Good morning, and welcome to the Akebia Therapeutics R&D Day. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded and a replay will be made available on the Akebia website following the conclusion of the event. I'd now like to turn the call over to Mercedes Carrasco, Senior Director of Investor Relations and Communications at Akebia Therapeutics. Please go ahead, Mercedes. Good morning, and welcome to Akebia's Research and Development Day. During the presentation, we will be making forward-looking statements subject to risks and uncertainties that could cause actual results to differ materially from those described in these statements. For more information, please refer to the SEC statements available on our website. For your convenience, a replay of today's call will also be available on our website after we conclude. To begin, John Butler, Akebia's President and CEO, will present opening remarks and a brief company and pipeline overview. Akebia's Chief Medical Officer, Dr. Steven Burke, will be joined by Dr. James Tumlin to review praliciguat, which is being studied for FSGS. Dr. Burke will then be joined by Doctors Michael Holers and Jonathan Barratt to discuss our complement inhibitor, AKB-097, and he will close with an overview of AKB-9090. Following the formal presentation, we will open for Q&A. With that, I will turn now to John Butler to begin. Thanks, Mercedes, and thanks to everyone for joining us today. I think we have a very exciting program set for you today because we have, we think, a very exciting company at Akebia. We have a company that has a very clear strategy and a very clear purpose. Our purpose is to better the lives of people impacted by kidney disease. There's three imperatives that we look at as a company that drives our strategy. The first is to drive Vafseo to become the standard of care for patients on dialysis treating their anemia. Second, we wanna build on our commitment to patients impacted by kidney disease. Third, we wanna create a future for Akebia beyond kidney disease. This third imperative really is this early-stage work that we're building on, the expertise that we've built in the hypoxia-inducible factor prolyl hydroxylase science. Some really interesting things to come. Today at our R&D Day, we really wanna focus on the middle imperative, building on our commitment to those patients impacted by kidney disease. To get there, we have to drive Vafseo. Vafseo is the revenue engine that drives our ability to invest in our pipeline, and we're at a very strong place. Just to remind everyone, Akebia is a commercial company already. In 2025, we did about $227 million of revenue. Now, a lot of that was driven by AURYXIA, our oral phosphate binder. As we've said in the past, AURYXIA now has generic competition. While that revenue stream will start to wane, we are set up for significant growth with Vafseo. Remember, Vafseo is going to be growing into a billion-dollar market in 2026, and we're set up to grow beyond 2026 as well. It's really important to remind folks. You know, we keep talking about TDAPA as an important component of driving growth, but the billion-dollar market is based on the value of anemia management treatment today in dialysis. We think we're building a body of evidence that's gonna allow us to capture a significant portion of that. Today, we wanna have operational access to patients. A year ago, we had about 40,000 patients who could actually access Vafseo. Today, we have about 290,000 patients who now have prescribing access to Vafseo. Very importantly, we're growing breadth. We've always talked about building on breadth. That means getting patients outside of U.S. Renal Care clinics to start on Vafseo. We're really starting to see a higher percentage of new patient starts from clinics outside of U.S. Renal Care. One of the real issues we had with building growth last year was adherence rates. We've seen adherence, first fill adherence rates increase in centers that have moved to observed dosing, 3x weekly dosing, from where they were before with QD dosing at 70%-75% to about 87% today. We're really encouraged by the first refill adherence that we're seeing. Today, we're in a strong position to see growth for Vafseo. Longer term, we're also building this body of clinical evidence that's gonna support the product. First, we've talked to you about this win statistics analysis from our INNO2VATE data. This analysis demonstrated that when you were treated with Vafseo versus darbepoetin, which is standard of care, you had a lower risk of dying or being hospitalized when treated with Vafseo. This is now pending publication in the Journal of the American Society of Nephrology or JASN, which is one of the highest impact factor journals in nephrology. We're going to support that data with data from the VOCAL trial that we're running with DaVita that's expected by the end of 2026, and data from the VOICE trial, which will have that same win odds outcome endpoint that will come in early 2027. We'll continue to build on that body of evidence. Today isn't about talking about AURYXIA, though it's critically important for everyone to appreciate that we're positioned well for growth. We're really excited about the pipeline that we're building around kidney disease. As I said, we have opportunities outside of kidney disease that we're not gonna talk about today that we're quite excited about. The products that we're focused on around kidney disease, I think you'll see each of them can occupy a unique position in the market, bring a unique benefit potentially to patients. The first product we'll talk about today is praliciguat, our soluble guanylate cyclase stimulator, which as Mercedes said, we're studying in FSGS. We started a phase II in December of last year. The second product is the one we in-licensed late last year from Q32 Bio, and that's AKB-097. Now, as you see on the slide, we recently got a generic name for AKB-097, abribafisp. Since I still haven't figured out how to say that three times fast, I think during the presentation today you're gonna see people continue to refer to it as AKB-097 or Ebri. This is a product that we are expecting to initiate a basket trial in three indications, IgA nephropathy, lupus nephritis, and C3G, in the second half of this year. The third product we'll talk about today is exciting because it's the first product from our own discovery efforts at Akebia. This is AKB-9090, which is a HIF-PH inhibitor, and the initial indication is for cardiac surgery-associated acute kidney injury. We are on the verge of initiating phase I in healthy volunteers shortly and expect to have data from that phase I study before the end of this year. We are clearly targeting severe kidney disease that have a high unmet need. I think you may look at this slide and say, "What a high unmet need." I mean, IgAN, there are a number of products available for IgAN. I have to say that was the first reaction that I had when the team brought AKB-097 to my attention. As we learned more about this product, and I think you're gonna hear about this in the presentation in the Q&A this morning, the IgAN treatments today don't have the benefit that you have with AKB-097. This tissue-targeted complement impact really can have a profound impact, we think, on IgAN, and I look forward to you hearing about that as well. In lupus nephritis, we know that there's significant opportunity to improve therapy there. C3G, again, the tissue-targeted effect we think can have a significant impact for patients. FSGS is another area where there's a lot of different products in development. Nothing has been approved today, and we think that praliciguat, as a soluble guanylate cyclase stimulator, has a unique mechanism of action which can play a unique role in therapy. AKB-9090 and AKI, well, AKI is a huge health issue for thousands of patients that hospitals spend a tremendous amount of money on. The idea behind a HIF-PHI for AKI, we think creates a unique opportunity to treat a very significant unmet need. First and foremost, we think these products can have a significant impact on patients. These are also very important business opportunities as well. If you look at praliciguat, while there's no product approved in FSGS, the first product that is under regulatory review for IgAN is about $120,000 per year treatment with about 40,000 patients. You know, even if praliciguat is gonna be focused on, you know, some percentage of those patients, you're talking about a multi-billion-dollar