Good morning. Thank you for attending Jefferies' London Healthcare Conference. My name is Kelly, one of the biotech senior analysts here. And in this first chat session, we are very pleased to have a ProKidney team. And maybe we can start with an introduction with both of you. Nick, maybe start with you first. Yeah, happy to. This is Nick Pereira, Chief Business Officer of ProKidney. Hi, Kelly. Thanks for having us. Ethan Holdaway here. I lead investor relations and corporate development at ProKidney. Great. Welcome both. Maybe firstly, could you give us a company overview to the investors who are new to the story, and what is the mechanism of REACT cell therapy, and now with the name of rilparencel, to treat diabetic chronic kidney disease? Absolutely, Kelly. Questions. How much time do I have? At a high level, we are a phase 3 clinical stage cell therapy company. Our product is rilparencel, which is heavily focused on stabilization of kidney disease, focusing on advanced chronic kidney disease patients and diabetes, really in the area where there's the highest unmet need. When we think about kind of the story of the patient journey or the product journey, it starts with the biopsy first. Then the cells ultimately arrive at our manufacturing facility, go through digesting, cell expansion, and then are pulled together with selected cells into the personalized therapy. I'll let Ethan speak to the mechanism of action. That's okay? Sure. Yeah. Thanks, Kelly. So the mechanism of action is it's an evolving story, if you will. And we've committed in the next 12 months, we've committed by the second half of next year to provide a more robust update on it. But we recently had some interesting posters we presented at ASN in San Diego discussing the product characterization of rilparencel. And one interesting finding was that if you look at the markers that are being secreted early in the manufacturing process and you compare them to what we see in terms of that profile in the final product, there's a reduction in inflammatory and fibrotic markers in that final product relative to what we're seeing in the early stages. So again, it's an evolving story, and we'll provide a more robust update next year. Okay. Terrific. Before we move to pivotal trial design and also the newest update we learned from your press release, maybe we can revisit the clinical evidence we have seen so far. And how does it fulfill the unmet need? Yeah, happy to. So just to clarify on that, I think we probably want to be talking through the phase two trials historically. So we had a number of phase two trials. The two notable ones, RMCL-002 and REGEN-007. So RMCL-002 basically was focused on patients with CKD between 20 and 50 eGFR. Effectively, there was a treated arm. It was around 80 patients total. There was a treated arm and a placebo arm that crossed over ultimately into a treated arm. So in the treated arm, patients received rilparencel. At that time, it was called ReACT, spaced out between six months, and then they continued to be followed up. Then on the placebo arm, after 12 months of being the standard of care arm, they crossed over into receiving rilparencel with 18 months follow-up. What we saw on the standard of care side for the first 12 months, it was about a negative 3.3 mL/min decline in eGFR function. But then after receiving rilparencel, over the following 18 months, it was about a negative 0.8 mL/min decline. Notably, in a subgroup analysis, when we're looking at RMCL-002, I think you probably remember this. This was exactly one year ago. We saw that in stage four patients with elevated UACR, rilparencel was able to show stabilization of kidney function over 12 months, while the placebo arm or standard of care arm had a negative 6 approximate decline in kidney function, mL/min. And so with that, that helped us determine when we looked at the phase 3 program, there was an opportunity to amend the patient population we're focusing on, narrow it, the scope to stage 4 patients in the 20-30 eGFR range, and then late stage 3B patients in the 30-35 who had elevated UACR. Then a study that's still kind of waiting to be read out, and we're looking forward to that in the first half of this year. REGEN-007 had two arms. So 002 had 80 patients, just to go back to that, 40 in each. In 007, there were two arms, 50 patients total, both arms, 25 each. Group 1 was really what we view as mimicking the phase 3 program. Unique element and the difference between 002, which is RMCL-002, was that it was spaced out by six months, and it was fresh product. Within REGEN-007, it follows now what our phase 3 program is, which is the injections were spaced out by three months each, and it was a cryopreserved product, and notably, it was the first time we were dosing both kidneys. Previously, for safety reasons, RMCL-002 was focused only on the single kidney that was