Okay. Welcome, everyone. Let's go ahead and get started. This is the Fireside Chat with ProKidney. My name is Vikram Purohit. I'm one of the biotech analysts with the research team. Before we get started, I need to read a brief disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, happy to have with me Tim Bertram, CEO of ProKidney. Tim, thanks for joining us.
Yes, look forward to it.
Tim, maybe just to level set for everyone in the audience, could you just quickly walk us through the REACT technology, what it is, the thesis that drove the formation of ProKidney, and then we can go from there?
Sure, and I'll be making forward-looking statements, also, they can be found on the ProKidney website. Yeah, the technology was started many years ago, about 20 years ago. It is a cell-based therapy. It was driven largely around the concept that there's been no successful products, small molecules in particular, that have been able to show a major impact on chronic kidney disease. It's largely because of the multimodal mechanism of kidney disease. So what we thought about was, does the kidney have the ability to heal itself in the earlier stages? We know that the acute kidney can respond quite well. So we asked the question: Is there something in the kidney that exists and is lost in chronic kidney disease?
What we found is that there are three cell types which are important in the maintenance of the kidney, in the development of the kidney, and in the healing of the kidney. What that allowed us to do was to develop a proprietary method of isolating these, manufacturing these, and then re-implanting these into patients. What we were very pleased to see was that the effects that we saw in animals could be reproduced and translated into early stage clinical trials, phase one. That observation really drove us to recognize that there was a therapeutic value here. One other point that was quite significant, value to the investment decision, and that was turned out humans have pharmacologically more active cells, these three key cell types, than do animals.
And, that observation really told us there was something there, and we followed that up in our mechanism of action work to show that those, that pharmacologic capability of these cells still exists, when they're, isolated. But that was what drove the formation. That's what we are. It's an autologous, homologous admixture of the three cells that's used in patients with late-stage chronic kidney disease.
Got it. Got it. And for those three cell types, what do we know about the MOA? And is there one cell type that contributes proportionately more to the therapeutic effect that you're proposing?
Yeah, very good question, Vikram. So, what we know about these cells is that they integrate, they're chemotactic, they migrate from the injection site throughout the kidney. They integrate into the parts of the nephron that they came from. So you can think of the nephron being composed of two pieces, the filtering piece, if you will, and what's generally thought of as the estimated glomerular filtration rate, which is measured. A lot of the ACE and ARBs, the current therapeutics, focus on that. And then the tubular metabolic piece. What we realized is that these three cells, one comes from the glomerulus itself, the podocyte, one forms the formation of the filtration barrier, the podocyte, and the third one is the ureteric bud, which contributes to the cells. They go back, integrate into the location from which they came from.
They replace the weak and damaged cells, begin to function, and then what they also do is they release cytokines that are responsible. And I alluded to that, that the pharmacologic activity is centered around VEGF, vascular endothelial cell growth factor, which is needed to keep the nephron functioning, and TGF-beta2, which is responsible for maintaining the integrity as well as influencing the interstitium. So these cells, we understand that's how they work. We also understand that they remain in the kidney for an extended period of time. Because it's autologous, the value is that you've got a chronic disease process, and you need this pharmacology to be active over an extended period of time. They integrate, and then as a result of that, you see the changes in the function.
What we found in animal studies is that the fibrosis and the chronic inflammation are downregulated by these cells. So that's what's there. Last point, and we're very excited, we'll be releasing some information at ASN this year, and that is: Is any one of the cells more important? It turns out that doing interactome analysis, we realize, and using the fundamentals of kidney biology, all three of these cells are needed, and they talk to each other in a way that allows them to execute the function in this complex disease and complex organ.
Got it. Okay, that's helpful. So now that we've talked about the science and the mechanism a little bit, maybe walk us through the manufacturing process. What needs to happen from a patient's kind of initial and a prescriber's initial indication of interest, all the way to actually receiving REACT?
Yes. Yes. So we have a proprietary method of manufacturing, and this was worked out over a number of decades, actually, and has been reviewed extensively by both FDA and EMA. The manufacturing process, because it's an autologous homologous, we start with taking something from you or the patient. The value of that is the kidney is highly immunogenic, so we don't have to worry about rejection. So by taking that biopsy, it's shipped to our in-house manufacturing. We've done all of our manufacturing in-house, and so for the past two decades, our ability to control quality and produce 95% of the time a product from the biopsy is driven because of our tight control of the manufacturing process and doing it internally. So once it comes in, we use our proprietary methods to expand those three cell types.