market opportunity across all of these indications. Whether you look at IgAN, which has treatments from $120,000-$390,000 per patient, or C3G, which is over $500,000 per patient, these are market opportunities where if we can have the kind of impact on the disease that we think we can with praliciguat, with AKB-097, with AKB-9090, these are incredibly important business opportunities as well. I think what's important to point out is when you look at these product offerings, whether it's praliciguat, a soluble guanylate cyclase stimulator. This impacts the nitric oxide pathway that's dysregulated in patients with kidney disease. It's a unique mechanism of action to impact patients with FSGS. AKB-097 has this unique approach to tissue targeting, targeted complement inhibition. We think that will make it a very unique offering in the market. When you look at AKB-9090, this HIF activates pathways that are necessary for cell survival following hypoxic AKI, but also, it impacts pathways that regulate metabolism, reduce oxidative stress and inflammation. We're approaching the disease from multiple points of contact, and we think that gives this a significant opportunity to succeed in a very serious disease. You know, as we look across our pipeline, we're really excited about the business opportunity, the opportunity to impact patients, and the fact that we're bringing unique products to bear across all of these indications. With that now, let me introduce the people who are really gonna give you the information you want around all of these disease areas and these products. Let me introduce our panel. Starting with Dr. Steve Burke, who's a KOL in his own right. Dr. Burk is our Chief Medical Officer and head of R&D. He has about 30 years of experience in renal drug development. Dr. Jim Tumlin is a board-certified nephrologist, a clinical researcher, and Professor of Medicine at Emory University School of Medicine. He's led and participated in numerous NIH-funded and industry-sponsored clinical trials spanning acute kidney injury, glomerular disease, and dialysis technologies. He is a widely published investigator and an editorial board member for leading nephrology journals. He's recognized nationally for advancing therapeutic innovation and improving outcomes for patients with kidney disease. Dr. Michael Holers is the first Smyth Professor of Rheumatology at the University of Colorado. His laboratory research efforts have been on the structure-function relationship and biologic roles of the complement immune system. From molecular genetic studies performed by his research group, first in class tissue-directed complement therapeutics were developed, and he served as the president of the International Complement Society and has been elected a member of several honorary societies. Finally, Dr. Jonathan Barratt is the IgA nephropathy Rare Disease Group lead for the U.K. National Registry of Rare Kidney Diseases and convener of the International IgA Nephropathy Network. He's the chief investigator for a number of international randomized controlled phase II and phase III clinical trials in IgA nephropathy, and was a member of the FDA and ASN Kidney Health Initiative identifying surrogate endpoints for clinical trials in IgA nephropathy work group. He's the co-chair of the U.K. Glomerulonephritis Clinical Study Group and the IgA nephropathy lead for the KDIGO Clinical Practice Guidelines for Glomerular Disease. First up will be Dr. Tumlin to give you an overview of FSGS and praliciguat. Jim? Well good morning, everyone. Thank you for your time today. As John said, I'm Jim Tumlin. I'm from Emory University and NephroNet, and we're gonna talk about a drug under development called praliciguat, and I think you're gonna find this to be an interesting story. We're gonna talk about FSGS, which is just an acronym for focal segmental glomerulosclerosis. This is a not uncommon glomerular disease, particularly among patients of African descent. I think one really important point for the audience to understand is that FSGS is purely a descriptive term, and the number of diseases and etiologies that can give you this morphology in the kidney exceeds 20, 30 different causes of disease. The right-hand slide of the histogram, the micrograph shows you four glomeruli, and the very dark intense places you see, these are areas where the glomerular capillary loops have collapsed, and they've been replaced by sclerotic fibrotic tissue and are no longer functional. You can envision as that sclerosing process goes throughout all the glomeruli and more of each individual glomeruli, you lose kidney function over time. The prevalence of FSGS is actually still growing, and I'm gonna show you that slide on that in just a second. As I mentioned a moment ago, it's more problematic and more difficult in people of African descent. There's been a recent identification of a very important gene called the APOL1 gene that explains a lot of the FSGS again in people of African descent, but that's probably maybe half of the entire population that has primary FSGS. Moving forward, there are a number of other diseases, as I mentioned, that are open to treatment for FSGS. This is a micrograph, electron microscopy. If you see the red, this is the highlighted cell called the podocyte. Podocyte's extremely important, and you can see these finger-like processes between adjacent podocytes. This is where the slit pore occurs in the kidney. This is the final barrier to proteinuria coming from the blood space and into the urinary space. The slide is to depict what I said a moment ago, that so many things can impair on podocyte function as well as survivability and apoptosis. That includes TGF-β, TGF-α and TNF-α and the Type I Interferons. They affect podocyte function. Altered genetics like defects in nephrin, podocin, and TRPC6. Endothelium. This has become a very important target pharmacologically in treating and stabilizing podocytes. Permeability factors like the cardiotrophin-like cytokine 1, suPAR, reactive oxygen species, a big player, in diabetic nephropathy. What we're gonna focus today is on impaired nitric oxide and VEGF production and pathways linked to soluble guanylate cyclase. This gives you another kinda electron micrograph diagram. The upper left-hand corner F, this is a normal glomerulus. What you're looking at is a zoom in on the glomerular tuft, and you can again see these podocytes with these massive finger processes wrapping around the glomerular capillary cells and within the glomerular tuft. Now if you look to the bottom right to E, you see that there's a higher magnification. Again, there are these finger processes where the final pores of slit pore function occurs in that area. Panel D is where a podocyte has either died, gone through apoptosis, or literally detached, and that area where the arrow is pointing is exposed basement membrane from the capillary cell. Now why is that important? I'll show you a slide in a minute. That's where that endothelial cell will adhere to Bowman's capsule and begin the sclerotic process. F is a larger magnification, the same thing, and you can see where these foot processes are pulled back and expose the underlying endothelial basement membrane. This is a cartoon to give you an idea of that. Whenever you have damage to a podocyte cell, so in this example, Steve's gonna show you some data on an Adriamycin model. Adriamycin damages the podocyte, induces apoptosis, and eventually that podocyte falls off the basement membrane, which I was saying a moment ago. In the middle panel here, you can see the diagram where the podocyte has fallen off, and the green is that basement membrane I mentioned just a moment ago. You can see at the top of that slide, that green is beginning to adhere to Bowman's capsule on the outside of the glomerular tuft. In the right-hand panel, you can see a fully formed sclerotic lesion. That sclerotic lesion propagates under a lot of different forces, some of which are responsive to augmentation of the soluble guanylate cyclase pathway, and leading to the sclerosis that eventually becomes the phenotype of FSGS. Now let's go through some more images of this. I've been mentioning this tuft adhesion. Again, on the right here, this is a conventional H&E scan. Where you see the three arrows, this is a real-time image of where that sclerotic process is developing. You can see the one at the upper left-hand corner, that sclerotic process is advanced and moving in, and you can envision