Novel Solutions for Chronic Kidney Disease Dr. Andrew King Talking Biotech Podcast 396 with Dr. Kevin Folta [00:00:00] Kevin Folta: Hi everybody, and welcome to this week's Talking Biotech podcast by Colabra. Now, kidneys are pretty remarkable organs. They filter a relatively large amount of blood every minute, and they push this through and around the kidneys, functional unit, this little thing called a nephron. Now kidneys are made up of millions of these tiny nephron units and they work together to filter blood. So the filter itself, the, the very basis of this looks like a letter U. And if you can imagine one end of the top of the U connecting to the plumbing that delivers what's filtered out. So vectoring it ultimately through this tiny network of tubules, it end up in the urinary bladder. So one end of the U is the exit. Okay, got that. Now at the other end, there's a hollow ball. And inside that hollow ball is a little cluster of blood vessels that comes through from the circulatory system. And that little cluster of balls that a little cluster of that little ball inside the, uh, inside the capsule, I think it's called Bowman's capsule if memory serves me right, uh, that little. Blob of neph of, uh, arteries and blood vessels. Inside there is called the glomerulus and thin walls, and this is where different molecules will move out of the blood and into the Bowman's capsule, into the nephron, the, the, the, uh, tube that's there. And from there they'll move down that tube, down the U and back up the U. And as it moves down and up the u the. Descending, an ascending lu of Henley, if I remember correctly, there's differential absorption of different molecules that are important or that have to be getting rid of. So there is a exchange of water and, uh, ions, uh, things like amino acids and proteins, or not, maybe not proteins, amino acids and, uh, sugars are reabsorbed and, and and held onto by the cell. And there's. Different kinds of transporters, some that are active, some that use, uh, Osmo regulation, a lot of different things that happen in the nephron, but it is an incredible tiny little plumbing machine, a little filter that en masse. Forms the kidney and allows us to purify the blood, and that's why disorders that affect the kidneys can be so problematic because even minor changes or damage that affect the permeability of these structures can have profound health consequences. So today we're going to talk about rare diseases of the kidney, and then we're going to offer some new potential solutions that address those issues. And today's guest is Dr. Andrew King. He's the Chief scientific officer of Chinook Therapeutics. Welcome to the podcast, Dr. King. [00:02:53] Andrew King: Hi Kevin. Thanks. Really looking forward to chatting with you today. Yeah, [00:02:56] Kevin Folta: me too. We've been trying to put this together for a long time. So first episode on something to do with kidneys. So when we refer to severe chronic kidney disease, what kind of diseases are we referring to? Yeah, chronic [00:03:10] Andrew King: kidney disease or C K D is really any progressive loss of kidney function over time, which in a most advanced state can result in. Dialysis or transplantation necessary to sustain life. C k D can be caused by a whole range of underlying etiologies. Uh, in the United States, the most common causes are associated with diabetes, hypertension, uh, rare groups of primary glomerular diseases, uh, and also rare genetic diseases like polycystic kidney disease, uh, or calcium moate kidney stones. So CKD is really an umbrella term for a large. Range of different causes that result in progressive kidney function loss. [00:03:54] Kevin Folta: Yeah. I guess I've seen, um, chronic kidney disease of unknown origin too. Is that kind of in the same boat of, of diseases or disorders? [00:04:03] Andrew King: Yeah. That's really when you're unable to identify the initiating etiology you have a patient with. Low kidney function, uh, they generally have a biopsy and can't really identify what the underlying cause was, and that's generally classified as unknown. [00:04:20] Kevin Folta: Okay, I see. So when you say biopsy, they, you can biopsy a kidney and look very carefully at the structure of nephrons and kind of get an idea as to where the breakdown is occurring? Yeah, [00:04:32] Andrew King: AB absolutely. Uh, kidney biopsy techniques have advanced significantly, uh, such that they are relatively low risk procedures are now, and generally speaking, most kidney diseases require a biopsy for definitive diagnosis, uh, based on the histological characteristics and sometimes some special stains to look for, uh, other aspects of kidney disease. [00:04:59] Kevin Folta: Okay, so how frequent are these problems? I mean, you talked about high blood pressure and diabetes, which is like one in every, you know, like every other person. So are there increasing diseases of the kidney in terms of their incidents? Yeah, [00:05:13] Andrew King: absolutely. Chronic kidney diseases are severe and growing worldwide. Problem, uh, just over 10% of the global