Akebia Therapeutics, Inc. ($AKBA)

Good morning, and welcome to the Akebia Therapeutics R&D Day. [Operator Instructions] 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 President and CEO, will present opening remarks and a brief company and pipeline overview. Akebia 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 Dr. 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, 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 want to build on our commitment to patients impacted by kidney disease. And third, we want to create a future for Akebia beyond kidney disease. And 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 want to focus on the middle imperative, building on our commitment to those patients impacted by kidney disease. But 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 in a very strong place. So 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. So while that revenue stream will start to wane, we are set up for significant growth with Vafseo. And remember, Vafseo is going to be growing into a $1 billion market in 2026. And we're set up to grow beyond 2026 as well. And it's really important to remind folks, when you're talking about TDAPA as an important component of driving growth, but the $1 billion market is based on the value of anemia management treatment today in dialysis. And we think we're building a body of evidence that's going to allow us to capture a significant portion of that. Today, we want to 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 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, 3 times weekly dosing from where they were before with [ QD ] dosing at 70% to 75% to about 87% today. So we're really encouraged by the first refill adherence that we're seeing. So today, we're in a strong position to see growth for Vafseo. But longer term, we're also building this body of clinical evidence that's going to 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, 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 endpoint that will come in early 2027. So we'll continue to build on that body of evidence. But today isn't about talking about Vafseo, though it's critically important for everyone to appreciate that we're positioned well for growth. But 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 going to talk about today that we're quite excited about. But 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, bringing unique benefit potentially to patients. So the first product we'll talk about today is Praliciguat, our soluble guanylate cyclase stimulator, which as Mercedes said, we are studying in FSGS, we started a Phase II in December of last year. The second product is the only [indiscernible] 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 097, [ Abrivafisp. ] And since -- I still haven't figured out how to say that 3x fast, I think during the presentation today, you're going to see people continue to refer to it as 097 or Abri. And this is a product that we are expecting to initiate a basket trial in 3 indications. IgA nephropathy, lupus nephritis and C3G in the second half of this year. And then 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 the 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. And 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. And I have to say that was the first reaction that I had when the team brought 097 to my attention. But as we learned more about this product, and I think you're going to hear about this in the presentation and the Q&A this morning, the IgAN treatments today don't have the benefit that you have with 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 could 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. And then AKB-9090 in AKI. Well, AKI is a huge health issue for thousands of patients at hospitals spend a tremendous amount of money on. And the idea behind a HIF-PHI for AKI, we think creates a unique opportunity to treat a very significant unmet need. So first and foremost, we think these products can have a significant impact on patients. But these are also very important business opportunities as well. If you look at Praliciguat, while there is 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, even if Praliciguat is going to be focused on some percentage of those patients, you're talking about a multibillion-dollar market opportunity across all of these indications. And whether you look at IgAN, which has treatments from 120,000 to $390,000 per patient or C3G, which is over $0.5 million per patient, these are market opportunities where if we can have the king of impact on the disease that we think we can with Praliciguat, with 097, with 9090, these are incredibly important business opportunities as well. And again, 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 nitrous oxide pathway that's dysregulated in patients with kidney disease. It's a unique mechanism of action to impact patients with FSGS. 097 has this unique approach to tissue targeting targeted complement inhibition. We think that will make a very unique offering in the market. And then when you look at 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 us a significant opportunity to succeed in a very serious disease. So 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. And with that now, let me introduce the people who are really going to give you the information you want around all of these disease areas and these products. So let me introduce our panel. Starting with Dr. Steve Burke, who's a [ CME ] in his own right, Dr. Burke 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 Emery 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 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 [indiscernible] 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. And 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 [indiscernible] University of NephroNet. And we're going to talk about drug under development called Praliciguat, and I think you're going to [indiscernible] story. So we're going to talk about FSGS, which is just an acronym for Focal Segmental Glomerulosclerosis. This is a not uncommon [indiscernible] disease, particularly among patients of African decent. And I think 1 really important