All right. Good morning, everybody, and welcome to our first session of our last day. We're starting here today with Bruce and James from ProKidney. Thank you guys so much for joining us this morning. Yeah, thanks for the invite, John. Glad to be here. I'd love to start, maybe, maybe high level. Obviously, recently, there's been a lot of change to the company. There's been some updated data, which, well, we'll get into some of the details on that, management changeovers, and what stands to be a very exciting 2024. But I'd love to turn it over to you for a couple of minutes and maybe give us an introduction to where ProKidney stands at the moment, and what should we, we should be looking for as we head into the next year. Yeah, thanks, John. So you're absolutely right. We've had some changes over the last month or so. It's been a busy November, and I'm delighted to lead the company moving forward. With our release of the data from 002, I'm excited to see the promise of REACT. There's a Phase II study, and we see some positive signals there that make us very confident in our Phase III program. And obviously, we've had to make some changes to that, which we'll talk about this morning, I'm sure. I'm excited about the team that I have, the new leadership, some people new on our leadership team, including Nikhil Pereira, who's in the room. An announcement coming out about Nick and the Chief Business Officer this morning. Just saw her. So it's great to have Nick on board and some other members of the leadership team joining me as well. So we're looking forward to a strong 2024 as we restart our clinical study program, and we come off our manufacturing pause. Excellent. Well, let's start with the 002 data that you talked about just releasing recently. The promise of REACT at its inception was the notion that we could slow or even reverse kidney function declines in chronic kidney disease. And the initial data out of the study 002 when we first saw it seemed to show some pretty impressive, unprecedented, frankly, improvements in eGFR and kidney function after injection. Those results have come in a little bit, but there's still some very interesting signals there. So could you describe what you see as the most interesting parts of that study, and what's giving you the most enthusiasm for the therapy? I will indeed, yeah. So first, I'd say anytime we see something that's unprecedented in science, we should, we should ask more questions. Maybe take a pause. So the data that was presented, initially presented in March of 2022, I think, the data that you're referring to, was a really early cut of 002 data. And as we've talked about before, month 15 and onwards in that early cut showed an upward slope in the average eGFR. And now, when we look at that data, and it's more mature, the slope is pretty flat. The average eGFR is pretty flat, and rightly so. The question is: Well, what happened? So why did it look that way back in March? And why does it look like it does today? Well, the easy answer is that the data is matured, but that's not sufficient to get into the details, enough of the details on that. So really, when you look at the details, there were 21, about 21 patients who made it out to month 15 and beyond, and the other 18 patients who were enrolled in the study hadn't made it out to month 15. When you look at those early enrolled patients, their average baseline eGFR was 5 ml/min higher than those that came in later in the study. Higher performing at baseline. So they had higher eGFR at baseline, so they had less severe kidney disease. And when you talk to the, you know, people that were part of the study program at that point in time, the investigators were more comfortable enrolling patients with less severe kidney disease early on, and then as they got used to it, they started to enroll more patients with more severe kidney problems. Makes sense. That, we believe, explains most of that change from an upward slope to a flat slope. Okay, makes sense. Yeah. So as we look forward to the registrational studies, which, as you alluded to, have seen a little bit of change, and data release coming in 2024 from that 007 study that I think you mentioned earlier as well, what are you seeing in 002 that makes you confident in those studies, and what are the readouts that you think are most impactful from the 002 data? So, first of all, the data release that we had from 002, just a couple of weeks ago, that is almost near full results. So there's still a handful, maybe about a dozen patients, who still have to have their last visit, but they've had all their kidney function measurements up to this point in time. So we'll release the full data in the first half of next year. We should have our full data tables locked by the end of February, and then early analysis done in March and April. So we'll definitely present the full data, likely at a scientific congress, in the first half of next year. I don't expect that's gonna change much, but what was exciting about that data was a couple of things that really hit me as being exciting. One, one was in the standard of care group that were followed for 12 months, had a change in their kidney function, and then got injected with REACT, and then they had preservation of their kidney function. Really, just a flat line for the next 18 months... And that preservation in this group of patients with advanced kidney disease is what struck me as being impressive. Mm-hmm. Still small number, still small follow-up, Phase II study, but, to me, it said REACT is working. And then the other point, if I could- Please. Yeah. So the other point that was also interesting was when we looked at the Stage 4 patients with the highest level of urine albumin, the most severe patients, the highest at risk of progressing to need dialysis, compared to standard of care, there was a difference in their progression as well. So we seem to have an impact on those higher-risk patients, more than what I anticipated going into the data. Maybe we could dive into that a little bit more? As you alluded to, that positive initial slope in eGFR being driven by less severe at baseline patients seems to suggest that the potential for improved kidney function might be better in less severe patients. But what you just said was that more severe patients were getting a better benefit. So can we