Good morning everyone, and welcome to the ProKidney American Society of Nephrology Kidney Week recap and corporate update. At this time, all attendees are in a listen-only mode and a question and answer session will follow the formal presentations. 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 clearer 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, and Dr. Conway, our ProKidney team, and especially the patients and investigators participating in our studies. 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 advanced 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 two 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. Now I'd like to hand it over to Dr. Anthony Conway to share recent scientific updates. Anthony?
Thanks so much, Bruce.
Today we will be sharing with you some recent data that we presented just a few days ago at ASN in Denver. Before I dig into that, for those of you who are not 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 are then injected back into the patient's kidneys via interventional radiologist with CT guidance, and then three 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 is 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 CKD and diabetes in cohort 1 of our REGEN-007 study, which is the design which most closely mimics our phase III design. 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? To be able to do that, we need to uncover what is happening in diseased kidney tissue after our product is administered.
A way that we have been addressing this is by developing and utilizing a variety of translational disease models to elucidate the mechanism of action of rilparencel. I will 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 deceased 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.
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. Taking an even further step back, because one of the questions that we always get is, "What is rilparencel?" This question, we started to ask where rilparencel, what cells within the individual kidney biopsies is rilparencel derived from. What we did is utilized three batches of process development made rilparencel, starting with kidney biopsies from patients with different stages of CKD. You can see stage four, two, and three. Also, the end of the first passage after rilparencel is digested and plated into culture plastic, and then rilparencel itself, or a late-stage manufacturing product.
You can then see we run these cells for single-cell RNA sequencing on the right, and can then see where they cluster and what the individual transcriptome is of each individual cell. For the purpose of this presentation, I'll be describing renal parenchymal, either as selected renal cells or renal parenchymal. Selected renal cells are the cells within renal parenchymal. What we did was a temporal inferred transition algorithm to be able to analyze what cells within the early passage came from the kidney biopsy. 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. You can see on the top right, a schematic of the nephron. Reminder, we're taking kidney biopsies from the kidney cortex of the patients.
The cells in orange on the top are coming from the intercalated cells, connecting tubule cells, and thick ascending limb cells of the nephron. So that's the distal part of the nephron. 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 renal parenchymal, 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. Dig in a little bit further, and this is from patient retains from a phase II study. You can see that these two distinct lineages associated populations are present within all 17 batches of renal parenchymal 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. 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 renal parenchymal batches, and they're shown on the left here. There's a remarkable consistent product profile within all 17 patients, despite this initial lineage heterogeneity and expression heterogeneity within the individual starting biopsies. You can see in the middle, this is looking at various example markers that are expressed within renal parenchymal. You can see a 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. I don't have time to go into all of the details here, but refer to our ASN poster. But take home message is renal parenchymal are cells of proximal and distal tubule origin exhibiting a reparative plasticity-associated transcriptional signature with partial retention of native lineage identity. All right. Next, what is renal parenchymal 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 different ones, either primary kidney cells in culture or a kidney-on-a-chip system, which I'll go into a little bit more detail.
What we are doing is inducing a disease state by adding in various injury mediators, and I will go into more details in a few slides, adding in renal parenchymal into culture, and then assessing a resolution of disease state phenotype over a period of time. These disease states are reflective of various pathways related to the pathophysiology of CKD. You can see here, we are bucketing our assays that we are 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. 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 Cathy Tuttle on the right.
To be able to interrogate each individual pathway, we are looking at specific readouts of these different pathways within our model systems. The idea is to see where we are able to resolve different disease states by renal parenchymal to be able to deconvolve how renal parenchymal may be able to preserve kidney function in patients with advanced CKD. Our first model system. This is our kidney-on-a-chip system. This is from a company called Mimetas in the Netherlands. You can see a schematic here in the middle. It is a microfluidic-based system. We are 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.
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 are adding in renal parenchymal into this region to mimic the intraparenchymal injection that we are doing in the clinic. We are then able to induce an injury phenotype, and those are mediators reflective of chronic kidney disease shown on the bottom left, high glucose, inflammatory cytokines, high lipids, uremic toxins. Then waiting over time and then seeing what changes have occurred as a result of renal parenchymal administration. First looking at the endothelial channel, the cells comprising the blood vessels, and I will have on the top right, the area of the nephron that we are referring to for each individual mechanistic slide.