point for the audience to understand is that FSGS is purely a descriptive term. And the number of diseases and [indiscernible] that can give you this morphology in the kidney that exceeds 20, 30 different causes of the disease. And the right-hand slide, the histogram, the micrograph shows you [indiscernible] and the very dark intense places you see these are areas where the [indiscernible] have collapsed, and they've been replaced by scleronic fibrotic tissue and are no longer functional. So you can envision is that [indiscernible] process goes throughout all the [indiscernible] and more of each individual [indiscernible], you lose kidney [indiscernible] over time. The prevalence of FSGS is actually still growing, and I'm going to show you that slide on that in just a second. And as I mentioned a moment ago, it's more problematic, more difficult in people of African decent. There's been a recent identification of a very important gene called [indiscernible] that explains a lot of the FSGS, again, in people of Africa decent, but that's probably maybe half of the entire population that has primary FSGS. And then moving forward, there are a number of other diseases, as I mentioned, that are open to treatment for FSGS. So this is a micrograph [indiscernible] go if you see the red, this is the highlighted cell called the [indiscernible] extremely important -- and you can see these fingerling processes between adjacent podocytes, this is where the slip for occurs in the kidney. This is the final barrier to proteinuria coming from the blood space and into the urinary space. And the slide is to depict what I said a moment ago that so many things can impair on podocyte function as well as survivability in apoptosis. And that includes TGF Beta, TGF alpha and TNF alpha in the type 1 [indiscernible] they affect podocyte function, altered genetics like depend [indiscernible] this has become a very important target pharmacologically in treating and stabilizing podocytes. Permeability factors like the [indiscernible] cytokine 1, [indiscernible] reactive open [indiscernible] a big player in [indiscernible] property. And what we're going to focus today is on impaired [indiscernible] VEGF production and [indiscernible] linked to solubilize guanylate cyclases. This gives you another kind of electronic [indiscernible] diagram. So the upper left [indiscernible], this is a normal glomerulus. And what you're looking at is the honedown on [indiscernible], you can again -- see these podocytes with these massive finger processes, we're wrapping around the [indiscernible] capillary cells and within the [indiscernible] now if you look to the bottom to E, you see that there's a higher magnification, again, there are these finger processes where the final 4 of [indiscernible] occurs in that area. Panel D is where a podocyte either died all through apoptosis are literally detached in that area where the area where the arrow is pointing is exposed based on membrane from the [indiscernible] cell. Now why is that important? I'll show you a slide in a minute, but that's where that endothelial cell [indiscernible] Bowman's capsule and begin this sclerotic process. F is a larger magnification the same thing. And you can see where these [indiscernible] pulled back and expose the underlying endothelial base of membrane. This is a cartoon to give you an idea of that. So whenever you add damage to a podocyte cell, so in this example, Steve is going to show you some data on an adriamycin model. Adriamycin damages the podocyte induces apoptosis that eventually that [indiscernible] falls off the base of membrane, which I was saying a moment ago, and the middle panel here, you can see the diagram where the podocyte has fallen off and the green is that base of membrane -- just a moment ago, and you can see at the top of that slide, that green is beginning to adhere to Bowman's capsule on the outside of the [indiscernible]. Then in the right-hand panel, you can see a fully formed sclerotic lesion that's [indiscernible] propagates under a lot of different forces, some of which are responsive to augmentation in the [indiscernible] pathway and leading to these sclerosis that eventually becomes the phenotype of FSGS. Now so -- let's go through some more images of this. So I've been mentioning this [indiscernible]. So again, on the right here, this is a convention -- and where you see the 3 arrows, this is a real-time image of where that sclerotic process is developing. You can see the 1 in the upper left-hand corner the sclerotic process in advance and move it in, and you can envision how that would consume the [indiscernible] over time. Now FSGS prevalence is growing. So every year, a new set of data is, right now, the [indiscernible] is there's about 88 cases per 1 million population. If you go back to 2008, the number of FSGS [indiscernible] was around 22,000. It's now just above 31,000 and continuing decline. 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 3 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 [indiscernible] with side effects, including white gate, steroid-induced diabetes, bone disorders, et cetera. The C&I drug like [indiscernible] and cyclosporine used at about 14% of cases. They are affected. But of course, they're weighted by their scarring, and I'm a little surprised [indiscernible] 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 is simply to tell you that these microtubules that [indiscernible] mods and filaments within the podocyte allows for the formation of the finger processes that I showed you on the [indiscernible] micro grant. Suffice it to say that Praliciguat is involved with pathways involving cyclic GMP kinase that regulates the functionality of these [indiscernible] and filaments and the formation of the [indiscernible] process. So the agent goes directly to the defect that you see that contributes in the proteinuria that is the [indiscernible] of FSGS. Okay. Let's talk a little bit more clinical, so this is a basic statement. Whatever the clinician does to reduce urinary protein in FSGS achieve them some degree of benefit. And what's old is new again, this is older data, and this is from [indiscernible] in the Toronto Registry. And