Prokidney Stock

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?

I think the nephrology community is going to welcome this because, as I said, this is going to be a nephrologist intervention. Now acknowledging fully that they will need to partner with interventional radiologists to deliver the therapy. But this really unlike the drug therapies will sit squarely in nephrology practice.

And nephrologists are very interested in innovation. And I think there is a real hunger, if you will, for kidney-specific therapies. So I agree with you that in the clinical trial, we've had to choose high-performing sites with particularly interventional radiology resources to deliver this treatment.

But if you look across the board, like at dialysis and transplantation, which in the early days seemed quite technically complicated. Once those were available and really proven to be preferred treatments for kidney failure, we see -- we saw a very rapid uptake. And if we imagine success of rilparencel, I really -- like I said, I see this sitting ahead of dialysis and transplant and really meaning the nephrologist intervention.

So my expectation would be that, yes, we -- and this is, again, how dialysis and transplant started, too. It was a few places who did it really well, and then we trained other people, there was policy and payments so that community practices could be reimbursed for delivering those therapies. I would imagine that cell therapy could look very similar to that. And so my guess is it's going to be welcome. It's going to be new, and it's going to be something that the nephrologists really feel that they own.

And I think that's -- frankly, I think it's going to be one of the things that continues to move nephrology forward, really, if you will, back into the mainstream of medicine where we're really able to intervene on a condition that leads to severe outcomes, kidney failure and death in a new way and that really makes a difference even at a public health level.

Thanks, Kathy. [indiscernible], on your second question, I think if I interpret it correctly, you're asking if there's any relationship between the starting biopsy profile and clinical outcomes.

Yes.

We have -- yes. So that's definitely a question that we would like to answer in the future given the overall numbers of patients we have in our PROACT 1 study, and that's something that we will do, but that will have to wait until after we have a readout on our clinical study. So that's a future potential question that we'd like to answer.

Our next question comes from Joe Pantginis at H.C. Wainwright.

So a question about the evolution of the product profile here. So regarding product consistency and potency, how are you incorporating single cell data into potency assays for the future and commercial launch?

And then, Bruce, since you mentioned things like CAR-Ts in the oncology space, a sensitive subject there, and I want to know how it applies here, people are really in tune to, say, any manufacturing failures. How should people view that here?

Thanks, Joe. I'm just writing this down, so don't forget any of this. So the evolution of the product through the course of manufacturing and the use of single cell data into our potency assurance assays. I'll just speak to potency assurance assay for a second around their CMC. So we obviously have been working with the FDA on our potency assurance assays. We have a matrix. The FDA has agreed to our approach to using a potency assurance matrix.

I will say, Joe, that there's still a little bit of work to align with the FDA completely on that matrix, but we haven't seen anything that we think is insurmountable at this point in time. With that said is the work that Anthony and his team are doing, it is quite possible that there may be something that comes from that work, which will even make our potency assurance matrix even better in the future.

And then I think around manufacturing or inability to manufacture product, which is clearly a big thing in the oncology space, especially given the pretreatment that many of these patients have to go through and the complexity of the CAR-T treatment. In the kidney space, for us, we're actually not seeing much in the way of manufacturing failure. I think for the vast majority, over 95% of our patients and maybe a little bit more, we're actually able to make product for them.

So any patient that does a biopsy, our goal is to get that manufactured product back to them. There may be some occasions where the product sample itself, the biopsy might be insufficient. But I would say that's a very unusual occurrence that we've seen across not just in our Phase III program, but across any of our clinical studies up to date.

Our next question comes from Yigal Nochomovitz.

Can you hear me now?

Yes, we can.

Okay. Yes. So you obviously showed a ton of mechanistic detail with a lot of experiments. I guess I'm just trying to distill it all down into sort of a punch line. So obviously, the therapy is injecting a relatively small number of cells relative to the kidney volume. And as you noted, generating a tissue remodeling and beneficial gene expression. And then I also saw that in the histological data at 28 days, it seemed like the population of the injected cells seem to be decaying a little bit versus the initial injection.

So I'm just -- so putting that in perspective, and maybe Dr. Tuttle can speak to this, what do you see as the best evidence that supports the transcriptional changes more broadly across the whole organ, especially in regions that are not close to the injection site as well as the durability of the effect in light of some of that histological data.

