Latest / BioSpace / Why investors are taking another look at kidney disease
Transcript
- speaker-0: My name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to Denatured. In this episode, I speak with Bruce Cullaton, CEO at ProKidney, and Dimitri Maxim, CEO at Nephrogen. We discuss why kidney disease has long been a hard target for cell engine therapies and what new delivery strategies, therapeutic approaches, and regulatory clarity mean for commercially viable products. Thank you so much, Dimitri and Bruce, for joining this episode talking about kidney diseases, which it's not just kidney disease. I definitely should clarify that. It's there's a number of indications within kidney disease, as we know we're gonna be talking about that. So if we if you can introduce yourselves, that would be great. Dimitri, let's start with you. speaker-2: Yeah, thank you, Jennifer. so yeah, I'm Dimitri Max. I'm the founder and CEO of Nefrogen. we're a spin-out from Stanford University in twenty twenty two. Before Nephrogen, I was a graduate and undergraduate student at Stanford in a couple different labs collaborating on gene delivery to kidney, and now we're trying to bring that to patients through Nefrogen. speaker-0: Right. Go for a bruise. speaker-1: Yeah, thank you. Thank you. Yeah, thank you, Jennifer, for the invitation to be part of this podcast. So I'm the as you said, I'm the CEO of ProKidney. I've been in this seat for about three years. We're a publicly traded company. And I've been in the kidney space for close to thirty years. I'm a trained nephrologist. I practice clinically and also worked at global med tech and health services companies. speaker-0: All right, let's get into this topic area. So to start off, kidney disease has historically been a difficult area for selling genetic medicines because delivery is so challenging. What makes it challenging and what has changed in the science, tech, or investment landscape that now makes the space more credible? speaker-1: I'm I'm happy to jump in. Jennifer, I would say it isn't really one breakthrough that sort of you know led to the advances that we're seeing today. It's it's more the coming together, I think, of of biological advancements or biology advances in technology to deliver therapeutics and then I think some real advances within the clinical validation space. And if I think back to twenty years ago, we lacked really three critical ingredient. So one is although we understood kidney physiology, I don't think we sufficiently understood kidney cellular biology. we also lack technologies capable of targeting specific kidney cells, not just the kidney itself, but kidney cells. And really importantly, regulators and investors had limited confidence, I think, in what therapies could demonstrate and how they could demonstrate meaningful clinical benefits. And today, I would say that's changed considerably across the board on those three fronts. You understand biology better than we did, far more than we did even five years ago. I think single cell RNA sequency has really changed how we think about and understand the kidney and the 30 plus different types of kidney cells. we've got better technologies, everything from Dimitri will talk about some of this gene editing, regenerative cells, exosomes. Even in the manufacturing space, that's really advanced. And then finally, I would say the kidney field itself, when I think of the the service component, the nephrologists and the regulators, that's changed considerably. I think the FDA has really opened new pathways for drug approval. Payers see the economic benefit, although there's still some work to do there. And overall, the clinical trial infrastructure has grown and matured around the world. Allowing us to take science into the clinic into validated clinical programs. speaker-2: Yeah, so I can speak a little bit to the gene therapy side, maybe of delivery. But I think that physiology, again, yeah, that was not the issue for a long time. Like we knew how the kidney was laid out. And then I think the second piece was okay, well, what are all the specialized cell types? 'Cause a lot of people don't realize the kidney has the most number of specialized cells of any organ in the body except maybe the brain, right? So I think knowing the sequencing data and and other advances in proteomics. And kind of high throughput screens to figure out what cell type is, what is really the the core like makeup of each cell. I think that was sort of the key barrier that kind of overcame the last 10 years. And then now on the gene therapy side, I think the kind of refinements of the physiology, so knowing like you have the glomerulus, everything that needs to get into the kidney, if you're getting a tubular cell, it has to bypass the glomerulus in some way, either through the tubular lumen or through the basilateral entry. like kind of the back door as we call it. And so it's either entering one of those two methods, but there's been a lot more studies to understand exactly how the capillaries are structured. Like for example, they have fenestrae and we know how big those fenestrae are. So when you're div developing delivery particles like an A V or an L and P, now we know how to make them get into the kidney. Right. And I think having the fundamental understanding in the physiology was refined over the last 10 years. And then knowing which cell types to target and knowing that specifically you need to get into specific cell types for specific diseases. think all that comes together to now actually make this relevant from a biotech perspective. I think the academic advances came in the last decade and now it's kind of the golden era. Now we're gonna do this in patience and actually bring it more therapeutics through to Mark. speaker-0: I love the idea of a golden era for patients. I like that optimism going forward. I always do in my podcast. You mentioned a really interesting point right now, Dimitri, about the differentiation of cells in the kidneys. Is that why it's been harder or li why it's attracted less C G T investment than the liver or the brain, just because of that structure? speaker-2: Well, so I guess my perspective on that is that so there was a big paper in science from Catalyn Sustuck's group at the University of Pennsylvania, which did single cell RNA seq, to basically show all the different types of specialized cells in the kidney, right? So you have your potocytes, you have glomerular endothelial cells, you have all these different tubular cell types. So then the number of specialized functions within the kidney is is massive. And so