Dan showed that if you do not get somebody to a complete remission. What you can see is the real survival rate is effectively 80% by 12 to 15 years. If you're even able to reduce the proteinuria by 50% now to a level below 3,500, you can see a significant improvement in the sort of [indiscernible] the audience to look to the left-hand side of the graph, this effect on renal survival and the reduction programs starts early, about 2 years of that therapy start to gain a benefit. And 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. So again, the take-up point of the slide is achieving even a partial remission is a win for the patient compared to those who had no response. Another way of saying the same thing. This is data that is combined from the [ RAIN ] trial and from other studies. And they look at the outcome of chances for ESRD based on the level of proteinuria. So the [indiscernible] is broken down in [indiscernible] 500 mostly 2 grams, 2 grams to 3.5 grams. And if you're above 3.8 grams, 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, your risk for ESRD is around 4.3%. If you're between 2 and 3.5, you're at 15.3%. And if you're above 3.5 or the [indiscernible], we have basically 1/3 of a chance of reaching dialysis. The right is more of the same thing and it indicates the short-term changes even in the short term, have benefits that are substantial for reducing [indiscernible] dialysis. Again, the illustration is the point that clinicians to get that protein down and definitely benefit their patients. And then the last data in this trial is changing the landscape of a lot of [indiscernible]. I think the audience should really understand the impact of the [ Parasol ] trial. And this study looked at, I believe, it was 1,800 patients, and they all had FSGS. And they analyze people based on their protein that they achieved, and this is really an important point. Irrespective of the therapy they gave. And it simply says here that if you got that patient by prednisone, by [indiscernible], by [indiscernible], if you got that program down below 700 milligrams you can see that the difference in the survival is substantial. And once again, there is that 2-year mark. So roughly after about 2 years, the 2 curves begin to separate and if you did not [indiscernible] that 700, you had a 40% progression by year 8. 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, we spoke earlier is a seminal keeper of that database. And they find almost a simpler imposable outcome between the 2 sets of data. If you get below 700, your chances of progressions are dramatically reduced compared that you do not do that for a nonresponder, once again, plus or minus 2%, a 42% progression by year 8. So the internal consistency of going [indiscernible] data and now the parasol and RADAR data really illustrates the importance of protein reduction. Now Praliciguat. So what is Praliciguat, Praliciguat is an agent that works with [indiscernible] that are nitric oxide sites and innodependent. 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 [ TRIPC-6 ] pathway. So what we're going to show you is just a little bit of preclinical data looking at the TNF-alpha induced inflammation and TGF-beta in human proximal tubular cells. We're also going to look at an [indiscernible] and mouse models to present that data and then also a 56 nephrectomy [indiscernible] model CKD. All right. Let's look at this. So this is a function of what Praliciguat does on reducing the toxic effects of a very important cytokine called TDF. If you don't know, [indiscernible] is probably the predominant cytokine that regulates forces that lead to [indiscernible] and interstitial fibrosis. So if you have a model here where TGF is administered to animals and you look at a glomera structure, you can see that what in the -- it's a little difficult to point out, but the glomerulus is full of [indiscernible]. There is a collapse of vessels. There is [indiscernible] inflammatory cells, there is fibrosis. And then that same animal model when treated with Praliciguat at 10 mg pre gauge per day, you're basically looking at a normalized [indiscernible]. So the effect in this model of TGF dependent [indiscernible] sclerosis is highly effective. The right-hand set of data shows you the more clinical aspect of this, you can see that in the animals that have high-salt diets and part of the TGF pathway the level of urinary protein is much higher and is blocked down significantly Praliciguat. Glomera sclerosis, you see again, almost a dose-dependent reduction in [indiscernible] the glomerulus with Praliciguat, it reduces TGF-beta production by the kidney and reduces the intersectional fibrosis. And one more our data point, I'll turn this over to Steve, is this is a mild preclinical looking at cultured human proximal tubular cells and the top panel, you see these have been TGF-beta. And you can see the clustering of the cells that is a hallmark of [indiscernible] cells that are undergoing what's called [indiscernible] transformation. What is happening these selves, they are literally turning into fiber blocks. And to remind you the importance of the fiber blast are, in fact, [indiscernible] to do the driver of the scarring formation within the interstitium with the kidney. But if you take those cells trade with TGF and Praliciguat [indiscernible] micromole you normalize the culture of proximal tumor cell. Now taking a look at the ride and data, there's a subtle thing that I want to point out. If you look at this day, there's 1 point where the [indiscernible] are treated with an antibody to TGF beta. And what's interesting is that in this particular study, the Praliciguat was superior to the TGF antibody in blocking this [indiscernible] transformation. And why is that important? Because in previous studies in FSGS blockers to TGF have been tried before and were unsuccessful. We then why would Praliciguat be more effective than an antibody in TGF. Well, obviously, we don't know but we think it has to do with the augmentation of downstream effects of the pathways that stabilized the fibrotic processes and by [indiscernible] growth. So I think that's my last slide, and I'll turn this over to Dr. Burke.

