ProKidney Corp. (PROK) Earnings Call Transcript

Good morning, everyone, and welcome to the ProKidney American Society of Nephrology Kidney Week recap and Corporate Update. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the ProKidney website following the conclusion of the event. I'd now like to turn the call over to Ethan Holdaway, Vice President of Strategic Finance and Investor Relations at ProKidney. Please go ahead, Ethan.

Thank you, operator, and good morning, everyone, and welcome to our webcast. Before we begin, I'd like to remind everyone that we will be making forward-looking statements during the presentation today. I encourage you to refer to our most recent SEC filings regarding risk factors associated with these statements. On the webcast this morning, are Dr. Bruce Culleton, ProKidney's CEO; Dr. Anthony Conway, ProKidney's Head of R&D; and Dr. Katherine Tuttle, Executive Director for Research at Providence Inland Northwest Health and Professor of Medicine at the University of Washington. I'd now like to turn the call over to Bruce. Bruce?

Thanks, Ethan. Good morning, everyone, and thank you for joining us today. At ProKidney, our mission is to transform the outlook for people with advanced chronic kidney disease by extending life without dialysis. Today's discussion will focus on the science supporting our work and the potential role of rilparencel within the evolving chronic kidney disease treatment landscape. I will start with a brief corporate update. Anthony Conway, our Head of Research, will then recap his team's presentation at the American Society of Nephrology's Annual Meeting, which just happened in Denver last week. These presentations provide an opportunity to examine the scientific rationale for rilparencel and how that research is advancing our understanding of its potential. You will hear how our MOA thesis is coming together. We're also pleased to welcome Dr. Katherine Tuttle, who will discuss therapeutic options for patients with chronic kidney disease, the needs that remain despite advances in care and where rilparencel if successfully developed and approved, may play a role. For investors on the call today, we hope today's discussion provides a clear understanding of both the science behind rilparencel and the clinical need we are working to address. Before I jump in any further, I do want to thank our presenters, Dr. Tuttle, in particular, Dr. Conway, our ProKidney team and especially the patients and investigators participating in our studies. So here on this slide, for those of you who are unfamiliar with our story, rilparencel is an autologous cell therapy currently in late-stage clinical development. Our Phase II data suggests that rilparencel may preserve kidney function in patients with diabetes and advance chronic kidney disease. In the U.S. alone, hundreds of thousands of people have type 2 diabetes and advanced CKD. Each day, roughly 350 Americans begin chronic dialysis, a reminder of the urgent need for treatments that can preserve kidney function and extend life without dialysis. Next slide, please. 2027 will be a critical year for ProKidney. We are finishing 2026 with excitement and momentum. Patient recruitment into our Phase III study exceeded our expectations. In August, we closed recruitment after a surge in screening across our 80-plus study sites. Previously, we guided to finish enrollment in 2026. Due to the surge in recruitment over the spring and summer, we will continue to enroll screened and eligible patients into the first quarter of next year. Our overall number of enrolled patients for the study has also changed from 470 to well over 500 participants. I'm happy to state that we remain on track for the top line readout of our Phase III study in Q2 2027. As a reminder, this is an interim analysis for accelerated approval using eGFR slope as the surrogate endpoint. Importantly, all patients for inclusion in this readout have already been enrolled in the Phase III study. Next slide. For those of you not familiar with our program, this is a depiction of our Phase III PROACT 1 registrational study. This is a rigorous design in which eligible patients are randomized to either the treatment arm, you see here the rilparencel arm or the sham-controlled arm. Study participants, site investigators and site personnel are blinded to the treatment allocation. For the surrogate endpoint analysis seen at the bottom of this slide, we are powered to detect a 1.5 ml per minute difference between the 2 groups in eGFR slope. We are assuming an annual decline in eGFR slope of 3 mls per minute in the control arm of the study. We've heard from many nephrologists that if our readout is positive, this 1.5 ml per minute difference, which is a 50% difference in kidney function decline between groups is very clinically meaningful, especially in these patients who are progressing to dialysis despite standard of care treatments. And now I'd like to hand it over to Dr. Anthony Conway to share recent scientific updates. Anthony?