We are able to show here, through a variety of different endpoints, that renal parenchymal promotes endothelial junction and barrier integrity. On the left, we are doing single-cell RNA-seq of endothelial cells, either with injury or control, and then either with renal parenchymal treatment or non-treated. You can see with injury, we are activating a variety of markers related to endothelial activation and endothelial to mesenchymal transition, various markers related to the pathology of CKD. Whereas with renal parenchymal treatment, the gene expression of these markers goes down. Similarly, we are seeing upregulation of barrier-disrupting and permeability-related gene expression with injury, and that concomitant glow goes down with renal parenchymal treatment. We are then able to look via functional validation of various markers related to endothelial junctions and cell-cell adhesion. CD31, VE-cadherin, ZO-1, these go down with injury and then are restored nearly to baseline with renal parenchymal 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 functional barrier integrity with a fluorescently tagged dextran, we are able to see that with injury, this permeability goes up and rilparencel is able to restore that. This is in a 2D culture in a Transwell system, so this effect is entirely mediated through the factors which rilparencel is secreting to these endothelial cells to restore this barrier integrity. Next slide, so this is showing the endothelial metabolic state, and this is using the Seahorse Metabolic Analyzer.
There is a lot of data here, so I will just show you 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. So they are transporting the oxygen, not utilizing it as much. So with rilparencel treatment, we are able to restore the levels of glycolysis that is in the control conditions, whereas this goes down in injury. Then similarly, we are able to actually below baseline create a more quiescent metabolic state with rilparencel treatment from two different donors. This is indicative, or it strongly suggests a pericyte-like endothelial cell metabolic stabilization that is occurring here. Then looking at pro-inflammatory signaling and recruitment cues in this kidney-on-a-chip system, we are also able to look both at the endothelial as well as the epithelial channel.
So this damage-associated molecular pattern secretion assay, so this is a antigen HMGB-1, which is naturally found within the nucleus and is actively secreted upon innate inflammatory signaling and stress to promote immune infiltration. So you can see here with injury shown in red, the level of DAMP secretion dramatically goes up, whereas with rilparencel cell treatment, we are able to restore it close to baseline. You see a similar trend here with the epithelial channel, but it is important to note that in the endothelial, you see a much higher level of HMGB-1 secretion, indicating a increased level of pro-inflammatory signaling from the endothelial channel specifically. Then looking just at the epithelial channel on the right, we can see that NF-kappa B, which is a transcription factor related to pro-inflammatory signaling, you can see that upon TNF alpha-mediated stimulation, which is a pro-inflammatory cytokine, that goes up.
The phosphorylation of NF-kappa B and its partner, I kappa B alpha, goes up, and then with rilparencel treatment, after three days, this significantly goes down back to baseline. Then moving now just to the epithelial channel, so the cells comprising the tubules within the nephron. We are able to show here that rilparencel cell is able to lower reactive iron species and activates a cytoprotective lipid peroxidation repair program in injured renal epithelial cells. 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 is involved in chronic kidney disease pathology. So you can see here on the left that with rilparencel cell treatment, gene expression related to iron homeostasis goes up.
On the bottom left, you can see that antioxidant gene expression in epithelial cells also goes up with rilparencel cell treatment. On the right, you can see that with rilparencel cell treatment, the total amount of iron goes down. Importantly, specifically the reactive ferrous iron species goes down with rilparencel treatment as compared to injury control. This is important because this ferrous iron is the reactive species that promotes the Fenton reaction, which drives lipid peroxidation, which is an oxidized form of lipid which induces mitochondrial and cell membrane dysfunction. Looking at specifically the oxidative damage lipid species here in mitochondrial dysfunction, we are able to show here with rilparencel co-culture, we are able to rescue this oxidative damage in mitochondrial dysfunction in epithelial cells.