dive into squaring that circle a little bit? Sure. I think, I think we need to go back then and just spend a little bit more time on that upward slope. Mm-hmm. So it was an upward slope, because of those less severe patients who, at baseline, had a higher eGFR. So if you just followed those 21 patients out, it's actually a flat curve. Mm. It's a flat line. Then, if you follow the other ones out that came out in the later, later part of the study, it's also similar to a flat line. It's just they're at two different levels, so their trajectory was really about the same. Makes sense. Now, one thing that also popped out at me when I looked at the O0 2 data was your annualized rate of eGFR decline. I know we discussed this in the aftermath of that release as well. When we look at the patients who were treated from month 0, I guess, the experimental arm, really- Yeah ... or exclusively experimental arm, as, as you can. Annualized rate of eGFR decline in those patients seemed relatively similar, to the rate of decline in the patients who were deferred, who weren't getting treatment in those first 12 months. Correct. Yeah. So I'll take you—if we could spend a little bit of time on that, 'cause that's— Please ... really important. So there are probably more than three, but there's three ways that I think about how you look at change in kidney function over time. One was the way that we presented in the main slides, and we presented it previously as a company as well, and that is where you take the average eGFR at different time points. The advantage of that is we can all do it, right? We all understand that. Yeah, I like analyses that I can do. It's true. We started to learn to do that probably in grade five or grade six, right? But it's something that visually makes sense to us. It's just the average plotted over time. The other way that's actually reasonably easy to do is change from baseline. And change from baseline means that everyone gets a baseline of zero, and then as you follow those patients over time, they're up or down or by so much. And then you take that average change from baseline and plot it. The benefit of that approach is that if you have two groups, and there's a difference in their baseline eGFR, it negates that difference. So we also present some of that in the slides that we presented a couple of weeks ago, too. So the advantage of both of those is you can see it, and most people are visual, and you can see it. The Linear Mixed Effects Model, which we included in the appendix, which is the annualized slope, which you referred to, is a number, and it doesn't always match with the visual. Now, if you have no loss of follow-up, if you're looking at two different groups, and they have the same baseline numbers, you generally end up with no dropouts, no missing data, you generally end up with the mean eGFR plotted looks the same visually as the change from baseline. And if you put a y=mx+b slope through the mean change over time, it comes out to look very similar to a number like the Linear Mixed Effects Model. The advantage of linear mixed effects is that it does take into account when measurements are done over time. So if it's measured at 3 months versus 2 months versus 4 months, it does take into account some dropouts. It does take into account the difference from baseline, that or g- Critically, the Linear Mixed Effects Model is the sort of modeling that the agency is going to be looking at primarily. Correct. And we did submit. When we got our RMAT for our Phase III program, we submitted the LMEM models to the agency, and that's what they based, partly what they're based their, our approval to move forward into the Phase III study. Mm-hmm. Now, you brought up two good points. Many good points, actually. Some great questions. So, one is certainly around the linear mixed effects. And what we see is, when we look at the data, the LMEM change from baseline and mean eGFR are very similar in that deferred group. They match pretty well. They're consistent. Mm-hmm. So that deferred group is the group that were on standard of care first for 12 months and then crossed over to receive REACT. And when that crossover happened, and you follow those patients for the next 18 months, those three ways of looking at the data are really consistent... what you've pointed out is that's not consistent, if you look at the first 12 months of the study. Essentially, the controlled portion. Correct. The active versus the standard of care group. I'd argue there's a control, a pre-post control in some way, too. Yes. So if you look at the active versus the standard of care group in the first 12 months, you don't see that same consistency in the data. Part of that is driven by the dropouts for the first 12 months. So the LMEM picks up on those dropouts, picks up on that data better than just the average eGFR would. Sure. That essentially penalizes your active arm to a certain extent. Correct. The other thing with LMEM as well, so it's not none of these measures are perfect. None account for survivorship bias. And that's why the agency, when you look at Phase III programs, that's partly why they want companies who are in this space to use hard endpoints for approval programs. That include a survival component. That include, like, are you alive or dead? Are you on dialysis or you're not? Right. Or has your kidney function changed by 40% or 50%? Something that is not arguable- Unambiguous decline. Correct. So that's why Phase III programs, like ours, is designed in that manner. So, the other downside of LMEM, not just the survivorship bias, but it's typically most useful if you've got longer follow-up- Mm-hmm. - and more patients. Of course. Yeah. So maybe this is a good segue into the 007 data next year and the Phase III programs. So, the 007 data is something that we've been very focused on, as it mirrors the Phase III programs a little bit closer, both in terms of the procedure, the product being given, and in terms of the patient population. But what should we be looking for in that data release next year that clarifies some of these questions we've just raised? Yeah about the 002 data? It's a great question, John. So, just as a reminder, there are two groups in the 007 study. The group that we're interested in, and you should be interested in, is what we refer to as Cohort One. And that Cohort