Thanks so much, Bruce. So today, we'll be sharing with you some recent data that we presented just a few days ago at ASN in Denver. But before I dig into that, for those of you who aren't familiar, I wanted to go over how rilparencel is made and administered in patients with advanced CKD and type 2 diabetes. First, standard biopsies are taken from each individual patient's own kidney. Those cells are then sent to our manufacturing site in Winston-Salem, North Carolina, where the kidney cells are isolated and expanded to large amounts. Those cells are then cryopreserved and shipped back to the clinical site where they're then injected back into the patient's kidneys via interventional radiologist with CT guidance and then 3 months later into the contralateral kidney. Since these cells come from each individual patient's own body, no immunosuppression is needed. And unlike CAR-T, there's no preconditioning, no genetic modification, and these are outpatient procedures. The therapy has been well tolerated in our Phase II studies and has been associated with a 78% slower annual eGFR decline in patients with advanced Cadian diabetes in Cohort 1 of our REGENT-007 study, which is the design which most closely mimics our Phase III design. And as Bruce mentioned, we have a top line readout for our Phase III study in Q2 of next year. One of the biggest missing pieces, though, is how rilparencel may be working. We have really promising clinical data, but how exactly is rilparencel mediating that effect. And so to be able to do that, we need to uncover what's happening in disease kidney tissue after our product is administered. And so the way that we've been addressing this is by developing and utilizing a variety of translational disease models to elucidate the mechanism of action of rilparencel. And so I'll be talking through all of these different models today with data being presented at ASN just a few days ago on the in vitro, ex vivo and in vivo rodent models. Each of these have various advantages and disadvantages. The in vitro model is relatively high throughput and can interrogate a wide variety of variables simultaneously to deconvolute specific aspects of the mechanism. The ex vivo model is from disease to donor human donor kidneys, so replicates the disease pathology within the individual kidney biopsy obtained from those individuals and then can assess molecular changes, which are occurring after the introduction of rilparencel into culture. And then rodent models have whole body physiology that you can interrogate molecular and cellular changes after the administration of rilparencel directly injected into the kidney cortex as it is in the clinic. So taking an even further step back because one of the questions that we always get is, what is rilparencel? And so this question, we start to ask where rilparencel -- what cells within the individual kidney biopsies is rilparencel derived from? And so what we did is utilized 3 batches of process development made rilparencel, starting with kidney biopsies from patients with different stages of CKD. You can see Stage 4, 2 and 3. Also the end of the first passage after rilparencel is digested and plated into culture plastic and then rilparencel itself or late-stage manufacturing product. You can then see we run these cells for single-cell RNA sequencing on the right. I can then see where they cluster and what the individual transcriptome is of each individual cell. And so for the purpose of this presentation, I'll be describing rilparencel, either as selected renal cells or rilparencel. Selected renal cells are the cells within rilparencel. And so what we did was a temporal inferred transition algorithm to be able to analyze what cells within the early passage did the -- came from the kidney biopsy. So you can see here on the left, the cells in blue are individual cells from the kidney biopsy. These span from epithelial cells of the distal nephron. And so you can see on the top right, a schematic of the nephron. And a reminder, we're taking kidney biopsies from the kidney cortex of the patients. And so the cells in orange on the top are coming from the Intercalated cells connecting tubule cells and they can sending limb cells of the nephron. So that's the distal part of the nephron. And then at the bottom, you can see that these cells are coming from the proximal tubule. Interestingly, you do see within this early-stage passage cells from interstitial cells as well as endothelial cells and even some immune cells. But at late-stage manufacturing in rilparencel, you can see that there's a convergence of cell phenotype, and these cells are coming exclusively from either the distal or proximal epithelial cells, and they do cluster separately here. Digging a little bit further, and this is from patient retains from a Phase II study, you can see that these 2 distinct lineage-associated populations are present within all 17 batches of rilparencel here. You can see then some population markers on the right of various genes that are highly expressed in either the proximal or distal subpopulation and they're present in all 17 batches. And due to this inferred trajectory analysis, we're determining that these cells are coming either from cells of the distal nephron or proximal nephron. You can see then we looked at various characterization markers across 17 rilparencel batches and as shown on the left here. And there's a remarkable consistent product profile within all 17 patients despite this initial lineage heterogeneity and expression heterogeneity within the individual study biopsies. And you can see in the middle, this is looking at various example markers that are expressed within rilparencel. And you can see an expression heterogeneity from the initial biopsy. Some are expressed more in the distal epithelial cells, some more in the proximal. But there's really a convergence of expression over the course of manufacturing towards the final drug product shown on the right in the green. And so I don't have time to go into all of the details here, but refer to our ASN poster, but take-home message is rilparencel are cells of proximal and distal epithelial origin, exhibiting a reparative plastic associated transcriptional signature with partial retention of native lineage identity. All right. Next, what is rilparencel doing? How are we answering that? So one of the first models that we're utilizing is this in vitro model system. We're utilizing a couple of different ones, either primary kidney cells in culture or kidney on a chip system, which we'll go into a little bit more detail. So what we're doing is inducing a disease state by adding in various injury mediators, and I'll go into more details in a few slides, adding in rilparencel into culture and then assessing a resolution of disease state phenotype over a period of time. And these disease states are reflective of various pathways related to the pathophysiology of CKD. And so you can see here, we're bucketing our assays that we're developing and utilizing into various common CKD pathways, oxidative stress, inflammation, metabolic dysregulation, fibrosis to be able to interrogate individual molecular readouts from each of these different pathways. But CKD is actually a complex disease, and this is really a cyclical vicious cycle