What we know in a biopsy, normal biopsy, is there's about 100,000 of these cells that are present, and that's in a disease state. Our manufacturing process increases those to almost 250 billion. So we can make 5-10 products from a single biopsy, and because it's autologous and homologous, we can re-inject that multiple times. That allows us then to have only one biopsy that gives the product then back to the patient. It takes about 12 weeks from biopsy to preparation and being able to inject. We use a frozen formulation, so we can preserve those extra product for subsequent injections, and then it's administered back into the patient using a conscious sedation, minimally invasive, invasive, 25-gauge non-cutting needle. Takes a few minutes. Cells are reinjected, and the patient returns to a normal life.
All of this is been extensively reviewed. We anticipate that we'll be able to take this into commercial setting as well.
Okay. And just to clarify, so when you say 5 to 10 product, does that mean 5 to 10 doses?
Oh, good question. So a dose is two injections. Our dosing is controlled by the volume injected into the kidney. In chronic kidney disease, the patient's kidney is slightly small, and so the duration we use an allometric scaling method to adjust the dose. It takes two injections to be able to make a full dose. So 5-10 would give you 2.5-5 doses, but product, 5-10 product.
Got it. So, one, I guess, for lack of a better word, manufacturing run based on a biopsy is roughly 2-5 doses?
Yeah. Yeah.
Okay.
Right. And we can always go back and rebiopsy because it's, it's an autologous, homologous. If for some reason, the cells don't grow or the patient needs additional dosing, we can do that.
Okay, great. I'll ask you one more platform-related question, and then we should get into some of your clinical data. In terms of administering REACT, does the center need to have any sort of specialized training or infrastructure in place in order to be able to, to give out the therapy?
Yeah. Yeah. The, we use interventional radiologists to administer the product. Interventional radiologists are highly skilled and trained physicians that are used to taking needles and putting a therapeutic into small areas in different parts of the body. We do have a training program that has been reviewed by both FDA and EMA, and it really just simply allows the interventional radiologist to know exactly where to place it and how to deliver it. But the training itself is relatively minimal. These are highly skilled professionals.
Got it. Okay. Before we go on to the 002 study and any current studies underway, I'll take a pause for any questions on the platform or some of the basics around REACT. Okay. If not, let's go over to RMCL-002.
Mm-hmm.
So you presented data there, but everyone may not be familiar with that. So maybe we can just kind of hit some of the highlights that you saw that gave you conviction that this is a therapy worth pursuing into pivotal program.
Yeah. So the RMCL-002 trial is quite significant, and it did form from the information, as you said, that allowed us to believe that we could take this into later stage development procedures. So it was a phase 2, 1:1 randomized controlled trial. We used very high risk CKD 3-4 patients with eGFR between 20 and 50 mL/min. What we did is by assigning these 1:1, one patient was assigned to a deferred or a standard of care, and one patient was assigned to the active, for a total of 83 patients that were enrolled in this.
What we did in that trial was, again, we took the biopsies, made the product, administered it to the patients that were in the active group, same kidney as was biopsied, and injected this six months apart, two times for the full dose, and then they were followed for two years. To get a concurrent control, the other patients that were enrolled, again, approximately 40 patients, were put on best standard of care, and we followed the best standard of care for one year. We chose one year because these were very high risk, and we wanted to make sure that the patients were able to cross over after their one year. It gave us a concurrent control.
We could see what best standard of care provided, and then it gave us a population of patients that we could come back and treat later. The outcome of that trial was actually quite interesting, and it convinced us to be able to go on to later stage development. What were those outcomes? First and foremost, the standard of care declined at a rate that was very consistent for this late stage. They lost about 3.5 mL per minute per year. In contrast, what we had in the active was preservation of kidney function. And this preservation of kidney function was important because what that did is it foretold the potential to be able to delay dialysis... So that active patient population then allowed us to see the effect of the drug when administered in one kidney.
