Thank you, everybody, for joining us this morning. We've got ProKidney here in sunny Miami, and we'll talk. I'm going to make that line every single fireside podcast, and we're going to talk about the progress and the outlook into 2025. Thank you, guys, so much for joining us.
Thanks, John, for having us. And I have yet to see the sun, but I'll hold you to it.
I promise you it's out there. So before we get into the nitty-gritty, maybe I would love to hear just your outlook heading into 2025 and what you think is most important for the coming year and where we should all be focused.
Yeah, no, sure. I think I'm sure we're going to jump into some of the recent announcements, but I'd say, as we look into 2025, I'll split it up into two halves. In the first half, we're looking to give a regulatory update with regard to the accelerated approval pathway that we're hoping for coming out of our meetings with the FDA. In addition to that, we will also be having the full Cohort 1, REGEN-007 data in the first half. And then I think it's an evolving story, but we look forward in the second half of the year to providing an update on the mechanism of action. Ethan, anything else?
No, I think you hit it. The big thing is, as you said, that update on the potential accelerated pathway that we have that should line up or coincide with the REGEN-007 full data that we're putting out next year.
Excellent. So let's start with that regulatory progress. You recently disclosed that Type B meeting confirmed a single trial would suffice for submission. Could you remind us or elaborate maybe on the key feedback from the FDA that led to halting the unnecessary PROACT 2 trial that was sort of still in its infancy?
Yeah, it's interesting. I'll never call it unnecessary, but I will say the conversation about this started, I'd say, earlier in the first half of last year or this year, actually, well, almost in 2025, whereby I think we'd gone through a lot. I think we can go back to 2023, but I prefer not to. Gone through the remediation. We're relaunching our phase 3 program and really asked ourselves, is this necessary? How do we find ourselves in a position to get rilparencel to patients in the quickest way possible? And so that was the decision that ultimately we came to in September, having consulted internally and also with external experts. So ultimately, in early October, we met with the FDA first to confirm that our decision to discontinue PROACT 2 and just move forward with PROACT 1 would be enough for us to receive full approval.
Overwhelmingly, the FDA was positive on that, assuming, obviously, a well-controlled study. But in addition to that, we asked them, is there a pathway for an accelerated approval? We have an RMAT. We haven't used it probably as much as we would have liked to. And they came back and said, yes, as long as there's an acceptable surrogate endpoint, such as eGFR, is one that's been used a lot in the nephrology space, there is an accelerated approval pathway for ProKidney. And so that's really what we're working on now. It's really identifying what is going to be the surrogate endpoint that we're going to be using. I think eGFR is quite logical. And then determining the number of patients that will be necessary for us to get a readout that will be effectively sufficient for the FDA to provide us a conditional approval.
But in the meanwhile, you're still enrolling and treating patients. The study is continuing to progress, and you'll make an appropriate amendment if and when you have that feedback.
Absolutely. So everything's progressing business as usual. We're enrolling patients. We're activating new sites and moving as if we're discontinuing with PROACT 1. And one thing, just really to clarify, this is not an additional study. We can work off of the PROACT 1 population.
Great. Now, the most important part of this, presumably, is that it streamlines the overall development timeline. And I know you're still working through this, but what are the potential ramifications for a BLA submission date, for a trial readout? How does this change your expectations for the timeline?
Yeah, so I think in September, when we made the decision to discontinue PROACT 2, we announced that we look forward to a readout on the phase 3 program for PROACT 1 in Q3 2027. The way we look at this now is, depending on the work that we're doing internally on how much follow-up we may do on eGFR, we see a pathway to us having a readout in advance of us running out of cash. So there's a potential for us to achieve that. And what we've said publicly to date is we have cash into 2027. So it's a pretty significant update with regards to the accelerated approval pathway.
The prior guidance was to a potential readout end of 2027.
Effectively, yes.
Okay. So let's maybe move to the endpoint. You talked about eGFR stabilization, eGFR being the focus for the trial. Can you elaborate a little bit on the challenges to achieving a stabilized eGFR in late-stage CKD and where you're seeing differences in eGFR stabilization across potential patient populations?
Yeah, so I'd say when you look at a healthy 60-year-old without CKD, the typical decline in kidney function or eGFR is about 1 mL per min per annum. And so we are focusing on really the patients who are on the doorstep of dialysis. These are late-stage, fast-progressing stage 4 patients with a few, really small subset of 3Bs as well, where the conversation that's happening is with the nephrologist as to, do you have a family member who can be a donor, or should we be preparing you for an AV fistula in advance of dialysis? So it's a very different population, I'd say, than a lot of the other, I'd say. I wouldn't even call them competitors, co-conspirators in a great way in the space, whether it's SGLT2s, MRAs, GLP-1s now coming into the scene. But what we are really looking for is stabilization of kidney function. And I think in our RMCL-002 study, we showed that in the elevated UACR Stage 4 population, the decline we were seeing in the patients in standard of care was about negative six mL per min decline in kidney function. And what we were showing was effectively a stabilization. So we think that's highly significant.