Thank you, Dr. Tumlin for that excellent presentation. Akiba was very excited by the preclinical package we inherited from Cyclerion. After a deep review, Akebia decided that FSGS was 1 of the most promising applications for Prali. But before making a final decision, Akebia conducted 2 additional nonclinical studies. One of 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 Prali for FSGS. Now I'll give a high-level review of the 2 study results. In this model shown here, animals received a single dose of adriamycin on day 0 and then prali treatment with or without the ACE inhibitor [ enalapril ] on day 6 to 14. Urine was then collected overnight and the animals were sacrificed on day 15 for kidney histology. As mentioned previously, adriamycin accumulation 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 fivefold increase in urine protein to creatinine ratio. Praliciguat doses of 3, 10 and 15 mg per kg did not decrease proteinuria when administered alone, as shown in the blue bars. But when combined with the [indiscernible] 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 prali 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 tubular interstitial fibrosis and degeneration, which drives the transition from reversible injury to progressive, irreversible chronic kidney disease. Now let's switch to the [ 5/6 nephrectomy ] data. The model involves in farting 5/6 of the kidney by arterial legation to cause hyperfiltration of the remaining glomeruli and the remnant kidney. This hyperfiltration causes proteinuria and glomerulosclerosis. Study drug treatment begins 2 weeks after the surgery, it continues for 7 weeks with periodic blood and urine collection and necropsy at 9 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 prali 1.5, 3 and 10 mg per kg alone, and the final 3 bars are prali at the same doses in combination with enalapril. Similar to the adriamycin experiment, the combination of prali with enalapril showed the greatest reduction in proteinuria, and that data is highlighted by the black circles. Praliciguat in combination with enalapril, but 3 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 prali 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 of 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 prali will be added on top of those therapies. In addition to generating additional nonclinical data, we reanalyzed Cyclerion's Phase II study in diabetic nephropathy. 156 subjects with CKD and macro [ abanminuria ] were randomized to placebo or praliciguat 20 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% to 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 prali groups achieving UACRs less than 0.3, 0.5 and 0.7 using the modified intent-to-treat population. In FSGS, approximately 2/3 of urine protein is albumin. So a UACR of 0.5 approximates a UPCR of 0.7, the parasol endpoint. And as shown in the table, the proportion of subjects achieving UACR less than 0.5 increased from 34.8% in the placebo group to 51.2% in the prali Group, an absolute increase of 16.4% and with a relative risk of 1.47. So a 47% increased chance of meeting this level of response in the prali 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 prali in adults with biopsy-confirmed FSGS. The study randomizes up to 60 subjects to prali or matching placebo for 24 weeks, after which the placebo patients will cross over to prali. 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 grams per gram. And this will inform us if we should proceed to Phase III. At this point, I'm going to turn over the presentation to Dr. Michael Holers to discuss our new tissue-targeted complement inhibitor [ abri. ] 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. Holers.