of disease pathology here, which is nicely demonstrated from this figure from Kathy Tuttle on the right. But to be able to interrogate each individual pathway, we're looking at specific readouts of these different pathways within our model systems. The idea is to see where we're able to resolve different disease states by rilparencel to be able to deconvolve how rilparencel may be able to preserve kidney function in patients with advanced CKD. All right. So, our first model system. So, this is our kidney-on-chip system. This is from a company called MIMETAS in the Netherlands. You can see a schematic here in the middle. It's a microfluidic-based system. We're adding in glomerular vascular endothelial cells on the left, and this is to mimic the blood vessel and then renal proximal tubule epithelial cells on the right, and this is to mimic the tubule. And so these are in close proximity to each other, just like they would be in the natural existing nephron within the kidney. The middle is an extracellular matrix, which is within the interstitial region. And then we're adding in rilparencel into this region to mimic the intraparenchymal injection that we're doing in the clinic. We're then able to induce an entry phenotype, and those are mediators reflective of chronic kidney disease shown on the bottom left, high glucose inflammatory cytokines, high lipids, uremic toxins and then waiting over time and then seeing what changes have occurred as a result of rilparencel administration. All right. So first, looking at the endothelial channel, so the cells comprising the blood vessels. And I'll have on the top right, kind of the area of the nephron that we're referring to for each individual mechanistic slide. And so we're able to show here through a variety of different endpoints that rilparencel promotes endothelial junction and barrier integrity. On the left, we're doing single-cell RNA-seq of endothelial cells either with injury or control and then either with rilparencel treatment or untreatment -- nontreated and you can see with injury, we're activating a variety of markers related to endothelial activation and endothelial to mesenchymal transition, various markers related to the pathology of CKD, whereas with rilparencel treatment, these markers -- the gene expression of these markers goes down. Similarly, we're seeing upregulation of barrier disrupting and permeability related gene expression with injury and that concomitant goes down with rilparencel treatment. We're then able to look via functional validation of various markers related to endothelial junctions and cell-cell adhesion, so CD31, VE-Cadherin, ZO-1. These go down with injury and then are restored nearly to baseline with rilparencel treatment. ICAM-1, which is a marker of inflammatory mediated gene in endothelial cells, this goes up a lot with injury and then is able to be attenuated to some extent with rilparencel treatment. Similarly, SMA, which is a marker of endothelial to mesenchymal transition, this is able to be partially restored with rilparencel treatment. If we look at a barrier permeability assay, so actual like functional barrier integrity with a fluorescently tagged dextran, we're able to see that with injury, this permeability goes up and rilparencel is able to restore that. And this is in a 2D culture in a trans well system. So this effect is entirely mediated through the factors which rilparencel is secreting to these endothelial cells to restore this barrier integrity. All right. Next slide. So this is showing the endothelial metabolic state, and this is using the Seahorse metabolic analyzer. So there's a lot of data here. So I'll just show you the kind of the take-home message is that endothelial cells are more naturally quiescent metabolically, and they utilize glycolysis primarily versus oxidative phosphorylation, which is a less oxygen-rich method of respiration. And so they're transporting the oxygen, not utilizing it as much. And so with rilparencel treatment, we're able to restore the levels of glycolysis that is in the control conditions, whereas this goes down in injury. And then similarly, we're able to actually above baseline or below baseline, create a more quiescent metabolic state with rilparencel treatment from 2 different donors. And this is indicative or strongly suggests a parasite like endothelial cell metabolic stabilization that's occurring here. All right. And then looking at pro-inflammatory signaling and recruitment cues in this kidney-on-chip system, we're also able to look both at the endothelial as well as the epithelial channel. And so this damage-associated molecular pattern secretion assay. So this is an antigen HMBG1, which is naturally found within the nucleus is actively secreted upon an inflammatory signaling and stress to promote immune infiltration. And so you can see here with injury shown in red, the level of DAM secretion dramatically goes up, whereas with rilparencel treatment, we're able to restore it to close to baseline. We see a similar trend here with the epithelial channel, but it's important to note that in the endothelial, you see a much higher level of HMBG1 secretion, indicating an increased level of pro-inflammatory signaling from the endothelial channel specifically. And then looking just at the epithelial channel on the right, we can see that NFκB, which is a transcription factor related to pro-inflammatory signaling. You can see that upon TNF-α mediated stimulation, which is a pro-inflammatory cytokine, that goes up, the phosphorylation of NFκB and its partner IκBα goes up. And then with rilparencel treatment after 30 days, this significantly goes down back to baseline. All right. And then moving now just to the epithelial channel, so the cells comprising the tubules within the nephron. We're able to show here that rilparencel is able to lower reactive iron species and activates the cytoprotective lipid peroxidation repair program in injured renal epithelial cells. And so the reason that iron is important is iron is involved in a process called ferroptosis, which is an iron-mediated method of cell death that's involved in chronic kidney disease pathology. And so you can see here on the left that with rilparencel treatment, gene expression related to iron homeostasis goes up. And then on the bottom left, you can see that antioxidant gene expression in epithelial cells also goes up with rilparencel treatment. On the right, you can see that with rilparencel treatment, the total amount of iron goes down. And then importantly, specifically, the reactive ferrous iron species goes down with rilparencel treatment as compared to intercalated control. And this is important because the ferrous iron is the reactive species that promotes the fentin reaction, which drives lipid peroxidation, which is an oxidized form of lipid, which induces mitochondrial and cell membrane dysfunction. And so then looking at specifically the oxidative damage lipid species here in mitochondrial dysfunction, we're able to show here with rilparencel co-culture, we're able to rescue this oxidative damage and mitochondrial dysfunction in epithelial cells. This is shown on the left, whereas lipid peroxidation significantly and substantially goes down after 4 days of co-culture with injured epithelial cells. And then