how that would consume the glomerular tuft over time. Now, FSGS prevalence is growing, so every year there's a new set of data on this. Right now, the prevalence is there's about 88 cases per 1 million population. If you go back to 2008, the number of FSGS patients was around 22,000. It's now just above 31,000 and continuing to climb. Why that is is not known, particularly since we are hopefully getting better about treating it, but this is a persistent trend that's been documented for at least the last 25 years. Well, it may be increasing prevalence, and maybe we're getting better, maybe we're not, but because I think this slide is very helpful to the audience in that basically the big three of treatment for FSGS has not changed much at all over the past 20 years. Predominantly glucocorticoids have been used to treat this. Being a practicing clinician that treats FSGS patients every day, glucocorticoids are fraught with side effects including weight gain, steroid-induced diabetes, bone disorders, et cetera. The CNIs, drugs like tacrolimus and cyclosporine, used in about 14% of cases. They're effective, but of course, they're weighted by their scarring. I'm a little surprised to see mycophenolate on this list because the data for this has been generally quite poor. Now, this diagram is a little bit deeper dive into the biology of a podocyte, and it's simply to tell you that these microtubules and actin and myosin filaments within the podocyte allows for the formation of the finger processes that I showed you on the electron micrographs. Suffice it to say, the praliciguat is involved with pathways involving cyclic GMP kinase that regulates the functionality of these actin and phi filaments and the formation of the foot plate processes. The agent goes directly to the defect that you see that contributes to the proteinuria that is the second one known of FSGS. Okay, let's talk a little bit more clinical. This is a basic statement. Whatever the clinician does to reduce urinary protein in an FSGS patient, you would achieve them some degree of benefit. What's old is new again. This is older data, and this is from Dan Cattran group at the Toronto Registry. Dan showed that if you do not get somebody to a complete remission, what you can see is a renal survival rate is effectively 80% by 12-15 years. If you're even able to reduce the proteinuria by 50% down to a level below 3,500, you can see a significant improvement in their survival. I would point out to the audience to look to the left-hand side of the graph. This effect on renal survival and the reduction of proteinuria starts early. In about two years of that therapy, you start to gain a benefit. Then in the complete response, which is less than 300, you see that for the first basically 10 years, there is little to no progression toward dialysis. Again, the take-home point of the slide is achieving even a partial remission is a win for the patient compared to those who had no response at all. Another way of saying the same thing. This is data that's combined from the REIN trial and from other studies, and they look at the outcome of chances for ESRD based on the level of proteinuria. The proteinuria is broken down into tertiles, 500 to basically 2 g, 2 g to 3.5 g. If you're above 3.8 g, you can see a virtual dose-dependent reduction in the renal survival, such that if you were maintained over time between 500 and 1.2 g, your risk for ESRD is around 4.3%. If you're between 2 g and 3.5 g, you're at 15.3%. If you're above 3.5 g or nephrotic range proteinuria, you have basically a third of a chance of reaching dialysis. The right-hand data says more of the same thing, and it indicates that short-term changes, even in the short term, have benefits that are substantial for reducing progression to dialysis. Again, illustrating this point that clinicians that get that protein down have definitely benefited their patients. The last data, and this trial is changing the landscape of a lot of forms of glomerular disease. I think the audience should really understand the impact of the PARASOL trial. This study looked at, I believe it was 1,800 patients, and they all had FSGS, and they analyzed people based on their protein that they achieved. This is a really important point, irrespective of the therapy they gave. It simply says here that if you got that patient by prednisone, by RAAS blockade, by mineralocorticoid blockade, by praliciguat or whatever, if you got that proteinuria down below 700 mg, you can see that the difference in the survival is substantial. Once again, there's that two-year mark. Roughly after about two years, the two curves begin to separate, and if you did not achieve that 700 mg, you had a 40% progression by year eight. Now they took this data, they compared it with another very famous and well-known registry called the RaDaR Dataset. This is out of the U.K., and Dr. Barratt, who spoke earlier, is a seminal keeper of that database. They found almost a superimposable outcome between the two sets of data. If you get below 700 mg, your chances of progression are dramatically reduced compared to if you do not do that. For a non-responder, once again, ±2%, a 42% progression by year eight. The internal consistency of going Dan Cattran's data and now the PARASOL and RaDaR data really illustrates the importance of protein reduction. Now, praliciguat. What is praliciguat? Praliciguat is a agent that works with soluble guanylate cyclase that is nitric oxide sensitive and NO-dependent. When activated, it stimulates the development of cyclic GMP, which goes downstream to affect a number of pathways, including PKG, as well as affecting pathways including the TRPC6 pathway. What we're gonna show you is just a little bit of preclinical data looking at the TNF-α-induced inflammation in TGF-β in human proximal tubular cells. We're also gonna look at an Adriamycin mouse model. Steve's gonna present that data. Then also a 5/6 nephrectomy rat model CKD. All right, let's look at this. This is a function of what praliciguat does on reducing the toxic effects of a very important cytokine called TGF-β. If you don't know, TGF-β is probably the predominant cytokine that regulates forces that lead to glomerulosclerosis and interstitial fibrosis. If you have a model here where TGF-β is administered to animals, and you look at a glomerular structure, you can see that. It's a little difficult to point out, but the glomerulus is full of hemorrhage. There is collapse of vessels. There is periglomerular inflammatory cells. There's fibrosis. That same animal model when treated with praliciguat at 10 mg / kg per day, you're basically looking at a normalized glomerulus. The effect in this model of TGF-β dependent glomerulosclerosis is highly effective. The right-hand set of data shows you the more clinical aspects of this. You can see that in the animals that have high salt diets and part of the TGF-β pathway, the level of urinary protein is much higher and is brought down significantly by the praliciguat. Glomerulosclerosis you see again almost a dose-dependent reduction in scarring of the glomerulus with praliciguat. It reduces TGF-β production by the kidney and reduces the interstitial fibrosis. One more data point I'll show you, and I'll turn this over to Steve, is this is a preclinical model looking at cultured human proximal tubular cells. The top panel you see, these have been treated with TGF-β. If you can see the clustering of the cells, that is a hallmark of proximal tubular cells that are undergoing what's called mesenchymal transformation. What is happening to those cells, they are literally turning into fibroblasts. To remind you of the importance that the fibroblasts are in fact the cells that do the driver of the scarring formation within the interstitium of the kidney. If you take those same cells treated with TGF-β and add praliciguat at 1 micromolar, you normalize the culture of proximal tubular cells. Now, taking a look at the right-hand data, there's a subtle thing that I want to point out. If you look at this data, there's one point where the proximal tubular cells are treated with an antibody to TGF-β. What's interesting is that in this particular study, the praliciguat was superior to the TGF-β antibody in blocking this mesenchymal transformation. Why is that important? Because in previous studies in FSGS, blockers to TGF-β have been tried before and were unsuccessful. Well, then why would praliciguat be more effective than an antibody to TGF-β? Well, obviously