This is shown on the left, whereas lipid peroxidation significantly and substantially goes down after four days of co-culture with injured epithelial cells. You could see also the mitochondrial coupling efficiency and spare respiratory capacity also goes up with rilparencel cell treatment, so the mitochondria are more functional. On the right, you can see a dynamic change in mitochondrial functionality restoration with rilparencel cell treatment, with essentially complete restoration of spare capacity and bioenergetic health at seven days of rilparencel cell treatment, indicating this is a dynamic effect as a result of rilparencel cell co-culture. Finally, we are digging into more molecular mechanism here. GPX4, which is a master antioxidant related to lipid peroxidation repair. The activity of GPX4 is required for rilparencel cell-mediated rescue of oxidative damage in mitochondrial dysfunction in epithelial cells.
In this case, this is an even shorter experimental time window. We are looking at glutathione and redox balance within just eight hours of rilparencel cell co-culture. You can see that with injury, which is the red dots, the glutathione redox balance goes down as compared to the black dot control, whereas with rilparencel cell, which is in blue, this is able to restore it back to baseline. 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 cell co-culture. At one day of co-culture, you see also a similar restoration of mitochondrial membrane potential and bioenergetic health index.
The next step for us is to really determine what factors within rilparencel cell are mediating these therapeutic effects. Right now, we are doing gene editing experiments to deconvolute what specific factors are necessary and sufficient for these therapeutic effects of rilparencel cell. This is just an example of seeing various differential gene expression of the cells within rilparencel cell upon co-culture in injured kidney cells, and these are giving us some clues as where to start. Finally, focusing on some of our in vivo mechanistic studies. Back in the early 2010s, before we got into the clinic, we were able to demonstrate that SRC or rilparencel cell treatment, in diseased kidney models in rodent and dog were 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. 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. The vehicles are with the excipient of rilparencel injected into the same region of the kidney. First off, we want to see where rilparencel is going after we're injecting it. We were able to do immunohistochemistry here, and this is in a humanized immune system rodent model that's been fed adenine to induce a CKD phenotype.
You can see in purple here at one 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 this subcapsular region, very interestingly. 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. This is shown 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 one day, three day, and seven days post-injection of rilparencel. You see a peak at day three, with ECM remodeling and vascular support related gene expression going up, with it starting to wane slightly by day seven. 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.
In this case, looking specifically at the rat endothelial cells, which we saw the most dramatic effect from our in vitro mechanistic studies. 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. Gene expression related to endothelial cell-cell junctions and ECM signaling is shown here. 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.
This was showing that there is a distinct tissue remodeling signature at the renal parenchymal injection site. This is three 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. In this case, this is in a rat kidney that does not have human immune cells. This is specific to rilparencel injection. You can see in this region of interest, or ROI, you can see that there is a significant upregulation of proteins associated with stromal perivascular remodeling, cell adhesion, autophagy, and a lipid remodeling profile that is differentially abundant in this rilparencel engraftment region. If we look at day 28, it is shown on the bottom right on the single-nuclei RNA-seq data, we are seeing specifically an M2 macrophage upregulation signature with SRC treatment.
This is related to reactive oxygen species scavenging, tissue repair, and remodeling. In total, all of these various lines of evidence are leading us to understand more confidently the MOA of rilparencel. What we are 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. 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. That being said, we are still digging into more studies to really confirm this hypothesis, including an upcoming human decedent study, as well as some biomarker studies in our clinical samples. Thank you very much, I will hand over to Kathy.
Well, hello, everyone, and thank you, Anthony, for that beautiful tour de force through the mechanistic data to support rilparencel as a true reparative therapy, even in people with advanced CKD. What I would 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. 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. I would point out that in the U.S., it is more like one in seven.
Importantly, in addition to causing kidney failure, it is increasingly recognized as a major cause of mortality, and the death rate from 1990- 2017 increased more than 40%. 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 9th leading cause in the timeframe of 2019- 2025. If we do not change what is happening, it is projected to be the 5th leading cause of death in the world by 2040. If we look at, again, U.S. and Western Europe, populations are actually quite similar in terms of total burden of disease, 44 and 40 million respectively, and responsible in one year alone for nearly 150,000 deaths in each of these regions.