Because we saw good preservation kidney function, it told us that what we wanted to do was this could go on to develop for our later stages. What I want to alert you to is that for us, the very other important observation was all we had to do was show that we could show an improvement over standard of care. That, that comparison, that concurrent control, gave us a very clear picture in a patient population, where there really is not good standard of care, what we could do was we could preserve kidney function in a way that was better than standard of care. So that was the observation that said, "Okay, we've got good preservation, we've got good delta, or difference from standard of care." We had a very good safety profile. We were impressed with the tolerability.
So when you put the whole package together, this had development, a potential development success.
Got it. And you have two pivotal studies underway right now, PROACT 1, PROACT 2. Can you tease out for us, how are these studies different from zero-zero two in terms of-
Yeah
... the patient population enrolled, and also in terms of the actual product itself?
Yeah, very good question. The differences are several. First and foremost, the product itself. Commercially, we wanted to get into a frozen product. The fresh product we used in zero two. So we wanted to test and evaluate, and we'd run another phase 2 to show that the frozen product was effective in comparability studies. But the difference is that the frozen product will be used in the phase 3. That's number one. Number two is that instead of injecting in one kidney, because our safety and tolerability has been quite good, it was very clear that we could inject both kidneys. So now we had access to the whole renal mass with these cells that were capable of promoting healing and maintaining kidney function. So that is a big difference.
Both kidneys are injected. In addition to that, one of the things that we wanted to do was to look very carefully at the control situation. Our zero two trial was an open label trial, was not blinded. The phase 3 will be sham, a sham biopsy, sham injection, but they'll also be blinded, so it's blinded for us, and we. So we haven't released follow-up information because it is a blinded trial. Big difference from the zero two. And then I think one of the other major aspects, in the zero two, we used eGFR. eGFR is only one of many endpoints that can be assessed. For the phase 3, it is a time to event trial. It's a composite with 3 components. One of them is a 40% decline in eGFR.
One of them is dialysis or a 15 mL per minute that is sustained for one month. Then the third component is death from either renal or cardiac. So endpoints were different, design was different, the product is different, but wholly, the same active biological ingredient. The patient population, which is an interesting difference, we saw effects in a broad range of patients from REACT. In the phase 3 trial, we used, again, this 20-50 for the study that's active here in the U.S., which is actively recruiting. But what we recognized was in working with payers the past year, is that they were more interested in seeing the sicker patients being used. As you know, from our other trials in phase 2, we have effects on these sicker patients.
And so what we decided to do was to really focus on the later stage, 44-20, or the 3-4 patients, the sicker patients. So that's a big difference. We knew in 02 that we could get the effect, but that's a difference in the phase 3. And then lastly, what's happened since we ran the 02 trial is the basic standard of care for these patients has changed. It's really been a renaissance in healthcare for the kidney. We're seeing the SGLT2s, the MRAs, some situations where triple therapy patients are put on all three. So what we decided to do was stratify the 016 to accommodate this, and we feel that that's important because this trial will read out when these are standard of care.
And so those are some of the differences that existed between zero two and the phase 3 program.
Great. And how is enrollment progressing so far in both studies, and what have you said, publicly about timelines for data from both programs?
Yeah. So it's, it's blinded, so and we have not released enrollment information. However, what we have released and guided on is, is that we anticipate that the, around the 2024, end of 2024, early 2025 time point, we would have an interim analysis. Because it's a, a time to event trial and because the standard of care is trend-changing, we're that timeline could change, of course. We have defined the number of events that are needed for us to do an interim analysis. But what's significant about that is that our interim analysis is really for investors. We approached the FDA about the possibility of conditional approval because we have an RMAT, and they said, no, they wanted two well-controlled trials. Back to the question around the progression.
We anticipate that there will be some data to release in the late 2024, early 2025 timeline, depending on how events are accumulating, and then depending on need for catalyst. Then also the 016, we've provided guidance that we will have first patient, first visit by the end of this year. So for all intents and purposes, we continue to work with regulatory agencies around the world, and continue to work very closely with EMA and FDA.
Got it. Got it. Okay, that's actually a good segue into the next question I had for you, and you already started touching on it, was regulatory interactions. So, you mentioned that the agency want to see, I think you mentioned kind of a more fulsome data set from both, from both programs. So, I mean, based on what you're seeing right now, what do you think, when do you think you'd have the full data set to be able to file and potentially get into the market then?