Kathy, do you want to take that? Or would you like Anthony to have a start?

Well, maybe, Anthony, you can start, and I'll follow you.

Yes. That sounds good. So yes, we do see somewhat of a decline in rilparencel engraftment over time. That being said, these are all in immunocompromised road models that we're injecting human cells in. So they're immunocompromised to some extent. So they have T, B, NK cell deficiency, but still have monocytes, macrophages, other innate immune cells to potentially promote a xenogeneic rejection response.

We -- unfortunately, we aren't taking biopsies after injection in our clinic. And so we can't confirm the engraftment there, but we will be doing that in our DCN study, our human DCN study. So we'll be able to confirm what the engraftment profile looks like over time. From what we see in our -- a variety of our different models, we do know that there is a paracrine effect in modulating some of these disease-relevant pathways.

And so we do see also basement membrane remodeling and blood cell vessel morphogenesis in the vicinity of rilparencel engraftment. And so it's reasonable to assume that there is paracrine factors being secreted by rilparencel that could be distributing more broadly within the kidney that could be promoting a more global therapeutic effect. So that's kind of the information that we have right now, but there's obviously more detail to come.

Yes. And I really don't have a lot to add to Anthony's comments other than to say that I think the DCN experiment is extremely important because that will be a way to test in humans, and you will have human tissue for biopsies.

And I think an important distinguishing feature, especially Bruce, as you've alluded to like CAR-T cell therapies and so forth, is that patients who receive rilparencel do not have to be immunosuppressed to receive it. And I think that from a clinical standpoint is extremely beneficial.

And then what I would say to you, Yigal, even though remodel tested a different intervention, we've shown that it's biologically plausible to repair the kidney. And I'm really struck by the correlations, right? The paracrine effects that we demonstrated in remodel, the endothelium being a major target cell and repair programs that restore the filtration barrier and clinically or physiologically manifest as preserved glomerular filtration. So there's still a lot of work to be done, but everything is pointing in the direction of highly likely to repair.

I will tell you one thing as a clinician that will need to be understood, and Bruce may want to comment on this is after the clinical trial, and I'm going to imagine success. What we'll have to learn is how many injections do people need. How often should they be given, especially if there is some waning of the effect. But that will be a pleasant problem to have to learn how to improve the therapy.

And then what I'm most excited about, I will tell you is in my patients who despite giving them the best GDMT I can remain at high risk, the idea of preserving kidney function and maybe delaying or eliminating the need for dialysis or transplant really is quite remarkable.

And like I said in one of the answers to earlier questions, I think this will become a nephrology intervention that will be a highly welcome advance in the field that's complementary to our advances in GDMT and really puts patient health and priorities ahead of dialysis and transplant, which while they were remarkable advances and they will still be needed are much -- are very difficult treatments to live with.

And in fact, if you look at the survival on dialysis of a person with type 2 diabetes, half are dead at 2 years. I mean this really could make an enormous difference for the population that we serve.

Great. And I just had one follow-up, Dr. Tuttle and also maybe for the company. I was struck by the convergence of the gene expression profiles in the in the autologous products, which obviously made me think and perhaps you as well, what could an allo product look like?

And I know the company obviously isn't doing that and it would require a different approach. As you pointed out, these patients don't need immunosuppression. But nonetheless, I just wanted to get your thoughts on that because that convergence of gene expression certainly looked very interesting biologically and suggests a common solution, which, of course, may portend some sort of an allo approach off-the-shelf approach down the road.

Yes. I guess I can take that. Yes. So I mean that's definitely something that could be envisioned. Right now, we're 100% focused on rilparencel. But yes, that's definitely something that I personally actually have a lot of experience in gene editing cells for allo cell therapy. So something that we could potentially envision.

Yigal, -- so thanks, Anthony. Yigal, I'm sure you understand that for now, we have to be very focused on finishing the clinical study, making sure that we meet all the manufacturing and CMC-related expectations of the FDA. So our team is completely focused on that -- on those aspects. Should we be successful, then it would make sense for us to think of what that life cycle would look like for a product. And this would certainly be one option that we want to explore at that point in the future.

Our final question comes from Dina Ramadane at Bank of America.