We know that this is an underestimate because death is often misclassified, and CKD is greatly under-recognized. This is a very low-range estimate of the mortality impact. If we walk back to diabetes, which really is the major driver of this 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. Unfortunately, what we know about diabetes prevention has not translated in a meaningful way to communities. While that certainly remains a holy grail, we need to face the reality that for the foreseeable future, and 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. 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 and growing population, will develop so-called diabetic kidney disease or kidney disease we attribute to diabetes. That really makes it the driver for half of all the chronic kidney disease in the world. 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. The mortality is primarily attributed to cardiovascular causes, especially heart failure and atherosclerotic cardiovascular diseases. 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 where it's 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. 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. 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.
In fact, if we look at how we classify kidney disease risk, it's really by two markers, urine albumin across the top ribbon, and then you can see eGFR levels across the rows. We developed this heat map where we use both markers. 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 risks, cardiovascular mortality, stroke, heart failure, for example, it's exactly the same grid. 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 five, and arguably 10 years, we have had an explosion of highly efficacious therapies.
In diabetes now, we really have four pillars, RAS inhibition or so-called ACE inhibitors and ARBs, SGLT2 inhibitors, a non-steroidal MRA in the form of finerenone, 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. 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 a rapid progression if we don't interrupt those final common pathways that are shared with diabetes. Currently today, we now know that RAS inhibition, SGLT2, just at Kidney Week, we presented some new data on finerenone now in non-diabetes CKD, so really filling out the pillars in the same way.
Another class, also for non-diabetes related CKD, are the endothelin antagonists. 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, that's because the mechanisms are complementary. So we're really now applying therapies that work in a complementary manner to reduce risks. As Anthony showed you, this gets very complicated. There are 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 of therapies are really designed to do. What can we expect out of this? Well, this is actually some actuarial modeling data, looking at combination therapies.
Now, 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 a third. Then on the cardiovascular side, risk of major adverse atherosclerotic cardiovascular events by about a third, 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 CURE CKD registry as well as clinical trials. 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 mil 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.
Among that population, though, the dominant risk becomes kidney failure outsurviving the competing risk of death. If we look at an individual level of what happens to kidney function with simply RAS inhibition alone, again starting about 40 and it declining at 5 mL per minute per 1.73 meters squared eGFR annually, you would expect kidney failure at seven-eight years. Again, this can be markedly prolonged, maybe as long as 20 years, but we still have residual risk to address. 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 may remain in the hot red KDIGO risk box despite our four 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 non-responders? 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 four pillars or not? Or what combination of background therapies might we use? What is the right time to deploy therapy? Again, I think you've 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 a therapy work or not work? 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. 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. 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've been involved in drug development, you know that many of the four 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 in diabetes or blood pressure lowering in hypertension.
They happen to have kidney protective 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, mainly to set the stage for the fact that what Anthony described to you in the various models has biological plausibility to translate to humans. This really comes from the REMODEL trial. 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 enrolled 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. They were very similar to FLOW or the people in the renal parenchymal trial, and they were randomized to semaglutide or placebo two to one, 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 on reinforcing that these patients responded to the treatment very similarly to the main clinical trial.
Albuminuria, which is a strong marker of kidney damage, reduced by 40%. Again, this is something important that Anthony said, and I am going to reiterate, these therapies now are preserving kidney function. We are not talking about slowing decline here. The blue line is semaglutide, the gray line is placebo. You see that it is 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 renal parenchymal context. We see a reduction in renal arterial resistance. This means blood vessels are more relaxed, they are healthier, they are responding better to physiologic stimuli.
We see the cortical ADC, which is a measure of fibrosis, that is diffusion coefficient. It gets progressively worse in the placebo group, but completely stabilized by semaglutide. Yes, we can stop scarring. 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 and difference between the two groups. Again, we are no longer talking about loss of kidney function with treatment, we are talking about preservation. Importantly, even if you are not familiar with renal physiology, there is 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. Now we will look at the tissue to see if that might be true, because tissue is the issue and structure begets function. You have seen some cell maps from Anthony out of the experimental models. Now I am 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. I will point out to you that many of these cell types had not even been identified. 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 downregulated were metabolic stress genes, and very much like renal parenchymal 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 renal parenchymal pre-clinical model. Also, 60% of fibroinflammatory genes were downregulated. When we looked 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 renal parenchymal 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. 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 particular 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 one 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, not endothelial cells. On the endothelial cell crosstalk, you see many more blue ribbons, and they're all blue and purple ribbons. 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 IV collagen is an important component of the basement membrane that is the layer between the endothelium and the podocyte. Also, in particular, I wanted to point out PECAM-1, CD31, and CDH5, VE-cadherin, for two reasons. One, in a glomerular context, these are well-known markers of repair and restoration of the filtration barrier. I was really taken by the renal parenchymal data where Anthony showed a very similar pattern, upregulation of both CD31 or PECAM-1 and CDH5, VE-cadherin within endothelial cells. Again, now I've shown you a human example that repair is possible. 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.