Yeah. Yeah. So the anticipation is that, and we're projecting this, that by 2026, we would have data, and we could continue marketing or look for commercialization in 2027. Now, our interactions, your question was predicated on our interactions with the regulators. They've been very positive. There's really nothing that works in this patient population, and we have received Regenerative Medicine Advanced Therapy, the breakthrough designation for cell therapies. What's interesting about that is although I said the interim analysis is for investors, which it is, and the FDA has not said that we could get conditional approval, RMAT does open the door potentially for conditional approval. So with the interim analysis, we would anticipate going back and see if that door would open.
However, we're still planning on, and we're still guiding, that we need two well-controlled completed phase 3 trials for this. Interactions with other regulators, we have seen there is a movement in guidelines for the cell therapies around the world, particularly as they start looking at our product and they recognize this patient population. It's a very large patient population, and it'll be the first cell therapy for this. So again, there's a fair amount of interest, and I would say they're working with us very openly to get our development with the target of 2027 for commercialization.
Got it. Got it. Okay. And, you mentioned it's a composite endpoint, the primary endpoint for both studies. So I think given that, a natural question that could come up for a lot of investors is how best to interpret that composite endpoint and how best to pick it apart and figure out what's the clinically relevant outcome. So what would your guidance be on that?
Yeah, that's really... So, think about our work in kind of three steps. So initially, we used the biomarker eGFR. We're now moving to time-to-event analysis. So with the eGFR, we know we're getting preservation of kidney function. So since two of the endpoints, one is time to dialysis and one is a 40% decline, one could anticipate that if you can preserve kidney function through eGFR, that you're going to see a difference with the standard of care. So that's one way of looking at it and thinking about it. But your question is more relevant in that, I said there's three stages. eGFR was initial biomarker. It's only part of our story. The time-to-event is a registrational piece, but again, okay, fine, you get registration.
The really interesting piece, and what really has attracted us 20 years ago about this is, can we delay or at least give a patient dialysis-free living for an extended period of time? And that piece is where you get in with the payers and why we're working with the payers. And I alluded to that earlier. By understanding what the payers want, which is a sicker patient population, and by understanding that their real interest is a delay in dialysis, that's where the value is, if you will, the reimbursement coverage. We've also designed an OOA trial to address that, to give the long-term analysis. And the way to think about these then is, eGFR at the early stage is a component of the time to event.
Time to event includes dialysis and kidney health, which gets then into the third stage, which is the pricing reimbursement. So that's kind of how the pieces fit together. It's how we're thinking and guiding on that.
Okay, understood. Just then a commercial question for you. What portion of the patient population do you think the design of the PROACT 1 and 2 studies kind of maps to? Like, what do you think is the entire set of addressable patients here in the U.S. based on those, those pivotal studies?
Yeah. So it's designed to go after the 3b/4. That is where the high costs in treating CKD, higher costs begin to increase. That patient population, there's about 2.5 million of those patients. So the addressable market is very, very large. I think the interesting piece is, for us, being able to really get those late-stage patients, which are impactful to payers, which also they're looking at a lifetime of dialysis, if we can extend that. And we've had many physicians tell us, nephrologists say, even extending by six months, you're going to really change people's lives with this. So the commercial TAM, very large, 2.5 million. The target for the sickest, target for where is most relevant for payers, and so I think...
And then also, obviously, for patients. So I think we're trying to hit kind of the trifecta where everybody wins, and of course, the investor wins because we've touched all the right places.
... Got it. Got it. And, in terms of potential pricing and reimbursement, any initial thoughts or considerations there?
Yeah, we're still working with the payers on this. Obviously, pricing reimbursement is a whole different conversation. But what we're anticipating, we're planning for is performance-based pricing somehow. Exactly what that looks like, we're still working through. We do anticipate, though, that with a performance-based pricing, this idea of being able to utilize the autologous homologous, so this ability to make 5-10 product, is the potential for redosing. And so one of the things we started this year, which we're quite excited about, is we have the product to be able to dose again. So if we can preserve kidney function, let's just say for argument, we preserve kidney function for 2-2.5 years, if you've got multiple product, you can come back and inject again, particularly autologous, there's no immune rejection.
