Well, not surprisingly, what they've said is that the home population, which is about 80,000 patients, is one clear area for them. You know, giving someone a drug to take home and take orally versus bringing them into the center for an infusion makes a ton of sense for them. The second area is patients on higher ESA doses. It's those high doses of ESAs that more associated with MACE, increased MACE risk, that are more associated with fluctuations in hemoglobin. 25%, they've had ESAs for 30 years, yet 25% of patients are still not within their ESA treatment goal. And those patients who aren't within goal usually are on higher doses of ESAs. Those patients are also the most expensive for dialysis providers, so there's a great willingness to try something different in those patients. 60% of the ESA use is used in 20% of dialysis patients. So, moving those patients to an alternative treatment makes a tremendous amount of sense. So once you've driven that demand, physicians wanna use the product, they've identified the areas, and, you know, then we'll grow beyond that, you have to contract effectively. Well, from our perspective, we knew that it was gonna be helpful to have Auryxia as well as Vafseo available, and that Auryxia entering the bundle, the phosphate binders entering the bundle in January of 2025, would drive the dialysis providers to need to contract around Auryxia. That has proven to be the case, and it's created a great opportunity for us to add Vafseo to those conversations and talk about the portfolio. Hugely important, and it really will ease the path to contracting. And it's so important because basically every single patient who's treated for dialysis is treated under, is part of a dialysis provider, and therefore, there's a contract that has to be in place for them to access the drugs. 85% of patients on dialysis are Medicare patients. About half of them are standard fee-for-service, and about half of them are Medicare Advantage patients today. But about 85% are Medicare, 10% are commercial, 5% Medicaid only. Now, when we think about this TDAPA reimbursement and the opportunity there, that is clearly for the patients who have fee-for-service. That is, you know, directly CMS-approved TDAPA payments for those patients. That's half of the 85%, so around 36%. Now, what we know is the dialysis providers themselves are going to the MA plans to negotiate for a TDAPA-like or an innovation payment for new drugs like Vafseo, and particularly for the phosphate binders, like Auryxia. That's forcing their hand to go to those MA plans. We're not responsible for that contracting, so we can't... I can't give you an accurate number of what percentage will fall into that category. We know it will be far north of 36% by the time that we launch. And that number is important because that's the patients who really will be the target for Vafseo, given the premium pricing at launch. You know, 36% of the 541,000 patients who were treated, or the ones who were treated for anemia, is roughly 200,000 patients. That's the minimum number of patients who will be our target population at launch, who will be able to access the product with a premium price. But of course, we'll be thinking about growing well beyond that, and I expect that it will be well north of 200,000 by the time we're launching. Our contract structure that we talked about on the call the other day is very, very kind of standard for dialysis providers. An off-invoice pricing through the contract term, and then volume-based rebates that start at unit one. So the more we sell, the more their rebates, so the lower the net price, and but we'll be selling a higher volume. And, you know, and kind of reiterate our WAC here, again, no patient in the dialysis market will be paying that WAC price, but it's a very important starting point for contract negotiations. This is just a cartoon really to help visualize what's gonna happen with pricing during TDAPA and then post-TDAPA, 'cause I don't think I mentioned, TDAPA is a two year opportunity. For two years, dialysis providers can bill for vadadustat, Vafseo, outside of the dialysis bundle on an ASP basis. So they retain any dollars that are in the bundle for anemia management, and they're able to be paid for Vafseo outside of that, and they get a contracted rate for Vafseo. So as you see, they'll always have a contracted off-invoice discount, and then as volumes increase, prices come down. I should have another curve on the graph here that shows volumes increasing as that price decreases. The red dot there is quite important. This is 2027 at the end of the TDAPA period. Physicians or dialysis providers need the predictability of the post-TDAPA pricing to adopt a product during TDAPA. It's all well and good that they can use a product during TDAPA, but if that pricing doesn't fall in line with what they have today, they're not gonna adopt it during TDAPA. We're giving them that predictability. Our pricing will come down into that range of about $2,500 per patient per year, but that will allow us to drive upside and demand during the TDAPA period. And, you know, I talked about, well, the TDAPA market's not the full market. Once we're in line with anemia management pricing post-TDAPA, well, that whole 500,000-patient population is available to move to Vafseo. So another opportunity for us to step up growth quite significantly. And to do that, you need to continue to generate clinical data, and that's the third leg of the stool, again, and why we think it's so important to continue to make investments and grow the product. We have a robust data set today. Just to remind everyone, our pivotal programs, Innovate and Protect, are published in the New England Journal. Great for the sales force to have that Innovate study publication in their hands. There's other great data like this, this publication in the Journal of Hematology that is on the pathway and the benefits of endogenous erythropoietin production and improved iron availability. But we have to continue to drive data that demonstrates for physicians the benefits of using Vafseo. That will keep the product growing in a post-TDAPA world. So, where are we today, and where are we going in the near future? So, approval, end of March, check. We filed for our TDAPA reimbursement in June. We announced our WAC pricing. Our TDAPA submission was accepted and is under review now. A couple of things to look for. Before