we don't know, but we think it has to do with the augmentation of downstream effects of the pathways that stabilize the fibrotic processes and by extension the glomerulosclerosis. I think that's my last slide, and I'll turn this over to Dr. Burke. Thank you, Dr. Tumlin, for that excellent presentation. Akebia was very excited by the preclinical package we inherited from Cyclerion. After a deep review, Akebia decided that FSGS was one of the most promising applications for praliciguat. Before making a final decision, Akebia conducted two additional non-clinical studies, one in the murine Adriamycin model of FSGS, and a second in the 5/6 nephrectomy model in rats. The results of those studies affirmed our decision to develop praliciguat for FSGS. Now I'll give a high-level review of the two study results. In this model shown here, animals received a single dose of Adriamycin on day zero, and then praliciguat treatment with or without the ACE inhibitor enalapril on days six to 14. Urine was then collected overnight, and the animals were sacrificed on day 15 for kidney histology. As mentioned previously, Adriamycin accumulates in podocytes and damages them, leading to marked increases in proteinuria, as shown in the black columns on the left side of the graph, as compared to the control animals in the white column. That's approximately a five-fold increase in urine protein to creatinine ratio. Praliciguat at doses of 3 mg/kg, 10 mg/kg, and 15 mg/ kg did not decrease proteinuria when administered alone, as shown in the blue bars, but when combined with enalapril in the green bars, resulted in a marked reduction that was greater than that seen with enalapril alone in the red bar. In addition, the combination of praliciguat and enalapril in the green plots showed a reduction in glomerulosclerosis, the scarring that develops in response to podocyte damage. The black lines represent the means, with individual animals within a group represented by circles and triangles. There was also a reduction in tubulointerstitial fibrosis and degeneration, which drives the transition from reversible injury to progressive, irreversible chronic kidney disease. Now I'll switch to the 5/6 nephrectomy data. The model involves infarcting 5/6 of the kidney by arterial ligation to cause hyperfiltration of the remaining glomeruli in the remnant kidney. This hyperfiltration causes proteinuria and glomerulosclerosis. Study drug treatment begins two weeks after the surgery and continues for seven weeks with periodic blood and urine collection and necropsy at nine weeks. This figure shows the mean proteinuria over time. Going from left to right, the black columns are the normal animals, and the red columns are nephrectomized animals. The green column is enalapril alone. The purple and blue bars are praliciguat 1.5 mg/kg, 3 mg/kg, and 10 mg/kg alone, and the final three bars are praliciguat at the same doses in combination with enalapril. Similar to the Adriamycin experiment, the combination of praliciguat with enalapril showed the greatest reduction in proteinuria, and that data is highlighted by the black circles. Praliciguat in combination with enalapril, the three columns on the right, also decreased serum creatinine concentrations compared with the vehicle-treated group, the pink bar on the left, indicating preservation of kidney function. Consistent with the creatinine data, the combination of praliciguat and enalapril showed a marked decrease in glomerulosclerosis, as shown in the black box. These results are very impressive and bodes well for the potential praliciguat to delay the progression to end-stage kidney disease. Importantly, all patients with FSGS will be treated with an ACE inhibitor like enalapril or an angiotensin receptor blocker, and praliciguat will be added on top of those therapies. In addition to generating additional non-clinical data, we reanalyzed Cyclerion's phase II study in diabetic nephropathy. 156 subjects with CKD and macroalbuminuria were randomized to placebo or praliciguat 20 mg or 40 mg for 12 weeks. The primary efficacy endpoint was change in urine albumin to creatinine ratio or UACR. UACR decreased by approximately 20%-25% with praliciguat, with both doses in the ITT population and in the modified ITT population of 133 subjects, as shown in this slide. At one site, the subjects on praliciguat had negligible blood levels, and so that site was excluded from the modified intent to treat population. We also analyzed the proportions of patients in the placebo and the praliciguat groups achieving UACRs less than 0.3 g, 0.5 g, and 0.7 g using the modified intent to treat population. In FSGS, approximately 2/3 of urine protein is albumin, so a UACR of 0.5 g approximates a UPCR of 0.7 g, the PARASOL endpoint. As shown in the table, the proportion of subjects achieving UACR less than 0.5 g increased from 34.8% in the placebo group to 51.2% in the praliciguat group, an absolute increase of 16.4% with a relative risk of 1.47 g. A 47% increased chance of meeting this level of response in the praliciguat group. Now, FSGS patients may respond differently than patients with diabetic nephropathy, but nonetheless, this analysis was encouraging. This next slide summarizes the design of the recently initiated phase II study in FSGS. It's a randomized double-blind placebo-controlled dose titration study to evaluate the efficacy and safety of praliciguat in adults with biopsy-confirmed FSGS. The study randomizes up to 60 subjects to praliciguat or matching placebo for 24 weeks, after which the placebo patients will cross over to praliciguat. The efficacy endpoints are change in UPCR from baseline and the percentage of patients with a partial remission. We will also analyze the percentage of patients with UPCR below various cut points, including 0.7 g /g. This will inform us if we should proceed to phase III. At this point, I'm gonna turn over the presentation to Dr. Michael Holers to discuss our new tissue-targeted complement inhibitor, AKB-097. Dr. Holers is a rheumatologist and leader in basic and translational research focused on the role of complement in immune regulation, with particular emphasis on B lymphocytes and autoimmune diseases. His lab at the University of Colorado has developed innovative human and mouse models to advance the development of complement inhibitors. Dr. H olers. I'm very happy to go through the background of AKB-097. First, with regards to the complement system, this is a very complex multi-protein system that's been known for many years. The main effects of the complement system are shown on the left, including lysis of bacteria and damaged cells, enhancement of pathogen clearance, and recruitment of inflammatory cells. However, we know, as in the lower left, the complement system is dysregulated in many autoimmune and inflammatory disorders, especially those involving the kidney. Now, with regards to the system on the right, one can see again that it's a complicated system. However, to simplify it, what I wanna point out is that there are convertases there in the pink, and AKB-097 targets those convertases. These are the multi-protein engines, if you will, of the complement system that drive the generation of the effector mechanisms. The other important point on the right side is the molecule C3, which is a major serum protein, which when activated, will covalently attach the targets. That covalent attachment is a very important function of this molecule. It is then degraded through a series of proteases to form the fragments shown in the red, most importantly, C3d. Now, the other complement inhibitors are focused, as shown here on the slide, in various proteins and are not specific for the convertases themselves. These are systemically active proteins and molecules that are used clinically, and their targets are shown here. AKB-097 aims to address limitations of current complement inhibitors. One problem is the other inhibitors are systemically active, and in order to get local control, you have to utilize the systemic inhibition to work very locally. AKB-097 enhances its activity through direct tissue targeting, which allows the inhibition to occur only where complement is being active. The high doses and frequent administration that's required of the systemic inhibitors is necessary to control the pathway. However, a reduced treatment burden is shown with preclinical data demonstrating that once-weekly dosing and perhaps every two-week dosing will be effective. The systemic