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 is why stabilized eGFR. Now, finally, I will show you some spatial transcriptomic data. Again, you have seen some of this in the experimental setting, now in humans. 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 one year of treatment. What you see is endothelial cells expand, fewer natural killer T cells and monocytes.
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 this circle in the middle, which is the glomerulus. This is now showing the purple dots where PECAM and CDH5 are being expressed. Not much action in the glomerulus. After one year of randomized treatment, the first thing you notice is the purple and blue dots around the glomeruli are gone. Now if we move to the middle and far right columns, the orange circles are now shuttled into the glomerulus and markedly upregulated. Again, PECAM-1, CDH5, that is VE-cadherin. These are indicators that the endothelium has turned on the repair programs.
Finally, I will 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. First thing on the top, I am showing you arterioles. Again, this is quantitative morphometry out of Kidney Precision Medicine Project. The red line, if you look at the upper left panel, is outlining the arterial wall, and the green line on the inside outlines what we call the intima or the lining of the artery. The space between the red and the blue lines is much wider on the left than on the right, and those purple dots on the left are immune cells. After one year of randomized treatment, we even see repair of the arterioles. We see now intimal thickness gone, subintimal immune cells gone. These are well-recognized mechanisms in atherosclerosis.
Now we even have insights into vascular biology that could extend beyond the kidney. 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 one year of randomized treatment. Now even conventional histology showing repair of the glomerulus and periglomerular region, but importantly, arterioles that are being reconstructed that we think may have something to do with the benefit on cardiovascular outcomes and that important competing risk. 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 in the kidney and is used in the process of glomerular filtration.
That we see the endothelium, again, an important cell regulated also by renal parenchymal can be reprogrammed to a repair phenotype. And this clinically leads to better microvascular function, less scarring. Then back, finally, the green box, what we see in the clinic, reduced albuminuria, a marker of damage, and again, the term preserved glomerular filtration. 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. 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.
Great. Thanks, Bruce. Yeah, so please hold for a brief moment while we pull for questions. Our first question comes from Joyce Zhu at JPMorgan. Please go ahead, Joyce.
Hey, guys. This is Joyce on for Anupam Rama. Thanks so much for taking our question and for hosting the call this morning. For Dr. Tuttle, what minimal difference in eGFR slope would you view as clinically meaningful? Assuming PROACT 1 achieves that, how would you use rilparencel in your patients? 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? Thank you.
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 if 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, and the study goes at least two years, that it's highly predictive of a benefit on the true outcome of kidney failure. In the rilparencel studies, the goal is to show a difference of more than twice that, 1.5. 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's 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 highly efficacious drug therapies, there still is residual risk in many patients. 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. There are people who are going to end up with clinical characteristics very similar to the trial, GFR of 30 to 45, and in those above 30, particularly if they still have residual albuminuria, who are still at high risk. Even though we may have reduced their 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. 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. 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 two around the market research. 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. As Kathy outlined, we do believe there will be a position for it again should the data turn out to be positive. Then from a payer perspective, we'll use some of that as we engage with payers. We haven't completed any formal payer research at this point in time, but that's also something that we could talk about in the future as well.
Great. Thank you.
Thanks for the questions, Joyce. Our next question comes from Vamil Divan at Guggenheim. Please go ahead, Vamil.
Great. Thanks. Can you hear me?
Yes, we can.
Yeah. Okay, great. Thanks for hosting this and thanks for summarizing obviously a lot of content we're digesting here. But congrats on all the work to better understand what's happening here. I guess my question may be tied a little bit to, again, more on the market research side. I'm not sure how much you can share now, but there's obviously so many patients that could be potential candidates. I'm 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 get a sense of who may be the priority targets in a way to think about. Also just in terms of the manufacturing, the processing side of things.