biopsied, so in REGEN-007 group one, we have followed patients to date with injection, and then three months later, second injection, the other kidney that was non-biopsied, and we are following up those patients for 21 months post first injection. The group two, though, is a bit more unique. It was a dosing exploratory trial in that respect, where we wanted to understand kind of what the potential triggers would be for the second dose, so similar to the first group, every patient received their first dose of rilparencel. But then there were two triggers, whether it was a 20% or greater decline in eGFR or a greater than 30% increase in UACR that led to that. I think we can speak to this a bit more later. But ultimately, what we took away from that second group was more the fact that we feel confident that dosing rilparencel in both kidneys is the optimal path. And so that influences our phase 3 program. But for both RMCL-002 and REGEN-007, what we have seen is stabilization of kidney function in the groups that we focused on. Okay, and what is the clinical evidence that for 007, the bilateral kidney injection actually could bring additional benefit compared to 002? Yeah. So I think the evidence we have right now is when you look at RMCL over, I'd say, 18 months post first injection or 15 months post second injection, people oscillate between the two. It's the same term. We've been able to show on the 13 patients, and these are patients whose baseline eGFR is much more similar to that of our phase 3 program, in and around 29- 30. The average from baseline decline was about negative 1.3 mL/min. So that gives us confidence over an 18-month period. That's pretty much in line with a healthy adult who's in and around 60 years of age. A healthy adult typically has about 1 mL decline in kidney function in an adult who does not have chronic kidney disease. Could you help fill in more details regarding the procedure itself? And what kind of feedback have you heard from physicians and the patients? And what kind of enrollment pace do you anticipate for maybe first on 007? Yeah, no, absolutely. So the procedure is a biopsy that's done from the renal cortex. Those cells are then harvested, expanded, grown, and then reinjected. It's two injections back into the renal cortex of the kidney. When you think about safety, thus far, I think we've had right around 200 injections, 100+ biopsies. And what we've seen is the safety profile of rilparencel is both on the biopsy and then the actual therapy has been in line with that of a standard kidney biopsy. So from that perspective, physicians have been quite comfortable with the safety profile. For patients, I think it's really an interesting question. When you're looking at patients who are effectively on the doorstep of dialysis, you really have to ask a patient, "Do you want to undergo, yes, one biopsy and two injections of rilparencel, which, as it stands right now, is really a one-and-done therapy? Or are you prepared to be getting an AV fistula created and then going three times a week, having your fistula pricked three times?" So when considering weighing that, many patients, I think, are quite excited about the opportunity to participate in the trial, but also the long-term commercial opportunity and the difference rilparencel can make for patients. And so your question, the second question was. Enrollment pace. Enrollment pace, so we haven't publicly said anything about the enrollment pace, but I would say we are actively recruiting and activating sites as we speak. We relaunched our phase 3 program, PROACT 1, which is now our primary program in June of this year. Okay. And given the profound impact of GLP-1 therapy, compare REGEN-007 to RMCL-002 because it's relatively newly started a trial. What kind of impact do you expect from prior GLP-1 treatment for patients? Or do you have certain exclusion criteria to mitigate the impact? Yeah. So I guess I'll work backwards. The first thing I'll say is all of the innovation that's happened around the kidney space with regards to standard of care and now GLP-1s. It's great for patients. No question about it. And I think where we slot in is, as I'd say, almost a rescue therapy in advance of dialysis. So when you think about REGEN-007, of the 13 patients we showed in our interim update, six of those patients, about 46% or so, were on GLP-1s when they started. Within four months, 50% of those had dropped off. And so in that respect, we have a general high level of confidence or level of comfort that there wasn't a significant skew in the data that we showed in the preservation of kidney function over 18 months with relation to GLP-1s. Okay. Great. And maybe moving to a pivotal trial. So you recently announced that FDA has confirmed a single phase three trial, PROACT 1, could be sufficient to support Full U.S. approval. And in the past, you