outside of the brain, there isn't really another organ. that matches that level of complexity. but then they also showed in that paper that each disease originates in a subset or in many cases a specific cell type. So I think the the difficulty is that if you can get to those cell types, you're you really unlock that golden era as we keep talking about, but it's really challenging, right? And that's why our companies here are are are working on this difficult problem. And I think It's becoming now that we at least know what we're getting into, and then we have some preliminary data to show that we can get to those cell types, that's enough for the investor community to sort of start to come around. But historically it's just been without knowing what cell types and enough granularity of where the diseases originate, I think just kind of scared people off. And so when like CRISPR was discovered and these other technologies, everyone was going after the easier, low-hanging fruit like the liver. you know, and and now just now the kidney is sort of starting to catch up in the very early days. speaker-1: Yeah, I mean I agree with Dimitri on all this. kidney is arguably one of the most complex organs outside the brain. And that leads to a lot of disease heterogeneity. CKD isn't one disease, it's multiple diseases, and some of them I think are just being discovered as we understand more about cellular dysfunction within the kidney. Another way to think about this, I I often say is the kidney isn't one target. It's really dozens of highly specialized targets packed into one organ. it's easy to think about it as one target, one disease, but it's actually multiple different opportunities. speaker-0: Interesting. Okay. And now let's talk a bit about a bit more about what each of you are doing. So Nephrogen is focused on gene specific delivery while Pro Kidney is taking a cell therapy approach. So how do you think about the different therapeutic strategies for kidney disease and where do you see the biggest opportunity? speaker-1: The way I think about that is is that different diseases require different tools. And I don't think that they're necessarily competitive. I think it's great to have different opportunities. And Dimitri can feel free to jump in, but I think gene therapies really excel when there's like single cell disorders, when you have a defined mutation, when you're replacing a missing protein, for example. And in my case with cell therapy, I think we excel knowing that. CKD isn't usually isn't usually caused by one broken gene. Like if you think about diabetes, for example, type two diabetes leads to maybe 40 to 50% of all chronic kidney disease. And the pathophysiology behind the advancing kidney disease of someone who's got diabetes is not just one problem. It's it's an accumulation of inflammation over time, maybe chronic fibrosis that eventually leads to microvascular damage and ultimately dialysis. So I do think it really depends on what the underlying physiology is and then you could use different tools to approach it. For me, I think the biggest opportunity is because of these advances, there's going to be more tools for clinicians to allow them to choose the right drug based upon the patient's biology. speaker-2: So yeah, to add to what Bruce is saying, I think on the gene therapy side, we're looking at it as like, how do we get to specific cell types? But I think we're looking at really defined diseases, right? So it's kind of two ways to look at the kidney world. There's the chronic kidney disease, let's try to get something that's pretty close but can treat a number of different CKD patients. That's the pro-kidney model, right? And then nephrogen is we're going after these specific diseases to s to start also, right? That's to prove the concept that we can deliver. Right, to the relevant cell types. And our ultimate goal is to go after all C K D, but I think it's just different stages of companies, right? We're starting with something that as a preclinical biotech, we have to go with the most defined target, the most genetically whereas pro kidney being several clinical trials into the clinic, it's a it's a different world. So I think all of it is really good for patients, obviously. But I think for for us, like we just have to be realistic about where the field is in different ways and and our data is still kind of restricted to individual diseases for now with the goal of eventually going after more broad C K D. D to me. speaker-1: Petri, would you also agree then there is room for multiple different paths to treat kidney disease, right? It's not just a gene therapy approach or not just a cell therapy approach, but there's there's definitely going to be a place for small molecules, for biologics. And for me anyway, as a clinician, this just opens up a lot more opportunities for patients, but also for providers to have a a larger toolkit, if you like, to be able to treat their patients. speaker-2: Yeah, I hundred percent agree. I think the the best statistic for that is just like SGLT two inhibitors, right? There's multiple SGLT two inhibitors, that's the same target from different companies, right? So if there's space within within small molecules, within a target to have multiple drugs exist, I think the fact that a cell therapy, a gene therapy, a gene editing therapy, like all these things, you know, could coexist, right? And I think in some indications people would argue that it will be a winner take all where the best therapy will win, right? But I don't think that's that that's definitely not the case in CKD. and not the case for a most genetic kidney diseases with the exception of ultra rare. speaker-0: So for CKD, chronic kidney disease, actually let's give a a really quick explanation for the audience here and then PKD also as well, Dimitri, what you're focusing on at first. speaker-2: Yeah, so PKD, it's a little confusing, is polycystic kidney disease. So that's the most common form of genetic kidney failure. It's the fourth leading cause of kidney failure. And then CKD is chronic kidney disease. So patients that have PKD are also CKD at some point. Like basically there's different stages of CKD. And Bruce maybe can comment on the specifics as a nephrologist himself. But I think that's sort of the model is like PKD is a genetic form within the CKD umbrella. And then the latest stage CKD patients are the ones that have complete kidney failure. That are the most expensive in legacy. speaker-1: Yeah, and Dimitri, what the way I I try to explain this, I guess, for a lay audience sometimes is that the definition of