So I'm very happy to go through the background of AKB-097. First, with regard 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 disregulated 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 want to point out is that there are convertases that are 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 to targets that covalent attachment is in a very important function of this molecule. It is then degraded through a series of proteasis to form the fragment shown in the red, most importantly, C3D. Now the other complement inhibitors are focused, as shown here on this 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. So 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 a pathway. However, a reduced treatment burden is shown with preclinical data demonstrating that once weekly dosing and perhaps every 2-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 the C3D fragment with very high affinity and very high avidity as I indicated before. Linked to the antibody is a negative regulatory protein of Factor H. This is an edogenous 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 a, as I said, a unique mechanism that allows this tissue-directed inhibitor to block complement and irreversibly inhibited at tissue sites. C3D is a very important target, as shown in this slide, this fragment identified with the same monoclonal antibody is 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, the 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 milligrams per kilogram of this inhibitor resulted in a very prolonged decrease in C3 activation in [ 37 ] and barely coming back at 2 weeks or 14 days. At the bottom, one can see that the AKB-097 itself was present in that tissue site for 7 and upwards of 14 days. Therefore, one can clearly see a durable binding of the inhibitor to sites where C3D is being actively generated. And when that durable binding occurs, further C3 activation is blocked. Practically, this is also shown in a model of [indiscernible] 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. But on the right side in the center, one can see this complete association, if you will, between systemic complement inhibition and local complement inhibition. So if one looks at the middle, 1 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 [indiscernible] membrane damage and [indiscernible] 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 [indiscernible] processes in these particular sites. Therefore, in some, 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. So 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 [ abri ] 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 [ abri ] over time in the days following single IV doses of 0.1 to 33 mgs per kg. On the right is the percent of baseline alternative pathway complement activity by dose over time. IV [ abri ], particularly at the high doses, such as 310 and 33 mg per kg, inhibited the alternative pathway systemically, which is good, and it shows it functions as a complement inhibitor. In the figure, anything above 50% is mild inhibition and associated with the low risk of infection, 20% to 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 [ abri ] over time in days following single subcutaneous doses of 3.75 and 10 mg per kg and also a 450-milligram dose administered once weekly for 5 doses. You can see that the peak plasma level of 10 mg per kg subcu is much less than the equivalent IV dose above. On the bottom right is a percent of baseline alternative pathway complement activity by dose over time with the subcutaneous administration. The complement inhibition with the 10 mg per kg dose is mild as compared to the near complete inhibition with the equivalent IV dose above. The 450 subcu dose which equates to an average dose of around 6 mg per 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 4 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-milligram subcutaneous dose with the thick green line. The 450-milligram 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-milligram subcutaneous exposure was at a level well below that, which would cause 50% or greater inhibition of the alternative pathway systemically. And 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 antidrug antibodies. Now I'm going to turn this over to Dr. Jonathan Barratt, a nephrologist with deep knowledge of glomerular diseases who can discuss the potential role of [ abri ] in treating complement-mediated kidney disease. Thank you, Dr. Barratt.