Is there, time component here in terms of how quickly the patient they will receive the product. What's your 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? Any insights on those questions would be helpful to understand the market opportunity here.
Yeah. Thanks, Vamil. Dr. Tuttle, do you mind talking a little bit about patient suitability and how you would see that? 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. 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. Type 2 diabetes remains the major driver. Currently, the rilparencel studies are in the population with type 2 diabetes and CKD 3b/4. Again, if they have a GFR above 30, there's an albuminuria requirement. But these are very typical patients that we see.
I do think that from a nephrology standpoint, this is going to be quite a welcome advance. It is a complementary therapy and a new mechanism that can be addressed. That's really what we've focused on now, is really getting at targeting mechanisms. 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. 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, and I think there'll be great interest, particularly by the nephrologists.
Thanks, Kathy. Vamil, to your second question around the time component to receiving product. 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. Some of the time 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. 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.
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 hate to say it, many of them are on death's 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 acceptable from a market perspective.
Okay. All right. Thank you very much. Congrats on all the progress here.
Thanks, Vamil.
Yes, thanks for the questions, Vamil. Our next question comes from Andy Tsai at Jefferies. Please go ahead, Andy.
Hi. Thanks for sharing all the new 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 SGLT2 inhibitor or contemporary therapy, another one like a GLP, and how might that percentage compare to the prior phase II studies? 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? 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? Should we expect any SAEs, or does this drug have a very compelling benefit-risk profile in your view? Thank you.
Thanks, Andy. That's a lot there. Let me try that. I will remind that Dr. Tuttle is also involved as a site investigator with our study as well. In addition to being a global expert in this space, she's also seeing patients and 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. 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.
I would say that 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've thought about enrolling patients in the study, might help as well.
Yeah, Bruce, I totally agree. 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. We are getting people on what we call GDMT or guideline-directed medical therapy. The really important thing to remember is if 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. We may have ratcheted it down, but they are still extremely high risk. 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 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. 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. 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. Thanks. How about the safety side?
Oh, 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. 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 biopsying a kidney or when you're putting a needle in a kidney. 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.
Okay. Great to hear. Thank you.
Yeah, 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've been Vamil, 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. To be clear, none of us have seen any unblinded data from the study.
Oh, yes. I inferred that. Yes.
Okay. Thanks, Andy.
Great. Yeah. Thank you for the questions, Andy. Our next question comes from Yuanyuan He at Evercore. Please go ahead.
Hi, this is Yuanyuan for John and Omar, so thanks for taking our question. My first question is for Dr. Tuttle. What do you see as the biggest hurdle potentially between identifying a suitable patient and getting them treated? Do you think a community nephrologist can manage that process, or do you think rilparencel will sit mainly in a specialist center? Then the second question is for management team. While we see that the ASN data suggests cells from different patients converge towards similar phenotypes during the manufacturing process, do you see any relationship between the starting biopsy profile and the clinical outcome in those patients? Thanks.
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 saw a very rapid uptake.
If we imagine success of rilparencel, like I said, I see this sitting ahead of dialysis and transplant and really being the nephrologist intervention. My expectation would be that yes, we, this is again how dialysis and transplant started too. It was a few places who did it really well, 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. My guess is it's going to be welcome, it's going to be new, it's going to be something that the nephrologists really feel that they own.
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, that really makes a difference even at a public health level.
Thanks, Kathy. Yuanyuan, 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.
Yes. 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. That's something that we will do, but that will have to wait until after we have a readout on our clinical study. That's a future potential question that we'd like to answer.
Great. Thank you so much.
Great. Thank you for the questions. Our next question comes from Joe Pantginis at H.C. Wainwright. Please go ahead, Joe.
Hey, everybody. Thanks for taking the question and all the details today. A question about the evolution of the product profile here. Regarding product consistency and potency, how are you incorporating single-cell data into potency assays for the future and commercial launch? Bruce, since you mentioned things like CAR T's in the oncology space, a sensitive subject there, 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 I don't forget any of this. 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. We obviously have been working with the FDA on our potency assurance assays. We have a matrix. The FDA's 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, as 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. I think around manufacturing, or inability to manufacture product, which is clearly a big thing in the oncology space, especially given the pre-treatment 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.