You mentioned some of those diabetic, what we think of as traditional diabetes mitigations, SGLT2s, obviously, GLP-1s coming into the space. This is something that I've been very focused on as a potential to change the background, change what's happening in the comp arms, change what the assumptions are for background rates in this population. So how do you expect those changes in standard of care to ripple down to those late-stage patients, and what impact do you think they could have on the trial?
Yeah, I think it's a very fair question. It's been in a lot of people's mind. I think there are a number of ways you can approach it. So I'd say, first off, all the innovations that's happened over the past decade and more so the last five years has been unbelievable for CKD patients and diabetics. And so we find that very promising. I wouldn't say it's too early to tell. I would say, and Ethan, I'll let you jump in on this point, but when you think about the SGLT2 trials, I think we have seen post the acute, there has been a much flatter curve relative. However, when you look at those trials, the average eGFR of those patients was really in the mid-40s, I'd say mid to high 40s.
At baseline.
At baseline, and then in addition to that, the number of patients who were Stage 4 ranged from around 10%-34%, depending on the trial, and that includes the GLP-1s as well. When you look at the FLOW study that most recently came out and you look at just a subset of patients who were also on SGLT2s, it was only about, I think, 15% of the patients, and when you actually looked at the hazard ratio for those patients, so it's either placebo plus SGLT2s or SGLT2s and GLP-1s, the hazard ratio was 1.07, and it wasn't statistically significant, so currently, it is difficult to tell what the standard of care event rate and what the actual eGFR slope will be going forward.
But there are, of course, also elements of when you're in this late-stage population, the cost associated with multiple drugs, whether it's MRAs, SGLTs, GLP-1s, combination of them, in addition to patient adherence. If you look at our REGEN-007 trial, I think we had six patients out of the 13 in the first cut that were on GLP-1s. Within four months, 50% had dropped off. And that was not by our choice, but physician-patient discretion. And there's also the physician element as well as to their discretion as to what drugs patients should be on when they are really in the later stage of their CKD. Ethan, any other points?
Yeah, I think just to put a bow on it, I think the three things that you spoke to, Nick, are there's still residual risk. These agents are great for patients, but patients are still experiencing declines in kidney function. These agents haven't been heavily tested in Stage 4 in the Stage 4 population. And the third point here is that in a practical setting, in a real-world setting, how many of these agents could a patient be on at once? Could they manage it from a compliance perspective, adherence, cost, side effects? There's a lot of variables here at play. And so we feel strongly that for better or for worse, patients will continue to progress to Stage 4, and there's that high unmet therapeutic need that we're looking to address.
Yeah, and I'd say just taking that all, the second run-in on is I think we feel comfortable with the 13% event rate we've put for standard of care arm in the phase 3 program based on all the points that we've made.
Okay. Fair enough. Yeah, I won't torture you too much about background.
We know this is your favorite topic.
This is my favorite topic. Let's move on a little bit just because I want to be aware of time. You've shown some nice work this year on mechanism of action, on improvement of inflammation, some biomarker design, but you said that there's more of that coming next year. So I'd love to get maybe a little preview, no detail, obviously, but a little bit of preview. The mechanism of action that the early phase 1 results sort of promised was a true regeneration of kidney tissue with a concomitant restoration of function that had previously been lost. Is that still on the table? Are you still thinking about tissue regeneration?
Yeah, so I'd say the way data was presented in the early cuts of RMCL-002 that showed that regenerative effect, I think, was just an immature data set, and some of the conclusions taken away weren't ones we would stand by.
Yeah, I want to be careful. I don't mean necessarily regeneration or positive eGFR slip. I'm talking about on a tissue level. You've got RMAT. You're injecting cells. Are you halting degradation of kidney tissue, or is there a potential to restore kidney tissue from a fibrotic state?
I think we're focusing on the stabilization. I think the kidneys are continuing to decline, where we've seen in the MOA work that was done and what was presented to ASN is the anti-inflammatory and anti-fibrotic effects that we see through the manufacturing process do give us a level of confidence that when injected, there is a signaling effect, paracrine and autocrine signaling effect throughout the kidney, notably in the tubules, but potentially throughout the nephron. And so I think in the tissue, there could be a restorative effect. I don't think we can hang our hat on that right now. But that signaling effect, I think, does slow down or potentially does slow down the storm that is happening within each of these nephrons.