you could see also the mitochondrial coupling efficiency and spare respiratory capacity also goes up with rilparencel treatment, so the mitochondria are more functional. On the right, you can see a dynamic change in mitochondrial functionality, restoration with rilparencel treatment with essentially complete restoration of spare capacity and bioenergetic health at 7 days of rilparencel treatment, indicating this is a dynamic effect as a result of rilparencel co-culture. And then finally, we're digging into more molecular mechanism here. So GPX4, which is a master antioxidant related to lipid peroxidation repair, the activity of GPX4 is required for rilparencel-mediated rescue of oxidative damage in mitochondrial dysfunction in epithelial cells. In this case, this is an even shorter time window, experimental time window. We're looking at glutathione and redox balance within just 8 hours of rilparencel co-culture. You can see that with injury, which is the red dots, the redox -- glutathione redox balance goes down as compared to the black dot control, whereas with rilparencel, which is in blue, this is able to restore it back to baseline. And then by blocking GPX4, which is with a small molecule called RSL3, you lose this therapeutic effect, indicating that GPX4 activity is required for this effect. You see similar effects with protein carbonylation, an oxidized damaged form of proteins as well as lipid peroxidation at 16 hours of rilparencel co-culture. And then at 1 day of co-culture, you see also a similar restoration of mitochondrial membrane potential and biogenic health index. And so the next step for us is to really determine what factors within rilparencel are mediating these therapeutic effects. And so right now, we're doing gene editing experiments to deconvolute what specific factors are necessary and sufficient for these therapeutic effects of rilparencel. This is just an example of seeing various differential gene expression of the cells within rilparencel upon co-culture in injured kidney cells, and this are giving us some clues as where to start. All right. And so finally, focusing on our -- some of our in vivo mechanistic studies. And so back in the early 2010s before we got into the clinic, we were able to demonstrate that SRC or rilparencel treatment in diseased kidney models in rodent and dog we're able to extend survival and stabilize renal function. This is with either syngeneic cells, so cells derived from that individual species or human rilparencel into immunocompromised rodents. Now with the advent of multi-omic technologies, we are utilizing an additional model here, the adenine-induced model of CKD and doing multi-omic analysis on kidney tissue with either rilparencel treatment or a vehicle treated control and the vehicles are with the excipient of rilparencel injected into the same region of the kidney. Right. And so first off, we want to see where rilparencel is going after we're injecting it. And so we were able to do immunohistochemistry here, and this is in a humanized immune system rodent model that's been fat adenine to induce a CKD phenotype. You can see in purple here at 1 day post dosing after injection of rilparencel into the kidney cortex, you see actually this large subcapsular deposition of rilparencel interestingly. It's also throughout the kidney cortex parenchyma, but the largest deposition by far is within the cell capsular region very interestingly. And you can see here at 28 days that some of these rilparencel cells are still present within this region, albeit at a lower amount. We then look to spatial transcriptomics to see what gene expression changes are occurring in this rilparencel-associated graft region. And so this is shown kind of on the bottom left here, we're able to identify a rilparencel-associated gene signature, which matches up very nicely with the IHC confirmation of rilparencel engraftment location. Then if we look at the whole transcriptome changes within this graft-associated region, we're able to see a distinct transcriptional signature of ECM remodeling, vascular development and support. So there's collagen being biosynthesized, blood vessel morphogenesis or gene expression related to blood vessel morphogenesis and matrix turnover occurring. This is a dynamic effect. And so this is comparing to vehicle control from 1 day, 3 day and 7 days post injection of rilparencel. You see a peak at day 3 with ECM remodeling and vascular support-related gene expression going up with it starting to wane slightly by day 7. Next, looking at single nuclei RNA-seq to dig even deeper, not just in the graft-associated region, but within the entire region of the kidney that has been injected with rilparencel. And in this case, looking specifically at the rat endothelial cells, which we saw the most dramatic effect from our in vitro mechanistic studies. And so in our rat endothelial cells, 28 days post injection of rilparencel, we're able to see a large upregulation of gene expression related to cell junction and ECM adhesion signaling, which matches very nicely what we were seeing in our in vitro model, which is a reminder, shown on the bottom right. So gene expression related to endothelial cell-cell junctions and ECM signaling is shown here. And then finally, we look to mass spec imaging to be able to determine the differential lipid metabolite changes as well as utilized a panel of mass tagged antibodies to see proteomic changes in a spatial organization after rilparencel injection. And so this is showing that there is a distinct tissue remodeling signature at the rilparencel injection site, and this is 3 days post injection of rilparencel. You can see on the top right here. This is with a mass tagged antibody to a human antigen to determine the location of rilparencel. And in this case, this is in a rat kidney that doesn't have human immune cells. So this is specific to rilparencel injection. You can see in this region of interest or ROI, you can see that there's a significant upregulation of proteins associated with stromal vascular remodeling, cell adhesion, autophagy and a lipid remodeling profile that is differentially abundant in this rilparencel engraftment region. And then if we look at day 28, and as shown on the bottom right on the single nuclear RNA-seq data, we're seeing a specifically an M2 macrophage upregulation signature with SRC treatment, and this is related to reactive oxygen species scavenging, tissue repair and remodeling. And so in total, all of these various lines of evidence are leading us to understand more confidently the MOA of rilparencel. And so what we're seeing here from our various models of CKD is that rilparencel is attenuating oxidative damage metabolic dysregulation, pro-inflammatory signaling to support cellular resilience, preserve vascular integrity and functional stabilization under chronic kidney disease relevant conditions. And so all of these lines of evidence are giving us really high confidence in how rilparencel may be able to preserve kidney function in patients with advanced CKD. But that being said, we're still digging into more studies to really confirm this hypothesis, including the upcoming human DCM study as well as some biomarker studies in our clinical samples. So thank you very much, and I'll hand over to Kathy.

