ProKidney Corp. (PROK) Earnings Call Transcript & Summary

Good morning, and welcome to the ProKidney virtual KOL event. [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, Senior Director of Corporate Development and Investor Relations at ProKidney. Please go ahead, Ethan.

Thank you, operator. Good morning, everyone, and welcome to ProKidney's Virtual KOL event and recap of the Phase II RMCL-002 final data. Joining me this morning are Dr. Steven Coca, Professor of Medicine and Nephrology at the Icahn School of Medicine at Mount Sinai; Dr. Arnold Silva, Director of Clinical Research at Boise Kidney and Hypertension and Care Research Network and Dr. Bruce Culleton, ProKidney's Chief Executive Officer. Before we begin, I would like to remind everyone that we will be making forward-looking statements during the presentation today. I encourage you to refer to the most recent SEC filings regarding risk factors associated with these statements. I would now like to turn it over to ProKidney's CEO, Dr. Bruce Culleton.

Thank you, Ethan. ProKidney is delighted to sponsor today's event. It comes at an inflection point for our company as we are now emerging in many ways from a 6-month company reset, and what better way to emerge from this reset than presenting final data from our largest Phase II study. And by having two esteemed Nephrologists present their own views on the unmet medical need for many patients with chronic kidney disease and providing an overview of the changing therapeutic landscape that's created more options for improved patient care. Today, it's my absolute pleasure to be here with Dr. Steven Coca and Dr. Arnold Silva. Dr. Steven Coca is a Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York; The associate share for Clinical and Translational Research for the Department of Internal Medicine and the Director of Clinical Research for the division of Nephrology. His research focuses on the utility of blood and urine biomarkers for risk stratification of patients with acute kidney injury and chronic immune disease. He's been part of several large NIH-funded consortium biomarkers in kidney disease. And he has over 300 publications, received multiple awards including the Distinguished Researcher Award from the American Society of Nephrology in 2021. Dr. Arnold Silva is Director of the Home Hemodialysis and Peritoneal Dialysis programs at Boise Kidney and Hypertension Institute. Dr. Silva has been appointed Clinical Assistant Professor of Medicine at the University of Arizona and has taught in many areas of biology, biochemistry, and physiology for California State University and University of California. He's been very active as an independent investigator in the basic sciences and clinical research throughout his career and currently acts as a principal investigator on many projects for Boise kidney. I'd like to start by saying a few words about our company. We are a company focused on helping patients with advanced chronic kidney disease. CKD has a substantial global impact on patients, their families and overall health care costs. Our goal is to preserve kidney function in patients with advanced CKD caused by diabetes, the #1 cause of kidney failure globally. We believe if our proprietary cell therapy offers the potential, the possibility, if you like, of keeping patients off dialysis by preserving kidney function. We have promising Phase II data but of course, this needs to be proven in our Phase III program. To do this, we've assembled a very talented team with several new leaders added over the last few months. Shortly, you will see how this talented team and all of our employees are contributing to our near-term milestones and will contribute to our success in the future. Let's take a step back and review why we believe rilparencel is so special. As you can see, chronic kidney disease is a significant problem. While 1 in 7 adult Americans have some degree of CKD. There are more than 3 million Americans who have type 2 diabetes and advanced Stage IIIb and Stage IV chronic kidney disease. These are patients that have few kidney treatment options and are at very high risk of progressing to kidney failure. Within this large population, I'd note that more than 135,000 CKD patients in the U.S. alone continue to progress to dialysis every year. We believe there's a substantial opportunity with our product rilparencel, as we believe we can preserve kidney function to delay or eliminate time on dialysis. Today, we will walk through data that provides the context for the importance of rilparencel. We hope you will see the unmet medical and societal need even in the face of a changing therapeutic landscape where patients now have greater options for cure than ever before, but many patients continue to progress to kidney failure. And we believe rilparencel may be able to preserve kidney function and possibly provide better benefit in high-risk CKD patients. And now I'm honored to hand over to Dr. Steven Coca for an overview of the treatment landscape for patients with diabetic CKD. Dr. Coca?