Thanks very much, Steve. So where we see this drug being a particular use are in a number of different complement mediated kidney diseases where we have very clear evidence that intrarenal complement activation drives glomerular injury, glomerular fibrosis and loss of kidney function. And these conditions are IgA [indiscernible], lupus nephritis and C3G. Now 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, and 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. And so when we think about lifelong therapy, we need to think very carefully about long-term safety. And 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. And as you heard from Dr. Holers, complement activities is essential to manage pathogenic diseases from microbes. And 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. And so there is a real opportunity here, I believe, to use these drugs in these comp-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. So 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. And we -- in that situation, we need to really concentrate on minimizing the potential long-term risks associated with those therapies. And therefore, our 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 needed to be given for many, many years. And so 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 3 [indiscernible] mediated kidney diseases, [indiscernible], lupus nephritis and C3G in an initial study to assess safety of 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 [ C5b29 ] as a biomarker of terminal complement pathway activation in the kidney. The study will be for initial 26 weeks, and we are targeting 30 patients with the hope that this study will start in the second half of this year. So thank you for listening, and I'll hand back.

Thank you, Dr. Barratt, for that overview of complement-mediated kidney diseases in the [ abri ] 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 CS-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 pro hydroxylase inhibitor developed at Akebia to prevent or treat CS-AKI. AKB-9090 works by stabilizing HIF in the kidney to activate cell survival pathways, alter metabolism, decreased 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, 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 9090 data from an ischemia [indiscernible] model we run at bats. The model involves removing one kidney and then including 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. 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 2 groups, 4 mg per kg over 8 hours and 30 mg per kg over 4 hours were particularly effective in decreasing the rise in serum creatinine, the main clinical marker of kidney function. And 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 New Zealand. The planned Phase II study will treat patients undergoing elective cardiac surgery requiring cardiopulmonary bypass. 9090 will be dosed immediately prior to surgery, immediately after surgery in 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?

So Dr. Holers, I think that would be for you. .

Great. Thank you. Certainly, it's 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. So we were able with colleagues to different strategies to direct inhibitors to tissue sites and came up with the C3d targeting approach, and it was shown in multiple studies to be the most effective way to do it. Our colleagues at [indiscernible] Bio when they had an optimized structure function relationships of this. And then 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 the two. So the other, I think, important point is that the Phase I PK data was entirely as expected. So we -- 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 should be -- that we would be able to separate these effects out in a clinically relevant manner.

Thank you, Dr. And 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.

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, 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 [indiscernible] levels in urine is turn out to be a very nice way of understanding local complement inhibition. So 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.

Yes. And I just want to -- as a nephrologist, I think I have to say this, and Jim will wrap me up, keeping biopsy tissue will be wonderful to see this in terms of showing that the drug is localized to the kidney tissue and then it is having an immediate effect on complement activation of those downstream inflammatory pathways. And 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 forward, but I think that is a real opportunity to link kidney tissue localization with what we're seeing in the urine. So that's another great opportunity to think about really showing the unique way of this approach.

Just to echo what Jonathan's saying, I totally agree that the utilization of repeat biopsies and something I'm kind of famous for. I've been in advocate for 20 years, is knowing and looking at the actual deposition, the working in and the activated complement at the tissue level cannot be underestimated. The [indiscernible] complex in New York I agree with Dr. Holers is in 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, it's going to be a major step forward.

Thank you all.

Let's switch to a few questions on praliciguat. First, how does praliciguat differ from [indiscernible] and antagonists AP1 inhibitors? And how does this provide an advantage? .

Really good question. There's a lot of activity in FSGS, as you know. So the [indiscernible] story is unique. So this is a gene product that's expressed in duality, autosomal dominant, particularly at almost to exclusion in people of African [indiscernible]. Now that's large percentage of patients with FSGS, but its pathway is fundamentally different than what praliciguat addresses or the [indiscernible] this is a [indiscernible] hormone proteins a part of the passive 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 FSGS. But [indiscernible] not going to be confused with the market for Praliciguat because you're going to know this person is [indiscernible] positive. The ERA story is a little different. ERA is activated by [indiscernible] injury of any type, and it's not limited to FSGS certainly seen in IgA is seen in lupus even in diabetes to a lesser extent. So blocking that pathway, which leads to downstream fibrosis and [indiscernible] in these patients is one pathway that would be treated. And it would not at all be opposed to co-treatment with Praliciguat, in my opinion.

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?

Yes, sure. So as I said a moment ago, ERAs are going to be used. Again, in my opinion, they're going to be a foundational drug of CKD. They will be used in IgA and they are used in IgA that will be used in FSGS and a number of other chronic kidney diseases. So that's one modality of therapy and going back to my comments for [indiscernible] that reducing proteinuria by an ER pathway is helpful, but you will not reduce the proteinuria sufficiently in every person and there's going to 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 is going to expand into secondary [indiscernible] as well. And so where there is an issue where there is podocyte dysfunction solubilized 1 cyclase signaling pathways, Praliciguat is going to have an advantage to stabilize and reduce that proteinuria.