risk associated with infection is clearly there with the systemically active inhibitors, whereas there is the potential for an improved risk-benefit profile with tissue targeting, as shown in the lower right. AKB-097, as shown here schematically, is a novel tissue-targeted complement inhibitor. Shown in the middle is the targeting agent that recognizes this C3d fragment with very high affinity and very high avidity, as I indicated before. Linked to the antibody is a negative regulatory protein, a factor H. This is an endogenous inhibitor that is capable of stopping the convertase and also, very importantly, completely inactivating the convertase by taking the C3b molecule and cleaving it in association with a cofactor. This is, as I said, a unique mechanism that allows this tissue-directed inhibitor to block complement and irreversibly inhibit it at tissue sites. C3d is a very important target, as shown on this slide. This fragment, identified with the same monoclonal antibody as used in AKB-097, is present across a wide range of renal diseases, as is shown across the slide at the top and the bottom. Therefore, this C3d fragment is present at sites where complement is being activated and, of course, where you would like to block this ongoing activation. First evidence of this prolonged and durable blockade was shown in a model of C3G, and in which in the top slide section, one can see that treatment with 5 mg /kg of this inhibitor resulted in a very prolonged decrease in C3 activation, 3 mg/kg, 7 mg/kg and barely coming back at two weeks or 14 days. At the bottom, one can see that the AKB-097 itself was present in that tissue site for 7 mg/kg and upwards of 14 days. Therefore, one can clearly see a durable binding of the inhibitor to sites where C3d is being actively generated. When that durable binding occurs, further C3 activation is blocked. Practically, this is also shown in a model of membranous nephropathy in rats in which treatment with AKB-097 in the ongoing disease results in the left side with a decrease in proteinuria, which is one of the major outcomes in this particular model. On the right side and the center, one can see this complete dissociation, if you will, between systemic complement inhibition and local complement inhibition. If one looks at the middle, one can see doses of AKB-097 that block the deposition and activation of C3 in the site, and that is what drives the decrease in protein. However, on the right side, those same doses that provide local inhibition have absolutely no systemic inhibition, therefore demonstrating practically the complete dissociation or separation, if you will, of a local versus a systemic effect. Also structurally, it's very important not only to see the function, but here we demonstrate in the same study a structural protection where in the middle treatment with this antibody results in glomerular basement membrane damage and effacement of podocytes in association with the immune complexes that are shown with the yellow areas. However, treatment with AKB-097 on the right side results in a maintenance of this glomerular barrier and protection of the podocytes with the maintenance of the foot processes in these particular sites. Therefore, in sum, what AKB-097 does in this model is goes to the tissue site, blocks complement activation without systemic inhibition, protects the loss of glomerular filtration such that proteinuria is diminished and as well protects the tissue site from damage. With that, I'll turn it over to Steve and allow him to go through some of the human phase I data. Thank you, Dr. Holers, for that excellent presentation. Now I wanted to review the key results of the Ebri phase I study that explored intravenous and subcutaneous dosing in normal volunteers. The top panel shows the results of the IV dosing component. On the left are the mean plasma levels of Ebri over time in the days following single IV doses of 0.1 mg/kg to 33 mg/kg. On the right is the percent of baseline alternative pathway complement activity by dose over time. IV Ebri, particularly at the high doses such as 3 mg/kg, 10 mg/kg, and 33 mg/kg, inhibited the alternative pathway systemically, which is good, and that shows it functions as a complement inhibitor. In the figure, anything above 50% is mild inhibition and associated with a low risk of infection. 20%-50% is moderate inhibition, and less than 20% is deep inhibition and associated with significant infection risk. The bottom panel shows the results of the subcutaneous dosing component. On the left are the mean plasma levels of Ebri over time in days following single subcutaneous doses of 3.75 mg/kg and 10 mg/kg, and also a 450 mg dose administered once weekly for five doses. You can see that the peak plasma level of 10 mg/kg subQ is much less than the equivalent IV dose above. On the bottom right is the percent of baseline alternative pathway complement activity by dose over time with the subcutaneous administration. The complement inhibition with the 10 mg/kg dose is mild as compared to the near complete inhibition with the equivalent IV dose above. The 450 mg subQ dose, which equates to an average dose of around 6 mg/ kg, will be used in the phase II basket trial. That dose did not decrease alternative pathway complement activity significantly with the initial or subsequent four weekly doses. To synthesize what I just presented, I am showing you the PK profile of the various doses studied in phase I, highlighting the 450 mg subcutaneous dose with the thick green line. The 450 mg subcutaneous dose exposure exceeded the level which should provide complete inhibition of the complement activity in the tissues based on the preclinical studies that Dr. Holers reviewed. In addition, the 450 mg subcutaneous exposure was at a level well below that which would cause 50% or greater inhibition of the alternative pathway systemically. As noted at the bottom of the slide, in the phase I study, there were no serious or severe AEs, no discontinuations due to AEs, no AEs related to immunogenicity, and minimal anti-drug antibodies. Now I'm gonna turn this over to Dr. Jonathan Barratt, a nephrologist with deep knowledge of glomerular diseases, who can discuss the potential role of Ebri in treating complement-mediated kidney disease. Thank you, Dr. Barratt. Thanks very much, Steve. Where we see this drug being of particular use are in a number of different complement-mediated kidney diseases where we have very clear evidence that intra-renal complement activation drives glomerular injury, glomerular fibrosis, and loss of kidney function. These conditions are IgA nephropathy, lupus nephritis, and C3G. We do have a number of emerging treatments for each of these conditions, but what has been very clear is that these treatments are likely going to be required to be given lifelong. These are diseases that affect young people, and therefore, we are talking about many, many years of drug exposure. Because in the clinical trials, what we've seen is when these new treatments are stopped, the disease comes back with the same degree of severity as there was present before we gave the initial treatment, particularly when we think about IgA nephropathy and those treatments targeting B- cells and those complement therapies as well. When we think about lifelong therapy, we need to think very carefully about long-term safety. What is very exciting about this approach, which I think of really as a second generation of complement inhibitors, is the ability to target tissue-level complement activation without impacting on systemic complement activity. As you heard from Dr. Holers, complement activity is essential to manage pathogenic diseases from microbes. Therefore, if we're able to limit the degree of complement inhibition to the tissue level where complement is actually being activated and causing tissue injury and leaving systemic complement activity alone, we will have a much lower risk of impairing the complement system's ability to deal with microbial pathogens. There is a real opportunity here, I believe, to use these drugs in these complement-mediated kidney diseases for them to be used over a chronic period of time without the associated potential risk of systemic complement impairment and that associated risk of increase of infection complications. I think when we think about the current therapies, there are still significant clinical unmet needs. There are a proportion of all patients in these conditions that don't respond completely