Thank you, Bruce, for that introduction. It's a pleasure to speak to you today about the treatment landscape for patients with diabetic kidney disease. My name is Steven Coca, I'm a Professor of Medicine and a practicing nephrologist at the Icahn School of Medicine at Mount Sinai in New York City. This slide depicts the temporal progression of studies that have occurred for efficacious trials in diabetic kidney disease over the better part of the last 3 decades. And from the '90s and early 2000s, we had -- we had evidence from trials of ACE inhibitors and angiotensin receptor blockers that they do slow the progression of diabetic kidney disease. But then there was a multiyear period over a decade after the ID&T and RENOWNED studies from 2001 into the 2010s, where there were many therapies that failed to show efficacy in DKD. This included potential therapies, including bardoxolone, solidoxide, MTTGF-beta monoclonal antibodies and many others that just failed to show benefit. And it led to some pessimism and nihilism, both in the scientific community and in treating patients in the clinics. And fortunately, as you can see to the right of this graph, in the last decade, we've had an explosion of trials, efficacious trials across multiple classes in this space. We have in blue the SGLT2 inhibitors trials, we have in orange the GLP-1 receptor agonist trials, in pink the trials of the nonsteroidal mineralocorticoid antagonist finerenone, and also in purple endothelin antagonist. And thus, we now have multiple agents that we can layer on to risk factor management in patients with diabetic kidney disease, resenting therapies that can be taken orally on a daily basis or injectables in the case of the GLP-1 receptor agonist. And we had exciting data from the FLOW trial presented last week at the ERA Conference showing that this is essentially now the fourth pillar of therapy to add on to this lifestyle management. Now simulation studies, assuming that you could apply these 4 drugs on top of maximum tolerated ACE inhibitor or ARV doses for DKD show remarkable restrictions and lifetime risk for CKD progression as well as all-cause mortality. These data just came out from Brandon Newman a few weeks ago, showing the simulation. But this is best case scenario where these patients get this multiple drug therapy over years on a daily basis and ongoing throughout their life. And this compliance is not typically reflected in clinical practice. There's probably -- with side effects, adverse events, compliance with a multidrug regimen as well as costs of these agents over time. So we know in reality that many of these agents are started and stopped in approximately 25% to about 50% of patients do not continue with SGLT2 inhibitors, GLP-1 receptor agonist or finerenone about a year or more after starting these therapies. In addition, while the risk reductions achieved by SGLT2 inhibitors in some of the seminal CKD and DKD trials, including credence, DAPA-CKD and Amphakidney are very impressive with the hazard ratios of approximately 30% -- representing a 30% to 40% risk reduction in development of the primary composite outcome that involves kidney progression. This slide also shows you that despite the efficacy, again, that we were so in desperate in need of to treat these patients with diabetic kidney disease, the #1 cause of end-stage kidney disease in the United States. There still remains a large residual risk despite these optimal therapies on top of the RAS inhibitors, and you can see that represented by this the red arrow that many patients are still progressing despite these therapies. These trials enrolled higher-risk patients with DKD, as you can see here represented across the [indiscernible] heat map, the eGFR and albuminuria matrix. Again, the FLOW trial showing that 24% restructuring with hazard ratio of 0.76. But one thing to note about these thousands of patients included is that they largely included patients with a GFR of 25 and above, which means patients -- many patients with Stage G4 CKD or DKD, were excluded from these trials due to potential concerns for advents that typically occurs in these advanced groups. So if you don't have data on -- robust data on the efficacy of these real agents in this group with enhanced kidney disease. And while they are capable of the [indiscernible] from simulations like this one done by [indiscernible], if you start [ multi-point intervention ] early when GFR is still preserved in this example GFR is 70, so that will be Stage G2, you can really delay aggressive decline in kidney function and a delayed need for dialysis by approximately 11 years. But in reality, these patients not referred to nephrology. A lot of attention is not [indiscernible] to them. We know the real-world data suggests that only 20% to 30% of these are actually receiving the guideline directed therapies, including the SGLT2 and GLP-1 receptor agonist. And in reality, the reflection of clinical practice is what go to shows here in the bottom left corner, patients who are who are recognized or referred at more advanced stages of kidney disease, in this case, with an eGFR of 30. And there while interventions may help to some degree, you can see the absolute benefit derived is much smaller at these late stages by the late application of these therapies. Again, representing the need for other types of therapies to potentially extend that runway and delay the onset of end-stage kidney disease. In conclusion, as you can see, it's been a very exciting time in nephrology in this space as there's been tremendous project progress and treatment options in diabetic kidney disease over the last 5 to 7 years. We now have therapies that can slow the progression to end-stage kidney disease. But I think I've also shown you we cannot completely stop progression. There's still a substantial residual risk of progression despite these modern therapies. And really, there's an inability to treat all higher-risk DKD patients with these triple or quadruple based oral or injectable therapies due to the issues I mentioned with clients or adverse effects over time. And even in an ideal world where you could treat these patients, it does not completely abrogate the progression, there is still progression occurring. And finally, we really have minimal data on how to slow progression in advanced diabetic kidney disease, especially those in Stage G4. Thus, I think this is a compelling statement is that there is a need for more treatment options for advanced stage of diabetic kidney disease to prevent progression to end-stage kidney disease, which is really just such a unfortunate outcome because even with survival, which is markedly truncated once patients start dialysis, it is a time-consuming, difficult way to live attached to machine at least 3 days a week for in-center hemodialysis, attached to machine even more often on home dialysis, whether peritoneal dialysis or home hemodialysis, and so many cardiovascular complications and infectious complications happen to these patients while on dialysis. So it is of utmost moral and clinical importance that we really do everything in our powers to prevent patients from progressing to end-stage kidney disease. Thank you for your attention. And with that, I'll pass it on to Arnold.