One for Dr. Tuttle. Do you expect the mechanism to work similarly across the spectrum of diabetic CKD severity? Or does the biology argue for a therapeutic window where you kind of need enough viable kidney tissue in order for rilparencel to protect?

And then one for Bruce. Given that this is an autologous product, do you have any insight into how much patient-to-patient variability you're seeing in the cellular composition in the secretum? And what evidence gives you confidence that this variability isn't translating into any meaningfully different biological activity?

No, thanks for the question, Dina. I think it is really important because even among nephrologists, there was this belief, and I'm going to call it a belief, not a fact, that advanced CKD, particularly like GFR less -- people with GFR less than 30, that kidney failure was a fail to complete, either death or kidney failure and the kidney was not repairable.

And I think, again, if you go back to the REMODEL example, who are people very similar to the rilparencel study or in FLOW, what we clearly showed is even in people with advanced established CKD repair is possible. I think what we can't answer is how far advanced does that hold up. But what we can clearly say is in those patients who are hurdling toward the need for kidney replacement therapy, we have shown that the kidney can be rescued. And that really is the window of opportunity.

And I know I'm repeating myself, but I think it's important, best guideline-directed medical therapy hit a GFR of 30, this is where this drug is going to drop in because if they're -- despite best medical therapy, if they still have residual risk, this is the opportunity. And again, I think REMODEL shows that it's biologically plausible.

How far can -- low can GFR go to be -- where kidney tissue can be repairable. I think that remains an unanswered question. And it's likely to vary between different people. There might be people with a GFR of 15 who have a repairable kidney and others where that threshold might be 25. So those are really good questions. But I think what we can say, the population that's being enrolled in the rilparencel study is a population where we've already demonstrated the kidney can be repaired.

And I would also make the case that the cell therapy really is a unique way to repair the kidney that would complement the medical therapy. So again, I'm going to imagine success. And those kind of questions are things that can be explored, like how low can you go with GFR? Do you have to have a diagnostic kidney biopsy, for example, to predict responsiveness.

So I welcome the questions and look forward to pursuing this line of inquiry once we have, again, imagining success once we've at least delivered the initial evidence to support cell therapy.

Thanks, Kathy. Anthony, do you mind answering the second question? And I think if I could just paraphrase it, it was, we have an autologous cell product, I mean that really every product is different because it comes from different patients. Can you talk about the variability that we're seeing in that end product?

Yes. Yes. I mean, so obviously, we're collecting characterization data on all of our Phase III patients, and we'll be likely doing kind of correlation analysis once we have top line data on product characteristics. But at least from our Phase II samples, we do see remarkably consistent expression profile, not just from single cell RNA-seq, but from our flow assays, our potency assays, et cetera.

The kind of 2 populations that we see, it's really just based off of single-cell RNA sequencing, which is whole transcriptome analysis, and you can identify via transcription factor expression where those cells that came from based off of those transcription factors, which are associated with distal proximal lineage. But the final product is, like I presented, remarkably consistent. There's a convergence of expression across every -- pretty much every factor that we've looked at. So there is a remarkable consistency, but obviously, we're going to be doing that analysis for our Phase III samples.

This concludes our Q&A session. I will turn it back to Bruce for closing remarks.

Thanks, everyone, for joining us today. I do want to particularly thank Anthony for all the work he and his team have done, and I think some very elegant studies and more to come. I'm obviously very excited about the work that's ongoing and what that will bring us as well.

And Dr. Tuttle, Kathy, thanks for joining us. Your presentation was outstanding. Your answers to the questions also outstanding. Clearly, you're a leader in this field, and we appreciate your support, not just as a clinical study investigator, but also supporting us today in this recap from ASN. Thank you.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Rati Pinge, Priyanka Grover and Joyce Zhou. Our next presenting company is ProKidney. And presenting on behalf of the company, we have CEO, Bruce Culleton.

Good morning, everyone. And thank you, Anupam and JPMorgan for inviting us back to the conference again. It's a pleasure to present this morning. So at ProKidney, our goal is to transform the treatment landscape for patients living with advanced chronic kidney disease. Patients who are at high risk of kidney failure and facing a real prospect of ending up on dialysis.