to the available therapies. The available therapies are going to have to be given lifelong. In that situation, we need to really concentrate on minimizing the potential long-term risks associated with those therapies, and therefore, a targeted approach inhibiting complement at the site of complement activation without widespread systemic complement inhibition is very attractive for a safety perspective in a treatment that is likely going to be need to be given for many, many years. That has led to the design of the phase II open-label rare kidney disease basket trial, where we are going to look at these three complement-mediated kidney diseases, IgA nephropathy, lupus nephritis, and C3G, in an initial study to assess safety of AKB-097 alongside getting early information on clinical efficacy by looking at secondary outcomes in terms of change in proteinuria, change in GFR, and of course, looking at plasma PK profile and evidence of inhibition of complement activation by looking at urine soluble C5b-9 as a biomarker of terminal complement pathway activation in the kidney. The study will be for an initial 26 weeks, and we are targeting 30 patients with the hope that this study will start in the second half of this year. Thank you for listening, and I'll hand back. Thank you, Dr. Barratt, for that overview of complement-mediated kidney diseases in the Ebri basket trial. Now I'll give a brief overview of Akebia's third program we are discussing today, AKB-9090 for cardiac surgery-associated acute kidney injury or CSA-AKI. AKI is a sudden decrease in kidney function that usually occurs in association with another serious illness or condition. Next slide. One such condition is cardiac surgery, particularly if it involves the use of cardiopulmonary bypass. Next slide. AKB-9090 is a novel HIF prolyl hydroxylase inhibitor developed at Akebia to prevent or treat CSA-AKI. AKB-9090 works by stabilizing HIF in the kidney to activate cell survival pathways, alter metabolism, decrease reactive oxygen species and inflammation to reduce kidney injury to tubular epithelial cells in the microvasculature. Next slide. Investigational agents targeting a single pathway have not worked in the past. In contrast, AKB-9090 activates a transcription factor present in all cells of the body, which then activates multiple pathways responsible for cellular adaptation to hypoxia. The figure on the right highlights the major pathways affected by HIF, and Akebia has data both in vitro and in vivo documenting positive effects on each of these pathways. Next, I will review some representative AKB-9090 data from an ischemia reperfusion model we run in rats. The model involves removing one kidney and then occluding the blood flow to the remaining kidney for 30 minutes. This is the ischemia part of the model. Restoring blood flow causes additional reperfusion injury. AKB-9090 was given at the start of the surgery. This particular experiment tested various intravenous dosing regimens on kidney function and histology. You can see in the figure on the left that the middle two groups, 4 mg/ kg over eight hours and 30 mg/ kg over four hours, were particularly effective at decreasing the rise in serum creatinine, the main clinical marker of kidney function. In the figure on the right, also improved the kidney histology, showing both the reduction in tubular epithelial and vascular damage. A phase I study has recently initiated in New Zealand. The planned phase II study will treat patients undergoing elective cardiac surgery requiring cardiopulmonary bypass. AKB-9090 will be dosed immediately prior to surgery, immediately after surgery, and the first few days while the patient is in the ICU. This trial will enroll subjects at higher risk for AKI based on the presence of preexisting chronic kidney disease and other comorbidities, and we'll look at the incidence, duration, and severity of AKI. This is my last slide, and we will now turn to Q&A. Thank you. We will now begin with a few questions on AKB-097. These questions come from the team at Jefferies. First, what is the most compelling evidence that tissue localized C3d targeting can deliver efficacy comparable to systemic complement inhibition without meaningful systemic immunosuppression? Dr. Holers, I think that would be for you. Great, thank you. This certainly is a very appropriate question, and maybe I'll just briefly review the history of tissue targeting, which is something that's been very active in the academic community for many years. In fact, over a decade. We were able, with colleagues, to work through a number of different strategies to direct inhibitors to tissue sites and came up with this C3d targeting approach, and it was shown in multiple studies to be the most effective way to do it. Our colleagues at Q32 Bio went ahead and optimized the structure-function relationships of this. In a number of different species, and I went through one of those in the prepared remarks, we were able to see a clear separation between these, between the two. The other, I think, important point is that the phase I PK data was entirely as expected. I think based on a series of preclinical models and a lot of prior work on the academic side, we're very convinced that we would be able to separate these effects out in a clinically relevant manner. Thank you, doctor. Of course, if any of our other panelists have anything to add, at any point, please, feel free to jump in while we go through these. Mercedes, next question. Great. What biomarkers will definitively show local complement inhibition versus a partial systemic spillover? That's Dr. Holers as well. Sure. I think we've learned a lot from recent studies of complement inhibitors, and certainly a biopsy will be very important where it's available. However, what's been striking, and perhaps Dr. Barratt will comment on this later and already brought it up, is that the soluble C5b-9 levels in urine turn out to be a very nice way of understanding local complement inhibition. Pairing that along with the regular serum levels of complement inhibitors and serum levels of the drug, and inhibition functionally, I think we will be able to very nicely see that the local control is occurring and the systemic inhibition is not occurring to any substantial level. As a nephrologist, I think I have to say this, and Jim will back me up. Kidney biopsy tissue will be wonderful to see this in terms of showing that the drug is localized to the kidney tissue, and that it is having an immediate effect on complement activation and those downstream inflammatory pathways. I think that's eminently achievable. We're doing a lot of repeat kidney biopsy studies at the moment in nephrology. That will be something that I'm sure we will be thinking about going forwards. But I think that is a real opportunity to link kidney tissue localization with what we're seeing in the urine. That's another great opportunity to think about really showing the unique MOA of this approach. Yeah. Just to echo what Jonathan's saying, I totally agree that the utilization of repeat biopsies is something I'm kind of famous for. I've been an advocate of that for 20 years, is knowing and looking at the actual deposition. The working end of the activated complement at the tissue level cannot be underestimated. The C5b-9 membrane attack complex in the urine, I agree with Dr. Holers is an advance, but it's difficult. Those assays are probably not quite ready for prime time yet. Having this, which is I know being done by other companies as well, is gonna be a major step forward. Thank you all. Mercedes? Great. Let's switch to a few questions on praliciguat. First, how does praliciguat differ from endothelin antagonists and APOL1 inhibitors? How does this provide an advantage? Okay. I'm gonna get you. Really good question. There's a lot of activity in FSGS, as you know. The APOL1 story is unique. This is a gene product that's expressed in a duality, autosomal dominant, particularly and almost to exclusion in people of African descent. That's a large percentage of patients with FSGS, but its pathway is fundamentally different than what praliciguat addresses or the endothelin antagonist. This is a pore-forming protein. It's a part of the innate immune system that is designed to kill certain parasites that are endemic to Africa. When you have this gene and another second hit, it affects the podocyte and leads to the phenotype of FSGS. That's not gonna be confused with the market for praliciguat just simply