Hello, everyone. Thank you, Dr. Coca for that excellent presentation. I am Dr. Arnold Silva, I am a nephrologist and Director of Clinical Research at Boise Kidney and Hypertension Institue in Boise, Idaho, which is affiliated with the Cardio-Renal research network, also known as CARE. And it's my pleasure today to speak with you about Chronic Kidney Disease, CKD, and the current treatment landscape and also where this is going as far as the future. To start, I think it's important to consider that chronic kidney disease is really a tremendous burden for us in clinical mesine worldwide. It affects over 40 million of Americans alone and there's similar numbers in Europe. So just looking at the U.S. and Europe we're approaching 100 million people that are affected by kidney disease. But disease in the kidney goes beyond that. It's linked to cardiovascular disease and metabolic disease. Our most common cause of chronic kidney disease, these type II diabetes, but also type I diabetes, glomerular diseases that are impacted by autoimmune disfunction, as well as hypertension and many other systemic diseases can affect the kidney. But a staggering number, we began to see this as we did larger clinical trials in chronic kidney disease is about 90% of our patients with chronic kidneys remain un-diagnosed. And that is a challenge in and of itself in that these patients have not been diagnosed and even not aware of their disease and thus, are not going to be seeking treatment. And various treatment options that continue to emerge in clinical trials for their underlying kidney disease. Chronic kidney disease is also progressive. And as patients lose any function, and we look at function as their GFR, their glomerular filtration rate, as their GFR declines, that's associated with an increased cardiovascular risk. And if they continue to progress to kidney failure, also known as in-stage kidney disease or ESKD. Those patients have a very high mortality. To put some numbers to that, a 40-year-old patient who has end-stage kidney disease and is on dialysis, their mortality is comparable to an 85-year-old patient in the general population. Now we've put a lot of efforts into our patients with end-stage kidney disease to improve both the quality of their life as well as extending quantity. But unfortunately, despite heavy investments in research over the last 2 decades, we've not improved survival in this population. The other issue that comes along with this is cost. Our patients with end-stage kidney disease are about 1% of the total U.S. Medicare population, but they consume about 7% of the Medicare budget. So given the high mortality as well as the high cost, the need to really look at chronic kidney disease much earlier has been when our focus has shifted to in the last 5 years. And a number of new therapies have emerged that do give us some encouragement, almost everywhere in the medical literature, you'll see that the SGLT2 agents which were initially developed to treat type II diabetes, along with the mineralocorticoid receptor antagonist, the MRAs. Both of these therapies have been shown to reduce Proteinuria, that is protein in the urine, and that is an independent risk factor for progression of chronic kidney disease. Both will help slow the decline in eGFR. But it's important to know that while these are encouraging things to see, patients continue to progress, and will lose GFR greater than 2 mls per minute per year. So roughly 2% or more despite these therapies is lost from their kidney function each year. And for us to really preserve kidney function to really address the progression of disease would need to reduce eGFR decline to less than 1 ml per minute per year. And upto now, we haven't had any therapy, medical or otherwise that has been capable of reaching that goal. Cell therapy, however, with REACT, does give us a lot of promise moving forward. This autologous homologous approach that has been developed by ProKidney now has an excellent safety profile in overall [indiscernible]. And given this is an autologous homolous approach, patient's own tissue that we're using. We haven't seen any immune reactions or tumors from this therapy and the overall procedural risks are also quite minimal, which has given us the green light really proceed with more studies with REACT. And I find it most urging that at our Phase II data in over 100 [indiscernible] has been shown to reduce the decline in GFR in these patients to goal, that is the less than 1 ml per minute per year. And I think that this is very promising for our patients as we move forward. And I think that as clinicians, this can really open the door to a whole new treatment paradigm for us in chronic kidney disease. And with that, I'm going to turn this back over to Dr. Culleton to finish up this presentation. Thank you.