Yes, Jim, I completely agree. I think podocyte injury is common across glomerular diseases. And this mechanism of action, while prior FSGS is the obvious choice. I think there's opportunity here to expand beyond that initial indication. So I completely agree with you.

The next question comes from the team at Leerink Partners and also [ Matt Caufield ] from HCW. I 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. So we talked a little bit about that again, a lecture is the Parasol data. And everyone emphasized to the audience that -- the [indiscernible] data is very important, but data from Jonathan's registered the RADAR data and data going back to the Toronto registry with [indiscernible] several years, many years ago, all show to the same thing. That if you reduce that protein or even by 50%, you benefited the long-term outcome in the patient. But to answer your question, the Parasol data say you won't [indiscernible] between 300 and 500. There's a bit of an argument among -- was a mistake? You okay?

Yes. Yes, we're good.

Okay. Sorry. So dealing that number between 300 and 500 may not be entirely possible for a lot of people that have had long-standing -- there's a phenomenon called scar proteinuria and really quite simply damaged kidneys can't resort protein as well. And therefore, there could be a floor which you really can't get below it any further. But suffice it to say, for the purpose of this discussion, between 300 and 500 would be optimal.

A few more questions back to AKB-097. Do you expect AKB-097 to be complementary to [indiscernible] inhibitors in IgAN and other indications?

Dr. Barratt?

I think it's ideally suited to be honest. I think the challenge we're facing in [indiscernible] is we have drugs that target antibody production. We have drugs that target complement activation systemically. And 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, and that may be appropriate for a short period of time. But as I said in my talk, when we're thinking about our [indiscernible], we're thinking about a disease that affects 30-year-olds, 40-year-olds. Our goal is for them to avoid kidney failure in their lifetime, we're talking about treatment exposure over 40 or 50 years. And I would be concerned about impairing the adaptive immune system and antibody production, while also taking out a key component of urinate immune system for 50 years. So 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. So 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, Jon. I just could not possibly agree with Jon more. I think that the complement inhibitor with an [indiscernible] alone is ideally additive. And now with Dr. Holers observations on localized activation C3D, now we have a method. So we'll repeat [indiscernible], we're going to be able to say that patient [indiscernible] moved back into a complement dependent form of the disease and therefore, would go with addition [indiscernible] for some period of time, I agree with Jonathan. I don't think it will 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.

So 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?

Steve first. Would love to hear other opinions.

Yes, sure. We inherited a protocol from Q32 and decided the quickest way to get into the clinic was to go after the 3 indications that have 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 the data while we transition to Phase II/III for 1 of the indications. So yes. .

All right. A few questions on AKB-9090. First, how does AKB-9090 differ from [indiscernible] and why is tissue targeted approach in 9090 expected to succeed while HIF inhibitors have historically struggled in AKI?

Yes, I can take that one. AKB-9090 obviously is a different structure than vadadustat. Vadadustat is acted upon by organic and ion transporter. So is taken up by the liver and primarily act in the liver. So for instance, the increase in erythropoletin that we see in patients with CKD that's coming from the liver, not from the kidneys, for the most part, whereas AKB-9090 is not acted upon by the [indiscernible] and so has much higher tissue penetration into the kidney itself. And we see very good target engagement in the kidney, even more so than in the liver. So 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. So based on our data, 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-PHs decrease acute kidney injury. That's why we're going to be the first one, hopefully to show that this pathway is attractable target in CS-AKI.

What early human signals, biomarkers, AKI shift staging shifts would meaningfully derisk this program before a large outcome study.

Sure. The Phase I study is in volunteers. So we'll just be looking at target engagement, so measuring increases in [indiscernible] production. The Phase IIa, we'll look at things like cardiac surgery associated incidence, severity and duration as well as additional biomarkers. And based on that, we would then plan a Phase III study. But we are also going to be looking at other organ complications of cardiac surgery. So 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. So we'll be looking at all of the applications 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 [indiscernible] do you expect prali's mechanism to be effective across patient subtypes, primary and genetic FSGS? And how are you [indiscernible] this in the P2 trial?