because you're gonna know this person is APOL1 positive. The ERA story is a little different. ERA is activated by mesangial injury of any type, and it's not limited to FSGS. It's certainly seen in IgA, it's seen in lupus, even in diabetes to a lesser extent. Blocking that pathway, which leads to downstream fibrosis and the arteriolopathy in these patients, is one pathway that would be treated, and it would not at all be opposed to co-treatment with the praliciguat, in my opinion. Great. Thank you. Next question comes from Julian Harrison at BTIG. Just to expand on that, can you talk about how the likely unmet need post ERAs in FSGS? Yeah, sure. As I said a moment ago, ERAs are gonna be used. Again, in my opinion, they're gonna be a foundational drug of CKD. They'll be used in IgA. They are used in IgA. They'll be used in FSGS and a number of other chronic kidney diseases. That's one modality of therapy. Going back to my comments from the lecture, that reducing proteinuria by an ERA pathway is helpful. You will not reduce the proteinuria sufficiently in every person, and there's gonna be some individuals for whom it would benefit additionally to praliciguat. Now, the Akebia trial is in primary only, but in my opinion, I'd love to get Jonathan's thoughts on this. It's gonna expand into secondary FSGS as well. Where there is podocyte dysfunction of soluble guanylate cyclase signaling pathways, praliciguat's gonna have an advantage to stabilize and reduce that proteinuria. Yeah. Jim, I completely agree. I think podocyte injury is common across glomerular diseases, and this mechanism of action, while primary FSGS is the obvious choice, I think there's an opportunity here to expand beyond that initial indication. Completely agree with you. Great. Thank you. The next question comes from the team at Leerink Partners, and also, Matt Caufield from HCW had a similar question. Praliciguat is entering a shifting regulatory landscape in FSGS. What level of UPCR reduction do you believe is clinically meaningful for praliciguat to be competitive versus the current standard of care? Great question. We talked a little bit about that again in the lecture, the PARASOL data. I really want to emphasize to the audience that the PARASOL data is very important, but data from Jonathan's registry, the RaDaR data, and data going back to the Toronto registry with Dan Cattran several years, many years ago, all point to the same thing. That if you reduce that proteinuria even by 50%, you benefited the long-term outcome of the patient. To answer your question, the PARASOL data say you want to be between 300 mg and 500 mg. There's a bit of an argument among- Steve, I'm sorry. There was a mistake? You okay? Yep. Yeah, we're good. Good. Should I continue? Go ahead. Getting that number between 300 mg and 500 mg may not be entirely possible for a lot of people that have had long-standing FSGS. There's a phenomenon called scar proteinuria, and really quite simply, damaged kidneys can't resorb protein as well, and therefore there can be a floor at which you really can't get below it any further. Suffice it to say for the purposes of this discussion, between 300 mg and 500 mg would be optimal. Great. Great. Thank you. A few more questions, back to AKB-097. Do you expect AKB-097 to be complementary to APRIL inhibitors in IgAN and other indications? Good. Dr. Barratt? Yes. Thank you. I think it's ideally suited, to be honest. I think the big challenge we're facing in IgA nephropathy is we have drugs that target antibody production. We have drugs that target complement activation systemically. Of course, knocking out a critical arm of the innate immune system while also suppressing a key component of the adaptive immune system does come with particular risk, particularly our ability to fight microbial pathogens. That may be appropriate for a short period of time. As I said in my talk, when we're thinking about IgA nephropathy, we're thinking about a disease that affects 30-year-olds, 40-year-olds. If our goal is for them to avoid kidney failure in their lifetime, we're talking about treatment exposure over 40 or 50 years. I would be concerned about impairing the adaptive immune system and antibody production while also taking out a key component of your innate immune system for 50 years. I think the opportunity here is if we specifically target sites of active complement activation at the tissue level while leaving systemic complement activity unchecked, then we have a much better safety profile to combine this approach with other immunomodulatory therapies. I think this is an ideal approach to think about combining with other treatments, and likely has the potential to have a safer profile over the longer term. Let me jump in on that, John. I just could not possibly agree with Jonathan more. I think the complement inhibitor with an APRIL/BAFF or APRIL antagonist alone is ideally additive. Now that, with Dr. Morgan's observations on localized activation of C3d, now we have a method. On a repeat biopsy, we're gonna be able to say that patient X, Y, or Z has moved back into a complement-dependent form of the disease, and therefore would go with addition APRIL/BAFF antagonist for some period of time. I agree with Jonathan. I don't think it'll be forever, but there will be periods of induction where you put the disease back under control and calm the inflammation. That's very helpful. Great. For AKB-097, do you plan on pursuing parallel cohort expansion in the basket studies if you see early signals or remain disciplined to the current indications? Yeah, Steve first. Love to hear other opinions. Yeah, sure. You know, we inherited a protocol from Q32 Bio and decided the quickest way to get into the clinic was to go after the three indications that had been previously discussed with FDA. We certainly have the opportunity to add additional diseases to the basket trial. It's also important to note that if we see activity in one of the current diseases, we can then transition into a phase II/III study for that indication, and we could add additional indications. The basket trial will continue to enroll and collect data while we transition to phase II/III for one of the indications. Yes. Okay. Good. All right. A few questions on AKB-9090. First, how does AKB-9090 differ from vadadustat? Why is tissue-targeted approach in ninety ninety expected to succeed while HIF inhibitors have historically struggled in AKI? Yeah, I can take that one. AKB-9090 obviously is a different structure than vadadustat. Vadadustat is acted upon by organic anion transporter, so is taken up by the liver and primarily acts in the liver. For instance, the increase in erythropoietin that we see in patients with CKD, it's coming from the liver, not from the kidneys for the most part. Whereas, AKB-9090 is not acted upon by the OATs, and so has much higher tissue penetration into the kidney itself. We see very good target engagement in the kidney, even more so than in the liver. It's clearly different. It activates all of the right pathways, as I alluded to in my talk, activating cell survival pathways, decreasing inflammation, affecting metabolism. Based on our data, yeah, I think it has a very good chance of working in a way that vadadustat would not. There's no clinical data showing that HIF-PHIs decrease acute kidney injury. That's why we're gonna be the first one, hopefully, to show that this pathway is attractive target in CSA-AKI. Great. What early human signals, biomarkers, AKI shift, staging shifts would meaningfully de-risk this program before a large outcome study? Sure. The phase I study's in volunteers, so we'll just be looking at target engagement, so measuring increases in erythropoietin production. The phase IIa will look at things like cardiac surgery-associated AKI incidence, severity, and duration as well as additional biomarkers. Based on that, we would then plan a phase III study. We are also gonna be looking at other organ complications of cardiac surgery. It's not just a problem with the kidneys. Patients end up. Well, they certainly end up in the ICU, and then they have to get off vasopressors, off ventilators. They have a lot of cardiac complications. We'll be looking at all of the complications associated with the surgery and coming up with a composite endpoint that captures the totality of the benefit of AKB-9090. Thanks, Steve. A question came in from Allison Bratzel at Piper Sandler. This is back to praliciguat. Given the heterogeneity of FSGS, do you