Well, hello, everyone, and thank you, Anthony, for that beautiful tour to force through the mechanistic data to support rilparencel as a true reparative therapy even in people with advanced CKD. And what I'd like to do now is really drop you into the framework and why this matters so much and why these mechanisms will really help us move forward. So first off, because I imagine not everybody here is an expert in kidney disease, I want to start with framing this on the scope of the problem. This chronic kidney disease really has become a global public health crisis. There are currently estimated to be 850 million people or 1 in 10 people in the general population with chronic kidney disease. And I would point out that in the United States, it's more like 1 in 7. And importantly, in addition to causing kidney failure, it's increasingly recognized as a major cause of mortality. And the death rate from 1990 to 2017 increased more than 40%. And just last year, the Lancet published an updated global burden of disease study where they showed that chronic kidney disease rose from the 19th leading cause of death in the world in 2013 to the ninth leading cause in the time frame of 2019 to 2025. And if we don't change what's happening, it is projected to be the fifth leading cause of death in the world by 2040. If we look at, again, U.S. and Western Europe populations, they're actually quite similar in terms of total burden of disease, 44 million and 40 million, respectively, and responsible in 1 year alone for nearly 150,000 deaths in each of these regions. And we know that this is an underestimate because death is often misclassified and CKD is greatly underrecognized. So this is a very low-range estimate of the mortality impact. Now if we walk back to diabetes, which really is the major driver of the CKD pandemic, what we see is the projections of people living with diabetes are also rather sobering. In 2024, nearly 590 million with a projection to 850 million by 2050. So unfortunately, what we know about diabetes prevention has not translated in a meaningful way to communities. And while it certainly remains a holy grail, we need to face the reality that for the foreseeable future, really for the rest of our lifetimes, even if you're young, there are going to be more people living on this planet with diabetes. And living with diabetes means living with diabetes complications. Even today, despite better diabetes care, still 4 in 10 with type 2 and 3 in 10 with type 1, which is another important growing and growing population will develop so-called diabetic kidney disease or kidney disease we attribute to diabetes. And that really makes it the driver for half of all the chronic kidney disease in the world. And while our conventional focus certainly has been on progression to kidney failure, what we need to recognize is this is also what's driving the mortality. And the mortality is primarily attributed to cardiovascular causes, especially heart failure and atherosclerotic cardiovascular diseases. So our job really is not only to preserve kidney function, which is extremely important, but also to reduce mortality. This is really now from a mechanistic stand, been framed within this cardiovascular kidney metabolic syndrome. I'm not going to go into the great details, but would like you to focus in the middle how central the kidney is in the whole paradigm, not only as a target organ of these metabolic complications driven by obesity and diabetes, but as an amplifier of cardiovascular risk. And the opposite is true when cardiovascular disease develops, whether it's heart failure or atherosclerotic disease, there's an opposite amplification of risk of CKD. So people who end up in this situation are really on a rapid downward spiral where both heart and kidney disease exacerbate each other, and we really have this what we call a competing risk paradigm. They're either likely to die of a cardiovascular event. And if they survive that, then kidney failure ensues. And in fact, if we look at how we classify kidney disease risk, it's really by 2 markers, urine albumin across the top ribbon and then you can see eGFR levels across the rows. And we developed this heat map where we use both markers. And again, without going into the details, in the red boxes, these are people very high risk, certainly for kidney failure in the bottom left panel. But even if we look across, again, our competing risk, cardiovascular mortality, stroke, heart failure, for example, it's exactly the same grid. So what we're really talking about is a group of people at very high cardiovascular and kidney risk who clearly need interventions. The good news is that over the past 5 and arguably 10 years, we have had an explosion of highly efficacious therapies. In diabetes now, we really have 4 pillars. RAS inhibition or so-called ACE inhibitors and ARBs, SGLT2 inhibitors, a non-steroidal MRA in the form of finerenone and a GLP-1 receptor agonist semaglutide. Diabetes has really opened the door, though, to therapies for non-diabetes-related CKD in addition to disease-specific targets. For example, you may be familiar with all the progress in treating IgA nephropathy. But it's important to recognize that even with those immunologic therapies, those people, once they have developed kidney injury, similar to people with diabetes, will have rapid progression if we don't interrupt those final common pathways that are shared with diabetes. And currently today, we now know that RAS inhibition, SGLT2. And just at Kidney Week, we presented some new data on finerenone now a non-diabetes CKD. So really filling out the pillars in the same way. And another class also for nondiabetes-related CKD or the endothelin antagonist. So we've made a lot of progress, but really, where are we? This is just showing that the reason that we're looking at these in combination, again, don't worry about the details, except that you can see the pictures look different. And that's because the mechanisms are complementary. So we're really now applying therapies that work in a complementary manner to reduce risks. And as Anthony showed you, this gets very complicated. They're metabolic, hemodynamic and fibroinflammatory mediators, and we really have to address the totality of mechanisms to ratchet down this risk. And that's what these combination therapies are really designed to do. What can we expect out of this? Well, this is actually some actuarial modeling data looking at combination therapy. So I want to give the disclaimer that combination therapy studies that have been done prospectively are in progress, not yet reported out. And these data come from post hoc or secondary analyses where people happen to be on one of these therapies in the background, and it gives us an opportunity to see the signal for how they might add up. So for example, the risk of kidney failure is projected if we use all of the pillars in people with diabetes and CKD to be reduced almost 60%, all-cause mortality by about 1/3. And then on the cardiovascular side, risk of major atherosclerotic cardiovascular events by about 1/3, hospitalizations for heart failure more than half and cardiovascular death, about 30%. Now that really has been remarkable progress. But I'd like to show you the data a different way and sort of set the stage for where rilparencel could drop into this paradigm. This is actually modeling-related data from our large CRE CKD registry as well as clinical trials. And if we look at this at a population level, with the standard of care with RAS inhibitor, if we take a typical person with a GFR of 45 type 2 diabetes and GFR declining at about 5 ml per minute, which has been the standard sort of paradigm that we use for modeling these data, we would predict that with a RAS inhibitor, the 50% survival would be at about 10 years for a population level. Adding SGLT2, GLP-1 and non-steroidal MRA progressively, we now can expect that about half the population will live to 20 years. And then among that population, though, the dominant risk becomes kidney failure out surviving the competing risk of death. So then if we look at an individual level of what happens to kidney function with simply RAS inhibition alone, again, starting about 40 and declining at 5 ml per minute per 1.73 meter squared eGFR annually, you would expect kidney failure at 7 to 8 years. And again, this can be markedly prolonged, maybe as long as 20 years, but we still have residual risk to address. And that is where we really thought that rilparencel can drop in. I think Bruce Culleton has used the term rescue therapy. For those people who remain in the hot red KDIGO risk box despite our 4 pillar or best medical therapy, they remain at very high risk. There are a lot of important questions to answer. Who would be treatment responders versus nonresponders? TBD stands for to be determined. That is going to be an important question. What therapy or combination will work best? Where do we drop rilparencel? Is it on top of all 4 pillars or not? Or what combination of background therapies might we use? What is the right time to deploy therapy? Again, I think you heard very compelling mechanistic data from Anthony that this really looks like a reparative tool in people who still have high-risk CKD despite best medical therapy. Why does the therapy work or not work? And how do we drop rilparencel as a rescue treatment and who needs this treatment? I think the other thing that's very compelling is that the source of rilparencel is from a person's own body. And again, as a nephrologist, I will tell you, this is really important. Transplantation, of course, is much better than dialysis, but we still have all the problems of immunologic incompatibility that lead us to use immunosuppressive therapies that while they've gotten better over time, they still are imperfect and there are many side effects. So here to be able to give a reparative therapy, a cell therapy that does not involve an autoimmune response is extremely compelling. The other thing that I would point out about rilparencel is this is fit for purpose. It's designed for CKD. Again, if you been involved in drug development, you know that many of the 4 pillar therapies, especially, for example, SGLT2, GLP-1 and even good old-fashioned ACE inhibitors and ARBs were made for other purposes, treatment of hyperglycemia and diabetes or lower blood pressure lowering and hypertension. They happen to have kidney-protected effects, but they actually really weren't designed for that purpose. And we really need drugs that are targeted and fit for purpose to the problem in front of us. I'd now like to turn to some human mechanistic data of a different intervention and mainly to set the stage for the fact that what Anthony described to you in the