We believe that our lead product, rilparencel, there's a meaningful opportunity to intervene and change the course of a patient's progression to kidney failure. So these are the customary disclosures and disclaimers.

So there are over -- today, there are over 3 million Americans with advanced chronic kidney disease. These are patients that over the next few years that are very high risk of developing kidney failure. Many of them will require dialysis. The lucky few will get kidney transplants. They all share one goal, and that's the need for more time. So more time for spending 3 days -- more time from not spending 3 days a week in the dialysis center, more time for life's moments and more time and flexibility with the people that matter the most.

So we are advancing this goal through the development of rilparencel, an autologous cell therapy that's made from patients' own kidney cells. Across multiple Phase II trials, we've seen kidney function stabilization with the use of rilparencel. Excluding our Phase III data, which is ongoing, we've treated over 150 patients and rilparencel has demonstrated a very favorable safety profile. It also doesn't require any preconditioning or immunosuppression after treatment, unlike many of the other cell therapies.

Importantly, we are now marching towards a pivotal Phase III readout in about 5 quarters from today. So in Q2 2027. Our goal is to make rilparencel available to patients who urgently need it and to provide different and better treatment options for patients with advanced chronic kidney disease.

So 2025 was a pivotal year for us. But before I touch on our accomplishments, I want to begin by recognizing the approximately 250 ProKidney employees whose hard work and dedication made last year a pivotal one for our company. Their commitment drove meaningful progress across every aspect of our business, and I'm extremely grateful for their contributions.

Key highlights from 2025. We aligned with the FDA on an accelerated approval pathway using eGFR slope as a surrogate endpoint. We presented positive Phase III data as a late-breaking clinical trial at ASN's Kidney Week. We generated significant momentum in the Phase III PROACT 1 study. That's our pivotal Phase III study and the readout that we anticipate in Q2 2027 because of this momentum around enrollment.

And finally, we initiated expansion of ProKidney's in-house manufacturing footprint in facilities in Winston-Salem, North Carolina. So 2026 is going to be a year of highly focused execution for us. We prepare for a readout in 2027 for our Phase III data. We expect importantly, to complete enrollment for the accelerated approval efficacy analysis by mid this year.

We will continue to execute on our R&D plan. That's important for us to be able to explain our mechanism of action. I'll get into that in more detail later in the presentation. We also maintain active engagement and dialogue with the FDA under our RMAT designation. And finally, as we continue to prepare for commercial launch, we build out additional manufacturing capacity in North Carolina, where we own and operate those facilities.

So just before I dive deeper into some of the data, I'd just like to quickly level set on some of the progress. So we are solely focused on the one product, rilparencel, a first-in-class autologous cell therapy and getting that cell therapy to market. We're running the ongoing Phase III study, just the one Phase III study is all we need for FDA approval in patients with advanced chronic kidney disease and type 2 diabetes. And we have generated robust clinical data to date.

We have a very experienced clinical -- a very experienced leadership team, and we have cash runway that takes us past the data readout into mid-2027.

So a little bit about how we make our product. So rilparencel is manufactured using a patient's own kidney cells. And unlike some other cell and gene therapies, rilparencel doesn't consist of any gene editing. There's no preconditioning, no pretreatment and there's no immunosuppression after a patient received rilparencel because it's their own cells.

The process starts by harvesting a small piece of kidney tissue through a pretty standard kidney biopsy. That kidney tissue is transported to our manufacturing facility. When it shows up, there are about 50,000 to 100,000 cells that are available for us to work with. We expand them through a series of passages, and we end up with well over 1 billion cells that undergo a selection process.

The product is then cryopreserved and shipped back to the clinical study site for injection into the kidney cortex. 3 months after the first injection, we inject into the other kidney in the kidney cortex. All the injections are done by CT imaging by a trained interventional radiologist.

This is just a little bit about our manufacturing facility. We've got -- we purchased 2 adjacent buildings. Our approximate square feet is 180,000. We currently support our clinical manufacturing from these facilities. We have ongoing capital investment to manufacture -- to grow out that manufacturing infrastructure and to support what's required for a BLA submission. And these facilities also have some administrative research and cGMP manufacturing operations for a cell therapy platform.