Thank you, Dr. Silva. It's my pleasure to present the final results of our recently completed Phase II clinical study. The data we will review supports our exciting Phase III clinical program, and we believe it demonstrates the potential of rilparencel to further improve the treatment options available for patients with advanced CKD caused by diabetes. On this slide, we have the design of RMCL-002, a Phase II study, which is now complete. We previously presented interim results from this open-label study in November last year. Just last week we also presented the final results of the study in Stockholm as part of the late-breaking clinical trial session at the European Renal Associations Annual Scientific Congress. In this study, patients with CKD caused by diabetes were randomized after kidney biopsy to 1 of 2 treatment arms. The active group or the deferred group. Active group patients received 2 rilparencel injections. The first as soon as rilparencel was available again 6 months later. Follow-up visits were scheduled every 3 months after the second rilparencel injection until 24 months after the second injection when the study ended for each subject. Deferred group patients received standard of care for the first 12 months after randomization. At the 12-month mark, they were eligible to receive the first of 2 rilparencel injections with the second injection administered 6 months after the first. Follow-up visits occurred every 3 months for 12 months following the second injection. Notably, the biopsy and the 2 injections were all performed in the same kidney. This differs from our other large Phase II study, REGEN-007 and our Phase III studies, PROACT-1 and PROACT-2, which I will explain in more detail later. As a Phase II trial, the study objectives were focused on the safety and efficacy of 2 REACT injections 6 months apart and delivered into the biopsy kidney using a percutaneous approach. Study endpoints included procedural and REACT related adverse events, along with change in kidney function as assessed by change in estimated glomerular filtration rate or eGFR. The characteristics and demographics of the 002 population were well balanced with patients with higher-risk CKD, comprising a significant portion of both the treatment groups. 43% of all enrolled subjects had Stage IV CKD. The average baseline eGFR was 34 mls and 32 mls per minute and UACR of 740 and 598 milligrams per gram in the active and deferred arms, respectively. Blood pressure and glycated hemoglobin were well controlled. The safety of rilparencel remains a significant focus for us as we understand the highest risk of CKD population often has multiple comorbidities and tend to be older patients on many medications. The biopsy and rilparencel injections continue to be well tolerated, and we are pleased to report that a most significant rilparencel related serious adverse events. The rate of procedure-related events is consistent with published reports of events observed during kidney biopsies which are commonly done to asses and diagnose chronic kidney disease. On the next 2 slides, I will be presenting some of our efficacy results. In my opinion, the most interesting data from the study. Additional slides will be available on our website. Overall, our conclusions do not differ from the conclusions we reached in November with the interim analysis. Here on the left side of this graph is the deferred group again as they receive standard of care. And then 30 of these patients received rilparencel at month 12 and again at month 18. They are followed out to 12 months after their second injection. Subjects in the deferred group who received standard of care showed a minus 3.3 ml per minute decline in average eGFR over 12 months. But after rilparencel injection, their average EGFR decline was only a negative 0.8% over the next 18 months. We feel confident that stabilization of eGFR after rilparencel injection in this high-risk population reflects the potential for preservation of eGFR in patients with diabetic chronic kidney disease, and it's one reason why we feel confident in our Phase III program. On this slide, we highlight the CKD Stage IV patients with severe Class A3 albuminuria. On the left, we have 13 subjects meeting this criteria who were in the active group, and 14 subjects in the deferred group for the standard of care group that met these criteria. Over 12 months, the average change from baseline in eGFR in active patients was minus 1.1 mls, in contrast, the average change in EGFR in the standard of care group was minus 6.1 mls per minute. This same standard of care group is also reflected in the bottom curve on the right panel. As we've previously described, these same patients received rilparencel after 12 months of standard of care. For these same subjects, we reset their baseline eGFR at the time of rilparencel injection, and their change from this new baseline is reflected in the top curve on the right panel. Their average change from baseline after injection was essentially 0 compared to minus 6.1 mls per minute for 12 months before the injection. As you can see, these subgroup analyses of high-risk Stage IV CKD patients, treatment with rilparencel was associated with the stabilization of kidney function as assessed by change in eGFR over a 1-year period. We feel this data strongly supports rilparencel having its biggest impact on the highest risk CKD population, a population that's progressing to dialysis. We believe the data in hand demonstrate rilparencel's potential for the preservation of kidney function in type II diabetic patients with advanced kidney disease. Rilparencel's benefit was most notable in the sickest patients, those who had Stage IV CKD with a high UACR. Consistent with previous study data, rilparencel was well tolerated and continues to demonstrate a safety profile in line with the kidney [indiscernible]. Because of the unmet need described by Doctors Coca and Dr Silva, we modified one of our Phase III pivotal trials, the PROACT-1 trial to enrich the number of patients with the highest risk of kidney failure. The amended protocol was submitted to the FDA in March. We have since received central IRB approval, and we look forward to enrolling new patients into the study very soon. We have a robust clinical trial program with rilparencel, as highlighted in this pipeline chart. I'd like to point out that interim results from our open-label REGEN-007 program will be available shortly. Patients in Cohort 1 of this study will receive rilparencel in the same manner as our Phase III study program. Rilparencel is injected into biopsy kidney and then injected into the contralateral kidney 3 months later. Furthermore, in the study rilparencel is cryopreserved, again, similar to our Phase III program. Results from this study will be helpful in providing us confidence in our Phase III studies. In closing, I'd like to thank Dr. Coca and Dr. Silva for their very helpful perspectives. I hope you find them as insightful as we do. This is a very exciting time here at ProKidney. We are all looking forward to build upon this 002 data with the interim analysis from GEN-007. We're also pretty excited to start manufacturing in our Phase III enrollment in the near future. With that review, I'd now like to open up the call to your questions.