expect praliciguat's mechanism to be effective across patient subtypes, primary and genetic FSGS? How are you evaluating this in the phase II trial? Okay. Jim. Good question. Yeah. I think for the genetic, it depends on which one you're looking at. I don't foresee praliciguat being something that would be an add-on to the APOL1 pathways. There's two different ones being approached, which I said previously was an antisense knockout and then a small molecule inhibitor with Vertex Pharmaceuticals. I kinda don't see that happening there. To the broader question, Jonathan alluded to this, whenever you have podocyte damage, this pathway of reduction of guanylate cyclase activity becomes relevant. This is the downstream pathway that is a consequence of a variety of different injuries. The answer to your question is, yeah, I see this being a broad application. Even if we don't have the ability to get to the point to be able to say that patient X has this etiology for their FSGS or patient Y the other, another etiology, because there's a certain commonality through the guanylate cyclase pathway in the podocyte, I think praliciguat's gonna have a broader application. It's smart. Just to clarify, for our trial that you're running, Jim, we're including primary and genetic, but we're excluding secondary FSGS. Right. Just to be clear. Still think it may apply. Thank you. All right, we've received a question from Ed Arce at WestPark Capital. What specific results from the phase II trial in DKD patients by Cyclerion are most encouraging in support of pursuing FSGS? I'm sorry, I didn't quite catch all that. Could you repeat it for me, please? Of course. What specific results from the phase II trial in DKD patients by Cyclerion are most encouraging in support of pursuing FSGS? I would say the 30% reduction in proteinuria is again, I just keep re-emphasizing that even a 30% reduction is likely to benefit people longer. Remember, that trial did not have a terribly long, I don't remember the exact length of time of follow-up, and that a reduction even at 30%, and I'm guessing that we're gonna see better than that with FSGS, is gonna have the potential benefit for the patient. That would be a way forward, I believe. Yeah, I would say that, yeah, the results look very similar to what sparsentan gives you above and beyond irbesartan, and that's both in terms of proteinuria reduction, but also the proportion of patients who meet certain thresholds of proteinuria. In that slide I showed you, I focused on the 0.5 g/g, but you see the 0.3 g/g, 0.7 g/g for the UACR, and that's very sparsentan-like. That's certainly encouraging. Not the same disease as FSGS. They have much more proteinuria in FSGS, so it'll be very interesting to see what we observe in that patient population. Great. As I'm looking at the questions, Mercedes, they all seem fairly derivative of ones that we've already asked. I think that's right. But anything else you want to share on that side? Any final thoughts from any of our distinguished guests that you wanna share before we close out? I mean, I'd just like to say I really like the idea of tissue-targeted complement for complement activation, and I think there is a potential that you will gain greater efficacy by delivering complement inhibition within three-dimensional tissues. We know you can block systemic complement activity with systemic drugs. What we don't know is what is actually going on in a complex organ like the kidney. How are we able to block complement activation both within the glomeruli but also within the tubular interstitium? That's another thing I think we haven't touched on really, is there's a lot of interest in the complement system driving interstitial scarring, which is common to every form of CKD. One of the beauties of this approach is this is an IgG4 antibody, which is eminently easy to stain for. Could we be seeing activity not only within the glomeruli in terms of calming down glomerular inflammation, but also within the tubulointerstitium and preventing local complement activation and progression of interstitial fibrosis, which is, to be honest, the major reason people end up on dialysis. If that is the case, then you have a big job on your hands because this approach is then relevant to all forms of progressive kidney disease. That's why I think this is so exciting because it could be a viable chronic therapy, leaving systemic complement activity unchanged and reducing significantly that risk of infection. Yeah, I think this is a really exciting approach. Can't wait to get my hands on it and to see how we biopsy these patients and see where this drug goes and see what it does, which I think will be fantastic and fascinating. To add a little bit to what Jonathan was saying, even a part of his good comments on the IgG4 staining, just reducing low-level complement activation, we need to remember that C5a, a product of activation of complement pathways, is a very potent chemokine for chronic inflammatory cells such as macrophages and monocytes, which are then drawn into the kidney and contribute to the fibrosis that Jonathan had mentioned. One quick comment about praliciguat. I would like to go back to emphasize something I tried to point out in my talk, that in fresolimumab, which was an antibody against all three forms of TGF-β, did not work in FSGS. The fact that we're seeing this admittedly in a preclinical model, that the downstream signaling pathways had better effect, I think speaks to the potency and the potential, I should say, of praliciguat. I would only add with regards to Dr. Barratt's comments that, you know, this is all being done in the context of active scientific exploration of local complement production, local complement control, and all of the data that we're generating and others are generating really points to the observation that local complement activation is occurring. That is the primary cause of injury, and you need to control it locally. That is something that we're all learning more and more about, and we all look forward to seeing what happens in the phase II studies. Well, I hope all the folks who are listening in on the call today are hearing the excitement from the panelists and, you know, it's that excitement that we at Akebia felt as well as we looked at oh nine seven. We really do believe this can be a very important drug, and we're working very diligently to put it in your hands, Dr. Barratt, as quickly as we can. I wanna thank our panelists today for their time and, you know, their very insightful comments. Hopefully, folks really benefited from that. I'm quite sure that they have. I think if we could put up the one final slide just to close out. No? Well, we have just- We're putting it up, John. What's that? We're putting it up. Great. Thank you. Really just to close out, to remind folks of all of the many catalysts that we have over the next 12+ months, here at Akebia. I mean, everything under the backdrop of driving vadadustat, Vafseo, to be standard of care in dialysis. You know, tremendous amount of work left to do there, but we're really pleased with the progress we're making. We're really pleased with the data that we're generating that suggests there's a real difference in managing anemia with Vafseo vadadustat that will really benefit patients in the long run. Just to remind everyone on the call, that is a billion-dollar market in the U.S. You know, we're excited about the progress we're making there. Now, you know, we have so much more to think about and talk to you all about with the number of catalysts we have. You know, we initiated the praliciguat trial in December. Thank you, Jim. We are going to be initiating the AKB-097 trial in the second half of this year. Obviously, the team is diligently working to do that as quickly as we possibly can. We have the phase I trial for AKB-9090 that's really just a few weeks away from dosing first in human, which is always an exciting moment for a company. you know, this building of the evidence that we talked about, the VOCAL top line data before the end of this year, the VOICE data in the beginning of 2027. you know, given that we have a open label basket study, you know, we can start seeing data from AKB-097 in 2027. We're really excited to continue to talk to you about this as we continue to execute as a company, and we look forward to it. Again, thank you again to our panelists for taking the time, and thanks to everyone for joining us today. We look forward to talking to you again soon.