So I'd like to spend just a few minutes to sort of set the stage on the unmet need in the patient population. So this is a complex slide. This is a framework of how we think about chronic kidney disease. It was developed by many scientists quite knowledgeable in this field, and this framework is used globally to understand the classification of chronic kidney disease, but also to understand the risk associated with different categories of chronic kidney disease.

So the rows represent kidney function as measured by estimated glomerular filtration rate or eGFR. You could see on the top row, if your GFR is above 90, you have normal kidney function. And in contrast, down on the bottom row, if your GFR is less than 15, you have what's called kidney failure. Most of these patients either have a transplant or are on dialysis or some are waiting to be started on dialysis.

The columns represent kidney injury as measured by the amount of albumin that's lost in your urine. And these are different categories of UACR. And then you could see that based upon where a patient may fall in a row or a column, then the heat map tells you what risk they have for developing kidney failure.

The area that's imposed by the blue line, the blue box, this is the area that we are focused on. These are the patients that we believe have the greatest unmet need. And these are the patients that we're currently enrolling into our Phase III clinical study. So we have seen over the last 5 years, a significant advance in the treatment of patients with chronic kidney disease. In particular, there's been many landmark clinical trials that have looked at patients who have chronic kidney disease and type 2 diabetes.

Some of these landmark trials are shown on this slide. Most of the participants in these trials have Stage II or Stage III chronic kidney disease. A few have advanced CKD that you could see on the right-hand column, subjects with Stage IV CKD. Primarily, the patients that have enrolled in these studies with Stage II and Stage III CKD, that exists because that's where the biggest population of patients with CKD currently reside.

There are well over 10 million Americans, well over that with Stage II and Stage III chronic kidney disease. But in contrast, patients with Stage IV chronic kidney disease are much lower. There's probably about 1 million Americans with Stage IV CKD. About 40% to 50% of them have coexistent diabetes, and that's the group that we hope to help with rilparencel.

A little bit of a complex slide here as well. So this is from one of these landmark studies that I just showed on the prior slide. The data here is illustrative of what's seen in the other landmark studies as well. So on the left-hand side in the left panel, you'll actually see change in kidney function as measured by eGFR. The blue line represents patients who are treated with dapagliflozin, an SGLT2 inhibitor. The red line represents those patients who are treated with placebo.

And much like other products in this space, there's an acute decline in eGFR, an acute decline in kidney function within the first 3 months. And then over time, that progression slows. But what you do see because of that acute decline, and if you look at the table in the box, the table in the left-hand panel, at month 24, there's a difference of only 1 ml per minute in progression of kidney disease. So 1 ml per minute.

So what that means in a population of, say, thousands of patients that becomes statistically significant. It's also clinically meaningful when you think about a population of patients with CKD. On an individual patient, 1 ml per minute doesn't seem like too much. Now these agents also confer cardiovascular benefit. And so they're also extremely important at reducing the risk of cardiovascular endpoints in these patients as well.

Now please take a look at the right-hand panel. So this is a slightly different look at this study where the endpoint is the cumulative incidence of a decrease in kidney failure in eGFR -- sorry, a cumulative incidence of a 50% loss in kidney function as measured by eGFR and kidney failure and death.

The placebo group is shown in red. The dapagliflozin group is shown in the blue. As you could see by looking at the blue curve, many of these patients continue to have events. Despite being part of the new pillar of care for patients with chronic kidney disease, these are not cures. Patients do continue to have events. They do continue to lose kidney function and many of them still end up on dialysis. So there's several ways that you could look at this to make that a little bit more meaningful. One is something called the number needed to treat. And in this study, you need to treat 19 patients with dapagliflozin for the course of the study to prevent one of these composite events.

Another way to look at it that's not shown on this slide, but it's in their paper, is that on average, treatment with dapagliflozin for 2 years delays dialysis for 4 months. So that's still relevant for a patient, but it's not delaying dialysis for years. It's delaying dialysis for 4 months. So that's the unmet need.

Now I'd just like to spend a few minutes on our clinical study program, our Phase III study design, an update on enrollment as well as just an overview of our R&D plan. So all the studies that we've -- all the clinical studies that we performed using rilparencel are shown on this slide.