various models has biological possibility to translate to humans. And this really comes from the REMODEL trial. So REMODEL was a companion trial to the FLOW trial, the one and only dedicated kidney outcome trial of a GLP-1 semaglutide in people with type 2 diabetes and CKD who are very much like the people being rolled in the rilparencel trial. The REMODEL trial was really designed to work out mechanisms in a human context as opposed to experimental models, which is why this study is so important not only for understanding the particular mechanisms of semaglutide, but to understand whether or not human kidneys could actually be repaired or rescued with a therapy. So they were very similar to FLOW or the people in the rilparencel trial, and they were randomized to semaglutide or placebo 2:1, and they had deep phenotyping by functional MRI, magnetic resonance imaging and in a subset of 33 kidney biopsies, not only for conventional histology, but for deep phenotyping, much like Anthony showed you in the animal models, except these were humans. This is just some of the clinical data, reinforcing that these patients responded to the treatment very similarly to the main clinical trial. So albuminuria, which is a strong marker of kidney damage, reduced by 40%. And again, this is something important that Anthony said, and I'm going to reiterate, these therapies now are preserving kidney function. We are not talking about slowing decline here. This blue line is semaglutide. The gray line is placebo. And you see that it's essentially stable with semaglutide treatment. So preservation of kidney function. On the functional imaging, we were able to show marked reduction in fat within and around the kidney, even though this was not a weight loss study, and the body weight loss was less than 5%. But back to this issue about the importance of the vasculature, again, Anthony talked about this in the rilparencel context. We see a reduction in renal arterial resistance. This means blood vessels are more relaxed. They're healthier. They're responding better to physiologic stimuli. And we see the cortical ADC, which is a measure of fibrosis that's diffusion coefficient. It gets progressively worse in the placebo group, but completely stabilized by semaglutide. So yes, we can stop scarring. And then on creatinine clearance, which is a better marker of kidney function than estimated GFR and really has to mostly be done in clinical trials, we see a large difference with progressive loss in placebo and actually a small but statistically significant increase in difference between the 2 groups. So again, we're no longer talking about loss of kidney function with treatment. We're talking about preservation. Importantly, even if you're not familiar with renal physiology, there's a concept called filtration fraction. I just want to spend a moment talking to you about. This is the proportion of blood that enters the capillary filtering unit, the glomeruli that is filtered. That is a measure of how effective the filtration barrier is as a mechanism to remove fluid and waste products. We see an increase in filtration fraction with semaglutide and a decrease with placebo. This is important because what it points us to is that the filtration barrier, which is lost in CKD, particularly in people with diabetes and advanced CKD can plausibly be repaired. And now we'll look at the tissue to see if that might be true because tissue is the issue and structure begets function. You've seen some cell maps from Anthony out of the experimental models. Now I'm showing you the same type of cell map only from human kidneys in this clinical trial. Importantly, we identified all 31 known canonical cell clusters, and I want to shout out the Kidney Precision Medicine project, which provided these technologies. It's a big NIH-funded consortium that I've been involved in for a decade. And I will point out to you that many of these cell types have not even been identified. But as a measure of quality, we identified every known cell type, and we had nearly 800,000 nuclei for interrogation. Very similar to what you saw in the previous presentation, the main type of genes that were down-regulated were metabolic stress genes and very much like rilparencel in the animal model, these were related to mitochondrial function, oxidative phosphorylation, that's energy generation in cells and less glycolysis stress, very comparable to what was seen in the rilparencel preclinical model. Also, 60% of fibroinflammatory genes were down regulated. And when we look inside the cell distribution, the cells that were most regulated were the glomerular endothelial cells. These are cells that line the filtration barrier, also some immune cells and some tubular cells. This is complicated, but I'm going to give you the USA TODAY version. I think it's important, again, in terms of drawing correlations to what we saw in the rilparencel experiments. This is from the single nucleus transcriptomic studies, and these are cell ligand interactions. If you look at the circle on the left, you see purple, blue, green and red ribbons. And these represent -- the purple and blue represent endothelial cell communications, the green natural killer T cells and immune cell and the red represents monocytes and macrophages. Here's the USA TODAY version. There's a lot of chatter going on. These cells are talking to each other. Immune cells in particularly are not only talking to each other and amplifying each other's inflammatory profile, but they're also having very negative inflammatory conversations with the endothelium. After 1 year of randomized treatment, look at the circle on the right, the green and the red ribbons are gone. The immune cells have gone silent. They're no longer having conversations with anybody, not themselves, non-endothelial cells. And on the endothelial cell crosstalk, you see many more blue ribbons and they're all blue and purple ribbons. And what is the crosstalk here? Inflammation has largely gone silent. And across the top, I've given you sort of the headliner. The main conversations they're having is about increasing expression of collagen and integrins. These are components of the glomerular basement membrane, the filtration barrier. Integrins help cells to attach, for example, a podocyte, which is a very important cell on the urine side. Type 4 collagen is an important component of the basement membrane that is the layer between the endothelium and the podocyte. And also, in particular, I wanted to point out PECAM1, CD31 and CDH5 VE cadherin for 2 reasons. One, in a glomerular context, these are well-known markers of repair and restoration of filtration barrier. And I was really taken by the rilparencel data where Anthony showed a very similar pattern, upregulation of both CD31 or PECAM1 and CDH5, VE cadherin within endothelial cells. So again, now I've shown you a human example that repair is possible. And in both of these interventions, these are highly upregulated mediators associated with repair. So I think what this provides is biological plausibility that we can repair the kidney. And I just want to point out that in the field of nephrology, this is very new. The old paradigm was always about slowing down bad processes. Now we truly see activation of repair programs and physiologic evidence that it translates to improved filtration barrier function. And that's why stabilized GFR. Now finally, I will show you some spatial transcriptomic data Again, you've seen some of this in the experimental setting now in humans. So first off, if you look at the little circles on the left side, here, the endothelial cells are represented in green, natural killer T cells, a bad actor immune cell in blue and macrophage monocytes, other immune cells without semaglutide treatment and after 1 year of treatment. And what you see is endothelial cells expand fewer natural killer T cells and monocytes. And in the structural context, the top row of histology images is without treatment or before treatment. And the blue and purple dots are immune cells. You see them all clustered around the circle in the middle, which is the glomerulus. And this is now showing the purple dots where PECAM and CDH5 are being expressed not much action in the glomerulus. And then after 1 year of randomized treatment, the first thing you notice is the purple and blue dots around the glomeruli are gone. And now if we move to the middle and far right columns, the orange circles are now shuttled into the glomerulus and markedly upregulated. And again, PECAM1, CDH5, that's E cadherin. These are indicators that the endothelium has turned on the repair programs. And then finally, I'll go back to something that may be more familiar to those of you with a clinical background, some more traditional histology and what we call quantitative morphometry. So first thing on the top, I'm showing you arterials. Again, this is a quantitative morphometry out of Kidney Precision Medicine Technologies. And the red line, if you look at the upper left panel is the outlining the arterial wall and the green line on the inside outlines the -- what we call the intima or the lining of the artery. And the space between the red and the blue lines is much wider on the left and on the right, and those purple dots on the left are immune cells. After 1 year of randomized treatment, we even see repair of the arterials. So we see now intimal thickness gone, subintimal immune cells gone. These are well-recognized mechanisms in atherosclerosis. So now we even have insights into vascular biology that could extend beyond the kidney. And then if you go to the lower panels in the glomerulus, you see lots of purple dots. We have yellow arrows there, that periglomerular immune response. That is really completely normalized after 1 year of randomized treatment. So now even conventional histology showing repair of the glomerulus impaired glomerular region, but importantly, arterials that are being reconstructed that we think may have something to do with the benefit on cardiovascular outcomes and that important competing risk. So we put this all together that we have now been able in a human setting to show mechanistic effects, including reduced kidney fat, improved hemodynamics or how well blood flow arrives and is in the kidney and is used in the process of glomerular filtration that we see the endothelium, again, an important cell regulated also by rilparencel can be reprogrammed to a repair phenotype. And this clinically leads to better microvascular function, less scarring. And then back finally in the green box, what we see in the clinic, reduced albuminuria, a marker of damage and again, the term preserved glomerular filtration. So I will stop there and be happy to participate in the Q&A session.