[Operator Instructions] With that, we'll take our first question from Justin Zelin at BTIG.

Maybe for KOL, Dr. Coca and Dr. Silva here. Obviously, with the FLOW study recently announced the results here in the New England Journal publication. Just wanted to get your thoughts on that data set and whether there's any overlap in the patient population here with REACT? And I have a follow-up.

Justin, thanks for the question. This is Steve Coca. FLOW trial, another exciting trial that I alluded to in the presentation. Again, those with severe albuminuria and going down to an enrollment GFR of 25. So there is some overlap. Two things to note from the trial, though, if I didn't display the Capital Meier curve, from FLOW, but they would look just like the ones with -- from the 3, SGLT2 inhibitor trials that I presented, and there's still a significant residual risk, a progression in the -- in the treated group with semaglutide. Also, there was a significant amount of stoppage of the drug, I think approximately 25% stopped by 1 year. So again, these are potential therapies that we can apply, but it's not going to -- one last point is eGFR slopes, again, attenuated with semaglutide, but still not achieving that goal of less than 1 milliliter per minute per year. So another arrow in the armamentarium, but still potential, again, to add more and address kidney disease because it is not completely advocate and attenuate that progressive eGFR decline. Arnold, do you want to add anything?

Thanks, Steve. I just really concur with what you have said here. And I think it points to the importance of us needing something more than just the correct medical therapeutic strategies that have been in development and that we continue to see encouraging results from these clinical trials yet, even though there is an attenuation in the eGFR decline, which, again, I find encouraging, it's really not enough. We do need something more than what we currently have available and currently have seen in even the most recent clinical trials.

That's very helpful. And my last question, both of you mentioned a goal of eGFR decline reduction to less than 1 ml per minute per year. Would that be a clinically significant goal for the REACT product? Or what would you deem to be clinically significant for this product?

I think that would be a great goal. As we see from the 002 data, it appears it to result in a slope less than 1 mililiter per minute per year. It is really the holy grail because the epidemiologic data of normal aging suggests that patients lose GFR at approximately 0.5 ml to 1 milliliter per minute per year. So anything in that realm is essentially equivalent to that loss due to normal aging.

And I agree as well. I think when we look at really anybody, we're all over time, losing kidney function. So there is a normal aging process. And whether it's diabetic kidney disease or kidney disease from many other different systemic diseases. I think getting under that 1 ml per minute mark is really where we're striving to be, and we're not there yet with the medical therapies.