actually proposed two trials. Curious, what kind of discussions have you experienced with regulatory agencies, and what actually drove this decision? Is it a clinical database? Yeah. So I'd say the company has had a pretty long history, and so a lot of these decisions, especially when they were first designing and getting approval of the phase 3 program and the pathway for approval back in 2022, it was a different time. I think a lot of things have changed with regards to CBER and their desire to really bring innovative therapies forward. We had been thinking about this. There was a lot of changes that happened at ProKidney over the past year, and we called it our reset, and so we had to address manufacturing issues that were resolved by May. We had to get the amendment done for the phase 3 program. And so really, in and around April, May, our CEO, Bruce Culleton, started asking these questions internally as to why do we need to be doing two 600-patient trials for our phase 3 program. We consulted the experts and gained a level of confidence. That said, in September, we made the decision to drop PROACT 2. The FDA, we had the pleasure of our Type B meeting with the FDA. And honestly, I'll say we could not have asked for a better outcome. They greenlit what we had proposed, which was a single 600-patient study, PROACT 1 for rilparencel. But in addition, they opened up the opportunity for an accelerated approval pathway for us and suggested, obviously, a surrogate endpoint. And one that's been used quite extensively recently, both as a primary endpoint in the IgAN space, but in other areas as a surrogate was an eGFR slope. And so what's quite unique even now is when you look at our upcoming REGEN-007 cohort one or group one data that's expected in the later part of the first half of this year, we believe it's going to be a useful read-through into what an accelerated pathway would be for rilparencel. Okay. Terrific, and could you also share how is this phase three designed in terms of powering and assumption, maybe hazard ratio, also event numbers, I mean, all the details regarding trial design? Sure. Yeah. Thanks. Thanks, Kelly, so as Nick said, it's a 685-patient study. Randomization is one-to-one. We've got a treatment arm and then a sham arm where patients would undergo a sham biopsy and two sham injections. In terms of powering assumptions, what we've stated publicly is we've got at least 80% power, assuming a hazard ratio of 0.6 and a one-sided p-value of 2.5%. When we think about event rates, we're looking for total number of events in the 120-event range, and we've based our assumptions for event accrual based on the anticipated baseline characteristics of the patient, and we've taken into account the recent improvements in standard of care. Obviously, that plan is separate from what we're now working on internally coming out of that FDA meeting, where we now have the option to potentially come up with an accelerated pathway, so that would look a bit different. But what I just provided was an overview of the events-based part of the study. Great. Just to confirm, has eGFR slope been confirmed as the surrogate endpoint, or is it still in discussion? It's still in discussion. The FDA suggested that we look into it. But now it's on us to go back internally and determine what's a clinically meaningful effect size, what is the time, what is the duration for eGFR slope that we're going to look at when comparing sham to the treatment arm. So there's a couple of other things that we need to sort out internally before we go back to the agency, have another meeting, and come up with that accelerated pathway. Okay. Given this is a pretty novel approach, curious if there are any interim analyses and also fertility tests implemented in trial design? Yeah. So there are no interim analyses planned. I think a big reason for that is for us to have enough events for us to get comfortable to do an interim analysis, we'd probably be looking at around 90 events. So at that point and at that pace of kind of accumulation of events, we're a handful of months away from actually hitting our final data for a composite endpoint. So especially with now the accelerated approval pathway, we don't believe it's worth giving up the extra alpha when the reality is it's maybe five or six months away from getting the final readout. Okay. Great. Now moving to manufacturing, this has never been an easy topic for any cell therapy programs, especially you actually had to solve some issues. Could you actually help us to understand how this process compares to maybe other very prevalent CAR-T therapies in terms of turnaround time, success rate, everything we need to know? Sure. Yeah. Well, the first thing I want to just mention is that when we did pause manufacturing, it was not due to safety issues. This was primarily identifying and remediating deficiencies