One receives two injections with REACT, three months apart, in one, the first in one kidney and the second in the other kidney, with the cryopreserved product. Mm-hmm. They're diabetic patients. Which is the same procedure that the Phase III patients are in. Correct, which is exactly the same procedure. So, those patients, you know, we'll have that data in an interim analysis for you in mid-next year. Why you should be excited is because they, they are diabetic patients. We're using the same procedure, the same product as we're using into the Phase III program. And the patient population has a lower eGFR than what we have for the baseline population in 002. Those more severe patients- Correct that we were talking about earlier. Yeah. We believe that's gonna give us a better window into what our Phase III program is gonna look like. Mm-hmm. and what I'd like to see when we do the interim analysis, and we're gonna report the data when we have double-digit patients and 12 months follow-up after the second injection. What I'm really looking forward to seeing is, it's still slope, still change in eGFR. I'm looking forward to seeing that group look more like the crossover group in 002. Right, that group that you mentioned earlier, with severe disease at baseline, who declined during the deferred period and then stabilized. And then climbed. Yeah, that's right. Yeah. Are you going to have sufficient baseline measures for the 007 patients to tell what their slope was before treatment? We have some baseline data, but not rigorous enough to say, "Look, this is 12 months, we collected this- On an individual basis. Correct. So we'll be relying on a historical control, essentially, thinking what severe CKD patients' kidney function ought to look like over the course of a year or a great year. Correct. Yes. Makes sense. Yeah. One other thing that I wanna make sure we touch about- Yeah ... I touch on, is the manufacturing pause- Yeah -that you alluded to in your, in your opening comments. Maybe you could take us through what exactly was observed and why it led to a, a pause in manufacturing? Sure. We had an EU QP audit, so qualified person from the EU, because we have a study program that we're rolling out in Europe. And it's regulations within EMA for that, for an auditor to come and look at a manufacturing facility before you can ship product. The FDA has, obviously, similar inspections. Yeah. The difference is the EU tends to do it every two years. Mm-hmm ... every 2-3 years, even during a study, whereas the FDA typically will wait until you file your BLA application. Right. You have to submit your documents, but they usually don't come visit. So the auditor came in October and identified a lot of things that we were okay with from a Phase III program in the U.S. Like, we don't think we're non-compliant with FDA regulations. But from an EU perspective, we felt like they needed to be at a point closer to how it would look for commercial manufacturing. And most of those were you know, you need to get your SOPs in better place, right? You're not tracking your process deviations well enough. There were some concerns around upgrading our environmental paperwork to show that we meet standard compliance for manufacturing. It sounds mostly like a documentation, you know, an SOP, rather than gross instances of, you know, infection or contamination. Correct. So there were no gross instances- Mm of contamination or infection or anything like that. But I also don't want to underestimate the importance of it, because it's work that we needed to get done. Mm. we took a pause because we were going through that amendment with one of our studies anyway, and it was just easier for us to do this work while we weren't processing samples. It's like, it's like changing a tire when you're still driving a car. Mm. It's more difficult to do that, rather than park the car. I- So, so- I would imagine so. So we've parked the car- Yeah and we're getting into compliance, and we anticipate that will happen within the next 4-6 months. The good news is the auditor said, "I'm here when you want me." So ad hoc meetings, updates, it's not like we need to wait for 6 months and say, "Here's our package." The auditor is gonna be there with us. Excellent. Yeah. So the expectation ought to be that manufacturing back online in the early part of next year. Correct ... and, with that, the studies, the Phase III studies, are continuing to enroll? Correct. Yeah. Our timeline that we've set for the manufacturing is, it's gonna be about a six-month pause, so that puts us into Q2. Makes sense. Yeah. As we look forward to Phase III, you alluded to this earlier, one of the Phase III is the PROACT 1 that had already been enrolling, had the inclusion criteria slightly altered, I think, in response to this observation from 002, that the more severe patients were getting the better benefit. You chose not to alter PROACT 2's enrollment criteria. Right. Can you talk us through what that decision process was? Sure. So first, we made the decision for PROACT 1 because of a lot of things. The culmination was the 002 data. But part of it was also, you know, the recognition that payers have a more greater interest in higher-risk patients. And nephrologists see this as an unmet need, and patients have some degree of desperation, if you like, once they reach that threshold of 30 or less in kidney function. Mm-hmm. So, that's why we made the changes to PROACT 1. PROACT 2, just as a reminder, the top level of eGFR is at 44. It's still Stage 3B. Mm-hmm. So these are still sick patients. And we left it like that for two reasons. One is, you know, that may help us with our commercial label, right, by having a higher eGFR, in some patients- A broader indication. That's right. A broader label, if you like. And the other point is, any small change to that protocol would be a 12-18-month delay in Europe. Mm. Right? Yeah. Even small changes. Right. You know, the FDA is more responsive. Believe it or not—the FDA is more responsive, so. Makes sense. Yeah. Okay. So, I think we're basically out of time here, but any final thoughts about what we should be expecting in 2024 and... No, I'm really looking forward to us getting back on track with manufacturing, and getting back into the clinic with our, with our patients and with REACT, and excited about being able to-