There are 2 ongoing clinical studies. One is the Phase III study. The other is a long-term follow-up study called Study 008 in patients that have been previously enrolled in one of our prior Phase II trials. So this is REGEN-006, our Phase III program, also called PROACT 1. This is a randomized sham-controlled blinded parallel 2-arm clinical study. I know there's been a lot of talk around FDA's expectations within the cell and gene therapy around clinical trials. This design meets their expectations.

So this is a robust clinical study design in a cell therapy, using a cell therapy. Patients enrolled in this study will have to have type 2 diabetes and advanced CKD. You could see the key entry criteria on the left-hand side of the slide. Randomized patients are stratified by SGLT2 use and baseline eGFR, and they're allocated to the intervention or the rilparencel group or a sham cohort, that's the control arm.

Patients and the principal investigators are blinded to the treatment allocation. As stated earlier, we have alignment with the FDA for accelerated approval using eGFR slope as the surrogate endpoint. In the same study, patients will be followed over time for the confirmatory analysis, which will be performed when 122 patients have one of the composite clinical events.

As stated earlier, we've done a really good job. The teams have done a really good job in enrolling patients this year. A special thank you goes out to all our study participants, our study sites and also to our internal clinical operations and manufacturing teams who've really been dedicated to this over the last several years, but we made significant progress this year and a special thanks to them.

So if we stopped enrollment today, which we're not going to do, but if we stopped enrollment today and just followed the currently enrolled participants, we would have 80% power for the surrogate endpoint efficacy analysis in Q2 2027. We're going to continue to enroll patients. And by mid this year, we'll have sufficiently enrolled patients for 90% power. And we are very confident based upon that enrollment, where we stand today and if you look like the pipeline of participants that are coming into the study, we're extremely confident that we will have our analysis in Q2 2027 for our top line surrogate endpoint readout.

So let me talk a little bit about our R&D. Last year, we made a commitment to invest additional funds to support a lot of R&D work to further elucidate the mechanism of action for rilparencel. So we had done as a company, a significant preclinical work in the 2011 to 2015 time period. This was deprioritized when ProKidney moved to the clinic.

Notably, this decision missed the real transformative shift, I would say, to single cell and spatial omics as a means to interrogate biological systems. So now we have 4 different related programs in progress. This includes in vitro, ex vivo, in vivo in animals and in vivo in human descendants.

We are working with some of the top scientists across major institutions in the U.S., and we anticipate release of data related to our MOA throughout 2026.

So shifting gears now a little bit to some big news that we had this year, and that was related to our Phase II REGEN-007 data and why it's important because we think it provides some window into what we'd expect with our Phase III results.

So as a reminder, we presented in 2024 results from another Phase II trial at the ERA meeting in Stockholm. This year, actually, last year, it was in November of 2025, we presented a late-breaking clinical trial at ASN Kidney Week, and I'll just get into the design of that study in the interest of time.

So importantly, patients were -- patients who were eligible had type 1 or type 2 diabetes, a GFR of 20 to 50 and a UACR between 30 and 5,000. Patients were -- in 2021, we started to enroll patients, and they were allocated randomly to 2 groups. The first group is the group of most interest to us. And the reason why that's most interesting to us is because those participants were treated in the same way as our Phase III clinical study program. They had a biopsy, then they were injected into the biopsied kidney and 3 months later, they got an injection into the other kidney. That's the same treatment schedule we have for our Phase III program.

Group 2 was more of an exploratory dosing design. In Group 2, all patients had a biopsy. They received an injection into the biopsy kidney and then there was a period of waiting. And a second treatment was only given if there was a trigger and that trigger was an increase in UACR or a decrease in eGFR. What we know is of those 25 subjects that were enrolled in Group 2, 15 of them had a second injection and the time to that second injection, the median time of that second injection was 10 months.

So a much longer time between first and second injection in Group 2 than in Group 1. Also I want to point out on this slide that there was a pre-injection period. That was the control group for both Group 1 and Group 2, and that included all historical eGFR values going back to 2 years.

The primary efficacy endpoint was the difference in annual eGFR slope in that pre-injection period versus the period following the last rilparencel injection. And the primary safety endpoint was frequency of procedural and rilparencel-related adverse events.