Thank you, Dr. Tuttle, for an outstanding review of the progress that's been made in the kidney space, but I think also a view to the future where repair and preservation of kidney function is definitely something that's now possible, and we hope to see a lot more data supporting that in the future as well. So I will turn it back to the operator for us to move through our Q&A. I don't think we have a lot of time left. But operator, if you could pass along the questions for me, and I will answer them directly or pass them on to one of our co-presenters today.

So our first question comes from Joyce Zhu at JPMorgan.

This is Joyce on for Anupam. For Dr. Tuttle, what minimal difference in eGFR slope would you view as clinically meaningful? And then assuming PROACT 1 achieves that, how would you use rilparencel in your patients? And then for the team, can you talk about any market research ongoing or done so far to help characterize how physicians view an autologous cell therapy approach like rilparencel? And how do you think that market research will help frame some of your payer discussions going forward?

So Joyce, thanks for the question. What we know from an abundance of clinical trial data and again, shout out to the CKD prognosis consortium is it's an intervention, shows a difference in eGFR slope of more than 0.75 ml per minute per 1.73 meters squared. I'm not going to say those units again annually that -- and the study goes at least 2 years that it's highly predictive of a benefit on the true outcome of kidney failure. And so in the rilparencel studies, the goal is to show a difference of more than twice that, 1.5. And so if the study should achieve its primary outcome, that would be highly clinically relevant from a nephrology perspective that the drug would be likely to preserve kidney function and ultimately, over time, prevent kidney failure. Where I think rilparencel will drop in is really in the patients, and there are really still quite a few of them. I tried to show you that in some of our modeling data. Where despite the fact that we have a highly efficacious drug therapies, there still is residual risk in many patients. And really, we have ways to predict that. It's not only the KDIGO heat map, but also risk prediction equations. But maybe to just keep it simple. So there are people who are going to end up with clinical characteristics very similar to the trial, GFR of 30 to 45 and those above 30, particularly if they still have residual albuminuria who are still at high risk. And even though we may have reduced the risk, the risk still remains high. They're still in that half of people who are likely to go on to have an adverse outcome of their disease. And I think this is really where rilparencel will drop in as a therapy for people who need something more than they can get with drugs and really the potential that this would come ahead of dialysis or transplantation and hopefully stave that off over a substantial amount of time.

Thanks, Kathy. Joyce, I'll take part 2 around the market research. So we have done some patient research as well as some provider research recently internally at ProKidney. We will be talking about that over the course of the next few months. I will say just in general that both patients and providers seem to be very responsive to the value proposition, the target product profile of rilparencel. And as Kathy outlined, we do believe there'll be a position for it again, should the data turn out to be positive. And then from a payer perspective, we will use some of that as we engage with payers. We haven't done any formal -- completed any formal payer research at this point in time, but that's also something that we can talk about in the future as well.

Our next question comes from Vamil Divan at Guggenheim.

Can you hear me?

Yes, we can.

Yes? Okay. Great. So thanks for summarizing obviously, a lot of content digesting here, but congrats on all the work to better understand what's happening here. I guess my questions are maybe tied a little bit to, again, more on the market research side. I'm not sure how much you can share now. there's obviously so many patients that could be potential candidate. Trying to understand from what you've seen from the company side or Dr. Tuttle, if you want to comment, just are there certain characteristics of different patients that may be more conducive to receiving rilparencel versus others just to sort of get a sense of who may be the priority targets in a way to think about? And then also just in terms of the kind of manufacturing and processing side of things, is there a time component here in terms of how quickly a patient is able to receive the product? What's your sort of goal as a company in terms of the turnaround time? And is there a threshold there where people get more or less willing to go through the process? So any insights on those questions would be helpful to understand the market opportunity here.

Yes. Thanks, Vamil. Dr. Tuttle, do you do you mind talking a little bit about patient suitability and how you would see that? And then if I need to fill that in with the eligibility criteria from the study as well, I'd be happy to do that, too.