in our documentation and more operating procedure side of things. But yeah, our manufacturing process works by you get the biopsy tissue from the patient, send it to our facility in North Carolina. We put the biopsy in a solution. We then put the cells through a selection and expansion process, formulate the product, freeze it, and ship it back to the site of care for reinjection. Our typical time frame for that manufacturing process from biopsy to the patient receiving the first injection is about three months. In the context of CAR-Ts, I just want to mention, while there is urgency to treat patients who are approaching dialysis, I'd say that a CKD patient typically, and I recognize this is a bit of a generalization, but we're typically the level of urgency isn't quite the same as a very advanced cancer patient. In terms of differences in manufacturing, I won't get too into the weeds with CAR-T, but generally, that's taking the blood from the patient, separating the T cells, and actually re-engineering those T cells and then putting them back into the body. Whereas ours is more in line with typical cell line development, where we're putting those cells through a selection and expansion process, freezing it, and then preparing it for reinjection into the patient. And just one thing also to address, we had the manufacturing pause associated with the QP audit that was required for us to ship product to Europe. It's strange to say, but it was a bit of a blessing in disguise because now we're a GMP-certified facility. And I'd say we are planning, and with incremental spend that's in our cash runway, we're preparing for the necessary such that we are prepared for commercial launch in the first few years. So while we did have to stop manufacturing, it allowed us to put ourselves in the best position to succeed for the future. Okay. Great. And maybe compared to CAR-T, it's less complex in terms of you don't need to do a viral transduction. But curious, in terms of heterogeneity of the cell product, is it more than T cell-based therapies? And what are your key QC metrics during the cell collection, manufacturing, and the release process? Yeah. I think it's hard for us to comment on the CAR-T rilparencel comparison because we haven't done an in-depth analysis of each process. But what I can say in terms of heterogeneity in the patient population, we're stratifying for SGLT2 as we recognize that these improvements in standard of care need to be accounted for. And then as far as our QC process, we have various checkpoints throughout the manufacturing process to ensure that that product is being monitored appropriately. And then we have certain release criteria. We do potency testing, sterility, things like that before the product is released and shipped to the patient. Great. Yeah. And just one other point on just heterogeneity. When you think about it, and this was in one of our ASN posters, when you think about the specific cell types, every single patient's going to have a different number of specific cells, senescent cells, you name it. But I think a key element from what we've seen is there is and there may be, so I won't say there is, but we look forward to showing that the autocrine paracrine signals of the anti-inflammatory and antifibrotic occur regardless of the specific cell types. And it's due to a slightly differentiated state of these cells. So when you think about that element, we get level of comfort. Depending on the patient, it wouldn't significantly impact the efficacy of the therapy. Fantastic. Lastly, maybe you could reiterate the important catalysts and the milestones we could anticipate from ProKidney in 12 months? Yeah. So I think first and foremost, and this is hot off the press as of last week, we've said we're going to further define the details of the potential accelerated pathway for rilparencel. And we're going to provide an update on that in the first half of next year. In addition, we will have full 12-month results for our REGEN-007 phase 2 study, which is very important because it provides a good read-through into our phase 3 program as it mirrors the dosing schedule. It has the cryopreserved product. And then in the second half of next year, as we said earlier in the chat, we will have a more robust update on the mechanism of action of rilparencel. And just to be finally a little bit salesy, I think with investors, obviously, they look for near-term milestones. This news from the FDA has really changed the outlook for us with regards to creation of near-term milestones, whether it's the recruitment of patients required for accelerated approval, full approval, and then the data that we'll hope to share for full approval and accelerated as well. Looking forward to it, and we're going to wrap up here. Thanks for great discussion. Thanks to everyone for attending. Thank you so much, Kelly. Thank you.