A few things to point out on our baseline characteristics. So the first I'll note is we were underrepresented in this study of patients who are important from a chronic kidney disease perspective, and that is black Americans and patients with Hispanic and Latino ethnicity. As you could see, we were also underrepresented by women who have chronic kidney disease. And we have recognized the challenge associated with this and have gone out of our way in our Phase III program to correct that. And I'm glad to say that we've seen some significant changes in enrollment in our Phase III program with making sure that we have better representation from patient groups that are actually overrepresented in the chronic kidney disease space.

Also note that we enrolled some patients with type 1 diabetes. That's not the case in our Phase III program, which is all type 2 diabetes. And please have a look at the eGFR as well. The average eGFR was less -- was just above 30. We've narrowed the target population in our Phase III program to patients with more advanced chronic kidney disease, and I anticipate an eGFR somewhere just north of 25 mls per minute in the Phase III program.

These are the main results of the study. In Group 1, the annual decline in eGFR slope improved by 78% after treatment with rilparencel. Pretreatment, the decline was minus 5.8. Post treatment, the decline was minus 1.27. That was statistically significant and very clinically meaningful in this patient population.

In Group 2, we didn't have a statistically significant result, but we did see an improvement in the annual decline by 50% in Group 2. And just as a reminder, that group was also treated differently than what our Phase III program is at this point in time.

Safety, no rilparencel-related serious adverse events. That's pretty consistent with what we've seen in our other studies as well. And the safety profile overall, even related to the injections is pretty consistent with what's reported, a little bit better actually than what's been reported with adverse events related to a kidney biopsy.

We include this slide to graphically represent the primary efficacy endpoint. And as you could see the slope of eGFR prior to treatment with the 95% bounds on that slope in the blue shade, you could see that slope changed considerably after patients were treated with rilparencel. This table represents serious adverse events that were observed.

We did see a few events in patients who had -- who were related to the kidney biopsy. This is well described in the literature. We had one hematoma, a patient with a hematoma that was uncomplicated in a patient who received a rilparencel injection, and there were no serious adverse events associated with rilparencel as a product.

Finally -- or sorry, so just in summary, our key findings, bilateral dosing of cryopreserved product, which mirrors our Phase III program resulted in stabilized kidney function after treatment with rilparencel and the safety profile is pretty consistent with what we've published previously.

Our focus now is on continued enrollment of PROACT 3 to complete our R&D plans for this year and to prepare for BLA submission and commercial launch after top line readout. I will say one other thing on REGEN-007 data. And we do think it's a window into our Phase III program, and we may get into this a little bit into our Q&A as well. But when we also cut the data for Group 1 and just looked at those patients who are Phase III eligible, so patients who met the Phase III criteria, we actually saw a greater difference in decline pretreatment versus after treatment.

So just quickly, a quick update on our key financials and milestones for 2027. At the end of September, we had $270 million in cash to fund our operations. This will take us into mid-2027 after our top line readout. We anticipate this year as one of our key milestones to complete enrollment for the accelerated approval cohort within PROACT 1. We expect that enrollment to be complete by mid-2026. And again, we're working towards that top line readout in Q2 2027, and we feel very confident about that.

So in conclusion, I'd like to finish by returning to what we have as our North Star. And our 250 employees come to work every day with one purpose, and that's to bring a transformative therapy to patients with advanced chronic kidney disease. And that's a therapy to extend time to provide more options and to bring hope to patients and their loved ones.

Thank you all for your attention today and your ongoing interest in our company.

Thank you, Bruce. I'll ask the first couple of questions, but there will be an opportunity for the audience to ask questions. So when I prompt, just feel free to raise your hand. Bruce, when I think about ASN last November, what do you think are some of the key points that the Street is underappreciating as it relates to rilparencel, the data you presented at ASN and the derisking that it has for PROACT 1?

So I think just on the derisking, Anupam, I think there's a few things that the Street underappreciates. So one is certainly the effect size, right? So the effect size that we saw that I just went over with our Phase II data, was substantial, we've taken a very conservative approach to that effect size in our Phase III readout.

We've assumed a -- in our power calculations, we've assumed a difference of only 1.5 mls per minute between the intervention group and the control group. What we saw in the Phase II data was a difference that was greater than 4 mls per minute. So arguably, we've taken a very conservative approach. And we've had some lengthy discussions in-house as to why we did that, why it's 90% power, why we've assumed a smaller effect size.