we get the TDAPA designation, you get a HCPCS code, which is the code that dialysis providers will use to bill for Vafseo. That assignment generally comes in October. It's one more thing to look out for. We're very excited about the ASN Kidney Week. At the end of October, it's kind of our coming out party for the product. It is, you know, incredibly important for us to... We're then within a couple of months of the product being available. So, you know, being able to talk to physicians there will be very important. We'll win that meeting. Excuse me. So then, of course, in January is when the product will be available. So from now till then, we're doing our dialysis organization contracting. That's well underway, and I really look forward to talking to you more about our collaborative studies that we're planning. We're very close to being able to talk about that. Not quite there yet. We wanna get those plans firmly in place, but we think that's gonna be very, very exciting and a great opportunity for the product. And then within the red box, or the pink box, we're talking about FDA feedback on non-dialysis. And this is a really critical value driver for Akebia as a company. You know, we're very focused on making the dialysis launch successful, but non-dialysis is an opportunity that more than doubles the opportunity for the product. There's a high unmet need here in non-dialysis. You know, particularly patients who have GFRs of 15 or below, who are truly pre-dialysis patients. You look at the data, 74% of them, with a hemoglobin below nine, are still not receiving an ESA. They don't wanna go for an infusion. The physician doesn't wanna give it. It's difficulty in reimbursement, and they do poorly. FDA has recognized that there's a high unmet need here, and in our CRL, they said, "Come back and talk to us about patient groups where the benefit risk is positive." You know, we believe we'll have to do clinical data to get that approval. But you look at the graph, the graph on the left, they simply looked at patients whose pre-hemodialysis hemoglobin was lower than nine or above nine. nine, not 10 - 11, nine. And whether it was three, six, or 12 months after starting dialysis, their mortality risk was higher. When you start dialysis anemic, you do poorly, and so managing them beforehand is critically important. And you see the same in a larger USRDS study on the right, where, you know, comparing patients who were at that 10 - 11 versus patients who were six months before dialysis were not, were below nine or below 10, and you can see the elevated mortality risk. This is a very, very important patient population. We've prioritized this to go to the FDA and get feedback by the end of the year. And we think that that will be incredibly important for, you know, being able to value that market. This is, I think, well more than doubling the opportunity for the product. Now, there's two other areas we've talked about, the new to dialysis patients. You know, we've talked about the three-month exclusion that we have in our label. The data doesn't support that. If you look at patients, there's over 1,000 patients who were on Protect or Innovate, who started dialysis on Vafseo or darbepoetin, and you saw no change in risk. We wanna talk to FDA about that. We also wanna talk about three times weekly dosing. When you look at the FOCUS study that we did, you can dose this drug three times a week with dialysis extraordinarily well. And if you look at the graph on the right, you reduce the ESA rescue significantly. ESA rescue was associated with MACE in our INNOVATE trial. Because we started at a lower dose of vadadustat, we had the same amount of ESA rescue that you saw with darbepoetin. When we managed the starting dose effectively in the FOCUS trial, you look at the graph on the right, and you look at a 100% increase in Mircera dose, at 900 milligrams, which is 450 milligrams a day, versus Mircera, you had half the ESA rescue. This is really, really quite meaningful, and we used a 100% increase. The label dose says increase it by 25%. If physicians increased it by 100, they were rescuing the patient. We think that might translate to a safety benefit as well. So we wanna talk to FDA about these, about these two issues, but non-dialysis is so much more important and so much more valuable to the company that we've prioritized that. Now, new to dialysis and three times a week, we'll talk to them in the beginning of next year. In the meantime, we're publishing that data. We've presented both of those data sets at the ASN meeting and other dialysis meetings, and we're looking to publish that. Physicians will know that three times weekly works. They'll see the publications, and they'll make that choice whether they want to use that or not as we launch the product. I know I'm running out of time. We have an exciting pipeline as well that I won't spend time talking about today. We think that there are opportunities to use HIF beyond the anemia of CKD. We did a COVID study with vadadustat during the pandemic. We clearly saw that there was activity there. We wanna do another study, a phase II with vadadustat in a more sicker ARDS population to prove the pathway, and if that works, then prioritize that for our compound 9090, and I've talked about how excited I am about the indication in retinopathy of prematurity for our other compound 10108. We've got a lot going on, and we're doing all of it from a position of financial strength. You know, we have $42 million in the bank. We have $170 million dollar revenue, a kind of ongoing revenue stream from Auryxia. We've managed our operating expenses extraordinarily well since we received the CRL two years ago. We've talked about a $150 million operating expense budget, which includes non-cash items, that we don't expect a significant step-up at all from that in 2024, and yet we're investing appropriately in the Vafseo launch. So, again, I went through a lot of material there. We're really at an active time. These are the things we have to do well, and these are the things we'll continue to update you on as we get closer and closer to product availability. Thanks, Ed. Great, John. Thank you. Truly, an exciting time with Vafseo launch, or availability, less than six months and potentially other indications further down the line. Thank you, John. I really appreciate your thoughts and perspectives. Thanks again for the invitation. Absolutely.