So we've started a trial this year of O15. It's a phase 1, it's a safety trial, but what it is, is it's taking patients that have been injected with REACT already and have brought them in. We're going down to an eGFR of 15, and we're looking now, this will be a full dose, so 4 injections total, 2 previously and 2 to come. And that study is starting to enroll, and we would hope to have data out next year. But this gets to this commercial question you were asking is, is how can we begin to put the pieces together so the real value proposition of providing a patient of lifetime dialysis-free living is tangible?
And so we're trying to use each piece of the platform and each piece of the technology in a way that we can address those with extending that time.
Got it. We have around three minutes left. Might be a good time to just pivot to two data readouts that you've guided to by the end of this year. So we touched on the RMCL-002 data you have so far, but you've mentioned, I think, with your 2Q23 update, that we could see some more interim data by the end of the year. So what could that look like?
Yeah. Yeah. So we want to have the RMCL-002 data by the end of the year, and what this will be is a real focus on these sicker patients. So if you keep hearing me say sicker patients, that's being driven by payers and the fact that we're seeing effects in that patient population. And so what we want to show is these patients that were crossed over from the standard of care, they had declined to being very robust CKD 4. They've gone down to an eGFR of about 28 average from 32, 33 average at the start. So we've now treated a number of those patients, and so we want to show investors the impact of this sicker population of REACT.
That will be useful then, I think, to guide us as to what we might be expecting in the phase 3, and then also give us insights into how to begin working with the payers.
Got it. And then you've also mentioned, a data update from a second study, a separate study, sorry, REGEN-007.
Yeah.
You've also mentioned that this could provide kind of an initial look or window into what-
Yeah
the phase 3 could look like. What are the similarities there between 007 and the PROACT studies? And again, how would you guide people to interpret the 007 data when they think about what they need to with the phase 3?
Yeah. Yeah. So the REGEN-007 trial has two cohorts, the 1:1 randomized. I want to focus on what we call cohort one or the preview of the phase 3. So as we indicated and talked about the differences, one of the things will be dosing both kidneys with the commercial formulation, and the dosing will be three months apart. And so what we've done in one of the cohorts is take the same patient population, 20-50. We'll be using the commercial formulation, and we will be injecting each kidney once, three months apart, and then following them for a year.
So that will be a very nice preview for investors to see what the likely outcomes in bench potential impact on eGFR begin to move us toward the idea of redosing, because the second arm has redosing triggers, and we're looking at both eGFR and UACR's potential redosing points for being able to extend this. So that's how the O15 and all these things fit together for extended dialysis-free living. Getting back, though, specifically to your question, the cohort one, which is the preview of the phase three, we've gotten a lot of conversations with investors about this, and one of the things that they've all said, and this can be quite pivotal for them and how they think about it. So what we've decided to do, we want to provide a fair enough number of patients that can be actually interpreted.
So we're looking to now release that data in the first half of next year, so that there is a sufficient number of patients where investors can look at it and say, "Okay, this I can make a decision on." And so the slight delay will bring an increased number, and I'd like to get very close to about 50% of the 25 patients that are in that cohort, so investors can say: Okay, this is a consistent, this is what we're seeing. Have a long enough follow-up that they know that it's either similar or different from what we've seen with the other trials. So that's how we're thinking about. That's the guidance, and we're really trying to listen to what investors have and then provide it in a way that they can make their investment decisions.
Got it. Okay, we're at time, so I'll close out with a final question. Just a reminder, your current cash balance, the associated runway, and kind of what that runway contemplates from the pipeline development perspective.
Sure. So we've got right around $445 million as of June. That will carry us into, for sure, late 2024, which is the interim analysis. We can extend that, because as you said, how are we thinking about the, the run rate and the burn? We can change and turn some dials to allow us to probably have that carry us into the 2025, first half of 2025 window. In terms of the impact of the development, we've got sufficient capital. All of our studies are funded. Our manufacturing can meet all of the supply needs of all of the clinical trials. We do all that in-house, as I said.
I think we're well-positioned to be able to not only bring data for investors to be able to make an investment decision, but continue to develop this exciting technology. I'm looking forward to talking to you next year and sharing some advances.
Great. Let's end on that note. Tim, thanks so much for your time.
You bet.
Really appreciate it.
You're welcome.
Thank you.
Thank you.