Good question. Yes. So I think for the genetic, it depends on which 1 you're looking at. I don't foresee Praliciguat up being something that would be an add-on to the [indiscernible] 1 pathways. There's 2 different ones being approached, which I said previously was an antisense knockout and then a small molecule inhibitor with the [indiscernible] we kind of don't see that happening there. But to the broader question, and Jonathan alluded to this, whenever you have podocyte damage, this pathway of reduction [indiscernible] activity becomes relevant. And so this is the downstream pathway that is a consequence of a variety of different injuries. So the answer to your question is yes. I see this being a broader application. Even if we don't have the ability to get to the point to be able to say that patient has this etiology for their FSGS or patient-wide, and other etiology because there's a certain commonality through the [indiscernible] pathway in the podocyte, I think Praliciguat is going to have a broader application. It's smart.

And just to clarify, we -- for our trial that you're running, Jim, we're including primary and genetic, but we're excluding secondary FSGS. 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 supporting the 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.

Right. So the -- I would say the 3% reduction in proteinuria is, again, I'll just keep reemphasizing that even a 30% reduction is likely to benefit people longer. Remember, that trial did not have -- terribly -- I don't remember the exact length of time follow-up and that reduction even at 30%, and I'm guessing that we're going to see better than that with FSGS is going to have the potential benefit for the patient. So that would be a way forward, I believe.

Yes. And I would say that, yes, the results look very similar to what [indiscernible] gives you above and beyond [indiscernible] and that's both in terms of proteinuria reduction, but also the proportion of patients who meet certain thresholds of proteinuria. And that slide I showed you, I focused on the 0.5, but you see the 0.3, 0.7 grams per gram for the UACR and that's very [indiscernible] like. So that's certainly encouraging. Not the same disease as FSGS. They have much more [indiscernible] FSGS. So it would be very interesting to see what we observe in that patient population.

So as I'm looking at the question, 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 for many of our distinguished guests that you want to share before we will we close out?

I mean I'd just like to say I really like the idea of tissue targeting 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 [indiscernible], but also within the [indiscernible]. And 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 all of -- and so 1 of the beauties of this approach is this is an IgG4 antibody, which is eminently easy to stain for. And could we be seeing activity not only within the [indiscernible] in terms of calming down glomera inflammation, but also within the [indiscernible] and preventing local complement activation and progression of institutional fibrosis, which is to be honest, the major reason people end up on dialysis. And 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. So 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. So yes, I think this is a really exciting approach. I 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.

Add a little bit to what Jonathan was saying even a part of good comments on the IgG for staining, just reducing low-level complement activation, we need to remember that C5a, a product activation [indiscernible] pathways is a very potent [indiscernible] 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. And what would comment about praliciguat, I would like to go back to emphasize is something I tried to point out in my talk that in [indiscernible], which was an antibody against all 3 forms of TGF-beta did not work in FSGS. And 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 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. And 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.

I hope all the folks who are listening in on the call today are hearing the excitement from the panelists and it's that excitement that that we at Akebia felt as well as we looked at 097, 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. So I want to thank our panelists today for their time, and they're very insightful comments. Hopefully, folks really benefited from that. I'm quite sure that they have -- and I think if we could put up the one final slide, just to close out. Well, we have just -- 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-plus months here at Akebia. I mean everything under the backdrop of driving vadadustat, Vafseo to be standard of care in dialysis. A tremendous amount of work left to do there, but we're really -- 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 [indiscernible] that will really benefit patients in the long run. And just to remind everyone on the call, that is a $1 billion market in the U.S. So we're excited about the progress we're making there. But now we have so much more to think about and talk to you all about with the number of catalysts we have. We initiated the praliciguat trial in December. Thank you, Jim. We are going to be initiating the [ abri ] 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 9090, that's really just a few weeks away from dosing first in human, which is always an exciting moment for a company. And then 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 '27 and given that we have an open-label basket study, we can start seeing data from 097 in 2027. So we're really excited to to continue to talk to you about this as we continue to execute as a company, and we look forward to it. And again, thank you again to our panelists, for taking the time, and thanks for everyone for joining us today. We look forward to talking to you again soon.