The next question comes from Judah Frommer.

Maybe just first to follow up on that. For the Phase III trials for 1 and 2, would the expected annual eGFR decline be similar to the rate you just disclosed or higher risk patients would be expected to have a quicker decline?

Is that for Bruce or for Arnold?

I guess -- I guess the high-level question maybe for the KOLs is just should eGFR decline be expected to be greater in the high-risk population?

Yes. I can comment there. I mean typically, what we have looked at in many of these trials are the high-risk population. And I think Dr. Coca showed in his slides, Often, these patients were with eGFR range in the 25% to 45% range. So that is a higher risk group. Many of those patients with proteinuria and they're often progressing at greater is for GFR loss over 4 ml per minute per year or certainly in that territory. So this is a population that everybody is interested in because they are losing function quite rapidly, both from their current eGFR where they stand with moderate to advanced disease, and many of these patients have significant proteinuria, which again is another risk factor. So yes, I would expect, especially when you look across multiple studies to see the patients in this group to be progressing at a faster rate. So Steve, if you want to comment as well?

Sure. I guess is the heart of the question, does it need to get to less than 1 mililiter per minute a year to be a success? I think, again, that is the ultimate goal, but for success on a clinical and scientific basis, of course, slowing the progression in this high-risk group compared to the control arm in a statistically significant manner is going to be a success. And let's not forget that although it is invasive compared to the other treatments, it is much potentially when it's the short-term pain, long-term gain. Compared to taking multiple medications on a daily basis or the injectables in the case of the GLP-1s, you get this done and you don't have to worry about that daily compliance. And so there's a potential for the ease of achieving this reduced risk, again, with the invasiveness, but without the -- we know how much problem patients have with multidrug compliance and they missed doses. They stop taking them for various reasons. They don't feel well, they think it's their medications. They hold them for on disclosed periods of time. You know that therapy is getting there with this treatment. And that's one of the reasons I've been so excited about the program from the beginning because it's hard convincing patients take these cells every day for something that's going to potentially reduce your future risk, not necessarily symptomatic at these stages yet, and you overcome that barrier with this type of therapy.

Okay. And just getting back to your comments on the FLOW trial. And obviously, GLP-1s are going to be a topic of discussion across lots of diseases these days. But I guess for the high-risk CKD patient population, I guess, how realistic is it that GLP-1s are going to reduce the prevalent population there? Or is the idea more that maybe there are fewer high-risk CKD patients over time because maybe patients are taking GLP-1s and they're not getting to later-stage kidney disease? Or do you think that this high-risk population could shrink as more patients do get on to GLP-1s?

I know there's been these potential debates about are we really going to shrink of this population. I mean, we still have a massive inflow of obese and diabetic patient population out there but all -- all estimates suggest we'll continue to grow double, triple over the next few decades. So yes, you're getting some reduction in that pool. But I still think the in is greater than the outcome what you're going to prevent and thus the total investable population is still going to be very largely robust despite GLP-1s or any of the other therapies.

The next question comes from Jonathan Miller at Evercore.

I would like to ask both the KOLs, a question about eGFR as the endpoint. Obviously, it's notoriously variable from a patient-patient basis, even within individual patients. So when you think about the variability of the data on an individual patient basis, could you talk a little bit about how the SGLT2 trials are mitigating that error rate and what are the best practices for running these trials with endpoints that can be a little noisy?

I can start on that one. Yes, eGFR can be noisy, especially at one point in time on an individual patient. But we do have all the trials to date and including the REACT trials, you have multiple time points where you're assessing eGFR in a repeated measured fashion. So that does help hone down on an individual base slope. And when you see FDA-approved endpoints for the sustained 40% decline sustained 50% decline in eGFR, all require a confirmation at 30 to 90 days later so that it's not just that individual fluctuation that can result in a noisier signal. I think even though there is some noise, it's not perfect. It is the clinical standard. And as opposed to employing something like a measured GFR with [indiscernible], well, that could be somewhat more accurate, it would not be represented in clinical practice.

Makes sense. And I guess the follow-up to then is given that EGFR is the gold standard, how do you rank that relative to disease progression into ESRD or on to dialysis or any of those time to event progression endpoints that ultimately are what cost payers a lot of money and what result in the real decline in quality of life of the patients?