Sure. This is really going to be the nephrologist intervention, right, or treatment because this is going to be the kind of patients that we see, people who are coming in with CKD 3B, 4 who have already, in many cases, received the standard of care and where there's still very high risk. So these are still common patients in our clinical practices. And so I think that for those sorts of patients who remain in high-risk categories, again, think of those heat maps, those red box patients, that's still probably the most common consult we see in nephrology. And type 2 diabetes remains the major driver. Currently, the rilparencel studies are in the population with type 2 diabetes and CKD 3B, 4, and again, if they have a GFR above 30, there's an albuminuria requirement. But these are very typical patients that we see. And so I do think that from a nephrology standpoint, this is going to be quite a welcome advance. And it is a complementary therapy and a new mechanism that can be addressed. And that's really what we've focused on now is really getting at targeting mechanisms. And I think the idea that the kidney can be repaired has sort of been a new epiphany for the field. And I think that the time is probably right for people to believe that this could be true. And I think the science that Anthony presented that aligns so well with how we understand the biology -- and the fact that we now have even human studies that show repair is possible really sets the stage for, again, imagining success with this trial that this will be quite a welcome advance. I think there will be great interest, particularly by the nephrologists.

Thanks, Kathy. Vamil, to your second question around the time component to receiving product. So in the study today, the sort of kidney-to-kidney time is approximately 14 weeks. The actual amount of time required to make the product is actually much shorter than that. I think it's around 3 weeks or maybe even in that ballpark anyway. And some of the timing that goes into the 14 weeks is also related to the fact that we're in a clinical study, we have capacity depending upon the number of biopsies we're trying to process as well as the final products we're trying to make, which may impact that 14 weeks. We think we can get it down closer to 8 weeks. And I can't say any better than that, but I think there's possibilities to even improve that over time as we improve our efficiency. So we don't believe that, that's going to be a substantial barrier to adoption. It's a little different with oncology patients. If we think of CAR-T therapy for many oncology patients, they do turn over product very fast. But often those patients are -- I mean, I hate to stay it, many of them are on death door and really do need that turnover on a rapid basis. In the advanced CKD patient population, they are sick, but most of them remain ambulatory at home and a lot of them continue with some substance of activities of daily living. They are not in the same ballpark as patients with advanced cancer who failed multiple different types of therapy. So 8 weeks, I think, would be quite approvable from a market perspective.

Our next question comes from Andy Tsai at Jefferies.

Thanks for sharing all the data. My questions are more about the Phase III data coming up shortly next year. Out of curiosity, what percentage of your Phase III patients do you think will be on a background SGLT inhibitor or contemporary therapy, another one like a GLP? And how might that percentage compare to the prior Phase II studies? And if there is a greater SGLT use or GLP use, how might that impact the efficacy outcome for both the drug and the sham arm? And then secondly, as we think about the safety profile for rilparencel, what kind of special AEs are you monitoring for in the Phase III? What did you see in the Phase II? And should we expect any SAEs? Or does this drug have a very compelling benefit risk profile in your view?

Thanks, Andy. That's a lot there. Let me try that. And I'll remind that Dr. Tuttle is also involved as a site investigator with the study as well. So in addition to being a global expert in this space, she's also seeing patients enrolling patients in our study. Kathy, feel free to jump in at any time. I will say just on the concomitant medication use, Andy, we have built into the protocol that patients are expected to be on an ACE inhibitor or an ARB and an SGLT2. And if they're not, then we're asking the sites to explain why their patient is not on those drugs. So it's my expectation and I can tell you that I've seen unblinded data from the study that there's a very high use of SGLT2s and a reasonable use of GLP-1s and a very high use of ACE inhibitors and ARBs. So I would say that the patients for the most part, are being treated with standard of care. Kathy, if you want to comment on how you think about this, too, as you thought about enrolling patients in the study might help as well.

Yes, Bruce, I totally agree. And so what we can say is that most of the people that we're enrolling, and I think Bruce alluded to this, it sounds like it's consistent across sites is these are the nephrologist patients. So we are getting people on what we call GDMT or guideline-directed medical therapy. And the really important thing to remember is that they remain in the hot red KDIGO box despite those therapies, their risk is still as high as if they were in that box without treatment. So we may have ratcheted it down, but they are still extremely high risk. And that's exactly the compelling reason to enroll them in the rilparencel trial because it's something that works differently and they still have very high risk. They -- they are likely to be in that 50% of people who unfortunately will not reap the benefits of the other therapies as much as other patients. So by intent, we use the term residual risk. We've selected a group of people with the most common form of CKD that related to type 2 diabetes who despite best medical care have very high residual risk, and that's the unmet need. So that -- I think that is the niche for rilparencel. It's not in competition with those treatments. It's in addition to because they need additional kidney protection because despite optimal therapy, they still have very high risk.

I see. And how about the safety side?

Just on the safety side. On the safety side, we're not seeing anything different. in our Phase III program than what we've described from our Phase II program. And as we've said before, the safety data looks -- the tolerability is very good. We do see events that one would expect when you're biopsy-ing a kidney or when you're putting a needle in a kidney. And those events are very similar to what's been reported in biopsy safety databases outside of the clinical study. So we're not seeing anything extra at all within our clinical program. Yes. Andy, I do want to say something. I just got texted. I want to be clear on something. When I talked about -- or maybe it might have been [indiscernible], when I talked about the use of SGLT2s and ACE inhibitors and ARBs, I have not seen any unblinded data. I want to be crystal clear on that. This would be combined blinded data when we're looking at baseline characteristics and baseline use of medications. So to be clear, none of us have seen any unblinded data from the study.

Yes, I inferred that, yes.

Our next question comes from Jon Knee at Evercore.

This is [indiscernible] on for Jon. So my first question is for Dr. Tuttle. So what do you see as the biggest hurdle potentially between identifying a suitable patient and getting them treated? And would you say -- do you think a community nephrologists can manage that process? Or do you think rilparencel will sit mainly in a specialist center? And then the second question is for management team. So while we see that the ASN data suggests cells from different patients converge to a similar phenotypes during the manufacturing process, do you see any relationship between the starting biopsy profile and then the clinical outcome in those patients?