chronic kidney disease is really the presence of kidney injury or the loss of kidney function that lasts for more than three months. That encompasses a whole bunch of different types of kidney disease, but in essence it captures durability, injury, and function. And the function can be tested easily by a kidney test, to EGFR measurement. It's a routine blood test that's done. And the injury today practically can be captured easily with urine tests where you look for albumin or protein in urine. There will be more biomarkers that come down the road to be more specific and probably even detect kidney disease in an earlier phase. But that's really how like to describe C K D. And today in in the US alone, there are probably thirty seven million people with some form of chronic kidney disease and eight hundred and fifty million globally, I think is the latest estimate. speaker-0: That's incredible the need for therapies as you're saying. How do you decide whether to pursue a disease modifying approach, potentially a curative approach, or something in between? speaker-2: So I can speak to that from deference angle, but I mean, so I'm also just full disclosure, I'm a PKD patient. So I have polycystic kidney disease myself. So I think for me it's personal in the sense I got into the kidney field when I was a high school student doing science competitions and then went to grad school focused on delivery. Cause I think for me, I felt that for PKD and and I think for kidney disease broadly, our perspective is that gene editing is sort of the final frontier. You have your first generation small b small molecules, then you have your biologics like RNA modifying therapies and things like that. Like Regulus therapeutics has a phase three drug acquired by Novartis for ADPKD or polycystic kidney disease. So I think the way we view it is that's the potentially curative approach is to do a gene edit. but I think Bruce can maybe speak to cell therapy because I would also group cell therapy kind of in that final frontier as well, even if there's been challenges with both gene therapies and cell therapies. I think if if we can overcome those challenges, it's really the f the final stage of of treatment for patients. speaker-1: Yeah. thanks, Dimitri. The any other thing I'd add to that as well is that I think that decision on on pursuing, let's say, a disease modifying approach or potential curative approach or something different. I think there are a lot of other factors that go into this. And Dimitri, your example is a great example of the personal reason for pursuing polycystic kidney disease. And I do think those personal drivers of decision making. Have played a role, particularly with regards to big personal donors who put a lot of their wealth behind developing cures for disease that's impacted their family. And then in other cases, I do think, Jennifer, it does come down to better understanding of where is the unmet need. And like many cases in today's world, there's often a financial angle to it. And that is an opportunity to create a a sustainable business model. by going after a certain disease or a certain process. So I think all that comes into play in sort of deciding what approach someone would use. Sometimes it also comes down to your capabilities and the assets that you have on hand. And and that does drive some of the decision making as well. So let's speaker-0: Let's flip down to the regulatory side, because that's always going to be a consideration in drug development, right? So how much do regulatory changes and better defined endpoints for kidney diseases matter in making these programs investable and scale? speaker-1: I can start, Dimitri, if you don't mind. So, Jennifer, I sit on a board called the Kidney Health Initiative. So the initiative was started, I'm going to say 15 years ago. And it was started as a partnership between the American Society of Neurology and the FDA. And the concept was there's an absence of drug development and kidney disease. What are the barriers and how do we remove some of those barriers to generate interest in drug development? But but Really just as important is how do we get investors interested in the kidney space? And and investors in particular want they want predictability, they want short timelines. And so one of the initial pieces of work that the kidney health initiative did with the FDA was work on a program to identify is there a regulatory path for a surrogate endpoint to get to market approval? And that initial work that was done by the kidney health initiative that really demonstrated that surrogate endpoints will be, could be used by sponsors to get initial regulatory approval, was a driving force behind a lot of the new investment within the kidney space. And we're seeing some of that come to fruition today as we see some of the newer products to treat IgA nephropathy, which really rely upon surrogate endpoints like albuminuria. to get initial FDA approval. And so from a regulatory perspective, I think that really drove a lot of the advances, made it easier for sponsors, made it easier for investors to see that we've got something predictable with shorter timelines. speaker-0: Yeah. That's quite interesting. Dimitri, any last comments just because I'm gonna be closing this up right right after you speaker-2: Yeah, I'll just say accelerated approval, I think, is is the key. I think in our indication, polycystic kidney disease, the FDA just granted accelerated approval to Regulus, which is a phase three drug. It's the first drug that's really well, not the first. There's been a number of phase three failures in PKD over the last decade, right? So it's the first one that's sort of promising. And I think the accelerated approval in some ways drove the acquisition and more investment from pharma. So I think this relationship between GFR slope and to patient and other endpoints is like kind of the key link that's been missing for a long time. And finally, the FDA is showing some willingness to work with sponsors. And that I think that's also driving a lot of investment because it shortens the trial duration of the costs needed to get kidney therapies approved. speaker-0: Brilliant. Well, thank you so much, Dimitri. And thank you so much, Booz, for joining this epid of episode of Denatured. I used to cover kidney diseases as a journalist, so I have a special affection for this topic area myself. And if you'd like to listen to more episodes of Denatured, please turn to biospace.com. And if you like to send me a pitch, shoot me an email at jennifer.smithparker at biospace dot com. Thank you so much.