That makes sense. Now, the other thing that I picked up on in your early data was what seemed like a stronger effect in earlier stage patients, patients where fibrosis was less advanced, where there was less of this signaling storm going on. And obviously, you focused on the patients where the unmet need is highest in that late-stage CKD patient population. But is it fair to expect that you might see even stronger signal from that MOA in an earlier stage population, acknowledging that development there is obviously different and maybe more challenging than a later-stage population?
Yeah, I'm not sure I can make that commitment. Ethan, I don't know if you have a different perspective there.
Yeah, it's hard to say, John, because our focus now is solely on the advanced CKD patients. And that's where we saw that interesting cut of data from the RMCL-002 study looking at that high UACR Stage 4 fast-progressing subgroup, and we saw greater separation. Now, was that because the product has greater effect in later-stage patients versus earlier stage or vice versa? We can't really say, but the effect was more pronounced, if you will, given the progression's faster in those patients.
Yeah, and so the tissue even that we're working with now, a lot of it will be coming out of the patients that we're currently treating or had recently treated in the REGEN-007 trial. So I think we're going to be focusing on that late-stage population going forward. And from a mechanism of action, that's I think where the majority of our energy is going to be.
I know in the early development, the dosing and mode of delivery changed a couple of times. You've looked at multiple injections in a single kidney. I know the current phase 3 is for one injection in each of the two kidneys, but it did seem, based on your early data, that giving multiple injections in a single kidney separated by some time had a benefit over giving only one and then waiting, at least. Is there a true dose response here? Is there the potential to continue dosing or redosing for greater effect after those initial bilateral injections?
Yeah, so a couple of things happened. We switched from fresh to cryo, so that was one change, and that was validated through comparability studies, so I can confirm that there's no difference there, and that was submitted to the regulators, and they were happy with that. I'd say on the redosing side of things, yes, we do believe two doses is the optimal, and I think some of the early data from REGEN-007 supported that decision when you look at cohort one versus cohort two.
Two doses versus one dose, but you've never looked at three or four.
Exactly. And so we currently are not running any trials to evaluate redosing. I think as we go through the phase 3 program, we're going to have more, and also the more work we do on mechanism of action, we're going to have a much better understanding of durability. I think redosing is definitely something we would like to explore in the future. And even just from a manufacturing standpoint, when you think about it, especially with it being cryopreserved, we will be able to, with one run, the goal is ultimately to be able to make multiple doses, more than just the initial two doses, such that in the future, patients have that option and availability of multiple doses. And when you think about doing one manufacturing run, it also leads to the cost of goods and manufacturing on a per-dose basis to decline over time.
Yeah, let's stick with manufacturing for a moment. You mentioned the switch to cryopreserved. You've mentioned doing the comparability there. But I know that with other cell-based products, especially heterogeneous cell-based products like the non-CARs, like the TIL products and stuff, the FDA has been very cautious or almost aggressive sometimes in their requirements for QC and their requirements for potency studies. How have your interactions with the agency been on product characterization and potency assays?
So Ethan, I can pass it to you on that one.
Yeah, yeah. So well, first off, I just want to address the fresh versus cryo. So FDA and other regulatory agencies have accepted our comparability studies. So we're good there. We checked that box. And we're actually currently, we have intellectual property that we're developing around potency assay testing as part of our release criteria for the product. But as part of what with our RMAT, we're in very close contact with the FDA regarding all of that stuff on the development side. And it's progressing along nicely is what I would say now.
Fair enough. As we think to a potential commercialization, maybe in 2027 or 2028, depending on the regulatory process, what's the current status of manufacturing capability, and how far can you get through a potential launch or through phase 3 through a potential launch with your current footprint?
Yeah, so as it was recently announced, we did acquire two facilities in North Carolina where we're currently the tenants. So part of that is in preparation for long-term commercial sustainability and the fact that we own the facility. I'd say we have incremental capital expenditures that have already been built into our cash flow projections that will put us in a position effectively by end of next year, whereby we will have enough commercial capacity, and it'll also go into our BLA submission such that we have enough commercial capacity for the first few years post-approval. So that's where we feel very comfortable. Just to remind that we did have the EU QP audit. We got a clean bill of health in July.
We're operating as a GMP-compliant facility as it stands right now, which I would say is further ahead than most cell therapy companies at our stage.
Excellent.
That build-out for manufacturing is embedded with our cash runway in 2027.
All right. Now, I see that we are unfortunately out of time. But just to go through one more time, we're looking forward to final data from '07 next year. We're looking forward to regulatory updates next year and guidance on endpoint and maybe on the actual timeline to PROACT 1. Anything I'm missing?
Nope. We have $400+ million in cash to get us into 2027.
Plenty of coverage to see some interesting data.
Absolutely.
All right. Well, thank you so much for joining us.
Thank you, John.
Thanks, John.