And honestly, it comes down to when we're ready to turn that card in May or June of 2027, we want to be sure that we don't find ourselves in sort of some port of nebulous p-value, something that's in the 0.06 or 0.08 or 0.10. So we wanted to be quite confident in the analysis at that point in time. So I think that was one.

The other thing I'll point out is consistently what we've seen in our Phase II data is we see a greater benefit in patients who have the highest risk of kidney disease and patients who have an eGFR that's less than 30. I think sometimes it's underappreciated that we changed the design of our Phase III program in early 2024 to narrow the target population from a GFR of 20 to 50, we narrowed it down from 20 to 35. And I think that also gives us more confidence moving into the Phase III readout.

And then I saw in the slide that you -- in 2026, we're going to get some fuller understanding of mechanism of action of rilparencel. What's your current understanding of the mechanism of action? And what could we learn this year?

So we certainly know a lot more about our product over the last couple of years, and we've done some -- we understand what happens when our cells come into our manufacturing facility and how that product looks different at the end of manufacturing.

And what we see in those cells that are coming out as our final product is that they have less markers of inflammation, they have less markers of oxidative stress, and they have less markers associated with fibrosis. So we know that those cells are quite different than the cells that come in from the disease kidney from the patients. We also know that the final product, the cells seem to be plastic, at least that's how it's described to us by our R&D leaders. And plastic means that if they're exposed to a different environment, they may actually have a different phenotype depending upon what that exposure is. So we've learned a lot about those cells.

Now our working hypothesis today is that we believe when the cells are injected into the kidney, they do have an anti-inflammatory effect. They do have an effect on oxidative stress. And we also believe that they take advantage of the innate sort of restorative mechanisms that are already in the kidney and they take advantage of those, and we think that's what's leading to stabilization of kidney function. But at the same time, Anupam, we -- as you saw our R&D plan, we have a pretty robust plan, and we are working with some -- not just internally where -- we have some great leadership in the R&D group, but we're also working with some top-notch people across academics in the country.

When we think about sort of that May, June data for next year, the top line of PROACT1, obviously, we're going to get eGFR slope. That's the key endpoint for AA, accelerated approval. Any other endpoints we should be focused on within that update? And then also on eGFR slope, kind of what's a win scenario?

Yes. So the key for the top line is, as you said, it's the eGFR slope. That's the key thing. We'll -- we've got some planned subgroup analysis around that as well, Anupam. But I would say the other key component of that top line readout is safety. I mean not only do we need to show the efficacy, but also we need to continue to demonstrate a very strong safety profile.

Questions from the audience? I've got one last one.

Yes, go ahead.

Very beautiful data. My question is, how many times does the biopsy sample expand in culture? And does every type of nephrons can proliferate? That's the first question.

So I'm sorry, I missed the second part.

Second question is does all type of nephronal cells expand after the culture?

Okay. That's great. Two great questions. So thank you for your question. So we've actually had some really good success at biopsies that come into our facility and biopsies that we're able to make actually cells on. We're over 95% across all our studies, and we've continued to improve on that in our Phase III program.

What we -- and then getting into the second half of your question, so the cells that come in from the kidney biopsy represent the standard kidney biopsy cell. The cells that we -- that are in the product that's finally made have primarily markers of tubular and epithelial cells, less so on the endothelial side, mainly markers of tubular and epithelial cells. And as I said earlier, they also have markers that are less inflammatory, less fibrotic as part of that final product.

Next question is, does injected cells reform the nephrons?

I don't think so. I don't think anyone has ever been able to demonstrate the formation of a full nephron. And so I don't think that, that's the case in what we're doing either. More to come in 2026, but I don't think we'll end up with that type of data to show that we're forming new nephrons.

Maybe final question for me. Your slides also talked about in 2026 becoming -- doing some commercial prep work. What does that encompass in 2026 heading into the data next year?

Well, so some of that encompasses actually getting ready for a BLA submission. And there's a long lead time to some of the items, especially related to CMC. So big focus and the internal team around ensuring that we've got everything ready for our CMC part of the submission.

And then the other thing is as you know, it takes a long time to build out future capacity around manufacturing. And so there's some early work being done around expanding our manufacturing capacity in our buildings as well.

Thank you, Bruce.

Yes. Thank you.