Great. Thanks a lot.
Yeah.
Thanks for the questions, Joe. Our next question comes from Yigal Nochomovitz. Please go ahead, Yigal.
Oh, hello. Can you hear me now?
Yes, we can.
Okay. You obviously showed a ton of mechanistic detail with a lot of experiments. I guess I am just trying to distill it all down into sort of a punchline. This therapy is injecting a relatively small number of cells relative to the kidney volume. As you noted, generating a tissue remodeling and beneficial gene expression. 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.
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.
Yeah, that sounds good. We do see somewhat of a decline in renal parenchymal engraftment over time. That being said, these are all in immunocompromised rodent models that we're injecting human cells in. They're immunocompromised to some extent. They have T, B, NK cell deficiency, but still have Monocytes, macrophages, other innate immune cells to potentially promote a xenogeneic rejection response. 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 decedent study, our human decedent study. We'll be able to confirm what the engraftment profile looks like over time. From what we see in a variety of our different models, we do know that there is a paracrine effect in modulating some of these disease-relevant pathways.
We do see also basement membrane remodeling and blood cell vessel morphogenesis in the vicinity of renal parenchymal engraftment. It's reasonable to assume that there is paracrine factors being secreted by renal parenchymal that could be distributing more broadly within the kidney, that could be promoting a more global therapeutic effect. That's the information that we have right now, but there's obviously more detail to come.
Yeah. I really don't have a lot to add to Anthony's comments other than to say that I think the decedent experiment is extremely important because that will be a way to test in humans, and you will have human tissue for biopsies. 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. I think that from a clinical standpoint is extremely beneficial. 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. 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'll be a pleasant problem to have, to learn how to improve the therapy.
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. 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 very difficult treatments to live with. In fact, if you look at the survival on dialysis of a person with type 2 diabetes, half are dead at 2 years.
This really could make an enormous difference for the population that we serve.
Great. 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 autologous products, which obviously made me think, and perhaps you as well, what could an allo product look like? 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. 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.
Yeah, I guess I can take that. That's definitely something that could be envisioned. Right now we're 100% focused on rilparencel. But 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. 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. Our team is completely focused 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 our product, and this would certainly be one option that we'd want to explore at that point in the future.
Yes. Thank you. Makes sense.
Great. Thanks for the questions, Yigal. Our final question comes from Dina Ramadane at Bank of America. Please go ahead, Dina.
Hey, guys. Thank you for the presentation today and for taking our question. 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 need enough viable kidney tissue in order for rilparencel to protect? 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 and the secretome, and what evidence gives you confidence that this variability isn't translating into any meaningfully different biological activity? Thank you.
No, thanks for the question, Dina. I think it is really important because even among nephrologists, there was this belief, and I am going to call it a belief, not a fact, that advanced CKD, particularly people with GFR less than 30, that kidney failure was a fait accompli, either death or kidney failure, and the kidney was not repairable. 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 hurtling toward the need for kidney replacement therapy, we have shown that the kidney can be rescued. That really is the window of opportunity.
I know I am 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 despite best medical therapy, if they still have residual risk, this is the opportunity. Again, I think REMODEL shows that it's biologically plausible. How far low can GFR go and 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 that kidney can be repaired.
I would also make the case that the cell therapy really is a unique way to repair the kidney that would complement the medical therapies. 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 eGFR? Do you have to have a diagnostic kidney biopsy, for example, to predict responsiveness? 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? I think if I can just paraphrase it was, we have an autologous cell product, meaning 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?
Yeah. We're collecting characterization data on all of our phase III patients, and we'll be likely doing correlation analyses 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 two 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-
Yeah
Pretty much every factor that we've looked at. There is a remarkable consistency, but obviously we're going to be doing that analysis for our phase III samples.
Thanks, Anthony.
Thank you.
Great. Thanks for the question, Dina. 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 am obviously very excited about the work that is ongoing and what that will bring us as well. Dr. Tuttle, Kathy, thanks for joining us. Your presentation was outstanding. Your answers to the questions, also outstanding. Clearly, you are 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.