population has chronic kidney disease, so that's 800 million people worldwide. Including over 37 million, uh, in the United States, uh, and lifestyle, uh, and environmental changes are contributing to a growing problem with chronic kidney disease. [00:05:39] Kevin Folta: Yeah. And you mentioned, uh, solutions like transplantation, but you know, that's expensive and challenging and you have to have typically a living donor. Right. Are you, is it really hard to get donors to solve the problem? [00:05:53] Andrew King: Yeah, it, it is very challenging and, and there are staggering costs, uh, to both the healthcare system and the individuals with chronic kidney disease, uh, including in, in transplantation. Uh, in the United States, there's about 23,000 kidney transplants annually. Uh, but there's generally on average a four year wait list, uh, to get a TR kidney transplant, uh, to have a kidney come available, uh, that actually ma matches, uh, with the patient. Uh, and it's extremely expensive. It's over $400,000 per transplant, and then the patient is on lifelong immunosuppression, which is associated with infection risk, as well as increased risk for cancer. [00:06:34] Kevin Folta: And then also that time period prior to transplantation. This is done like on dialysis, which is maybe something that you have to go to weekly. So it's also a big personal cost and million infringement on, you know, convenience and everything else. Right? I mean, this is a really invasive, uh, problem to have in your, in an invasive health problem. [00:06:55] Andrew King: Yeah. Di dialysis is devastating for, for the patient and their family. You actually have to have dialysis at least three times a week. So an average patient on dialysis has over 150 hospital and dialysis center visits per year. Um, and it's for multiple hours, uh, at a time. Uh, the cost of this is expensive as well. Over $200,000 a year, uh, annually leading to an annual u US healthcare cost of over 130 billion for chronic kidney disease. So it really [00:07:27] Kevin Folta: is staggering. Yeah, so 130 billion of cost to the system, a really significant cost in terms of personal cost and time, and, uh, really looks like it needs some new therapies. So what, what are the current slate of therapies that are used to treat chronic kidney diseases and, and why? What, how can they be improved? [00:07:49] Andrew King: Yeah. Un unfortunately, innovation in chronic kidney disease therapies, uh, has been very slow and the currently available treatments. Are generally non-specific and supportive and often repurposed, uh, medicines from other indications like anti-hypertensives, uh, and anti-diabetic drugs, uh, that don't actually target the, the pathways in the kidney, uh, driving kidney progression. There has been, uh, some recent advances. I, I think we may be at the tip of an iceberg, uh, for significant. Innovation moving forward with chronic kidney disease. Uh, there's been a few recent approvals that are targeted, uh, to more direct aspects, uh, of kidney pathogenesis, and I think that's gonna be, uh, the real opportunity moving forward as we have much greater understanding of the genetic and molecular pathogenesis. Of human chronic kidney disease. Now that we have the opportunity, uh, to discover and develop targeted medicines, uh, to these key pathogenic pathways, uh, that will really have meaningful impact, uh, on this large population with huge unmet need. [00:09:03] Kevin Folta: So that really is a good lead in to what's happening in your company because you're targeting some specific diseases. But they seem to be, and correct me if I'm wrong, they seem to be a little more rare. And how does that offer specific challenges such as recruitment for clinical trials or you know, even the interest in investment into a disease which has, you know, doesn't have this gigantic number of people who are suffering from it. [00:09:31] Andrew King: Yeah, we, we are focused on rare diseases, uh, but we're focusing on the common rare diseases, uh, if that makes sense. So that actually, uh, can ha have a patient population. For example, our lead indications in I g a nephropathy, uh, there's 150,000 biopsy proven IG a n patients in the United States. Uh, so that's a relatively substantial population that supports. Um, clinical trial, uh, enrollment, and also a really strong commercial opportunity. Uh, the other advantage of focusing on rare diseases is there's been a significant evolution from a regulatory perspective, specifically for rare diseases. One of the reasons that innovation has been challenging in the nephrology space is that traditionally sponsors have had to, to hide kidney outcome trials. Uh, so that's following patients to these hard endpoints like dialysis or transplantation. Uh, those studies can be up to 5,000 patients take up to five years of duration and cost over 500 million. So it's been very challenging, uh, for sponsors to move into this space. The recent, uh, change from a regulatory perspective. Has recognized that it's just not feasible to do these kinds of studies in rare diseases. Uh, so there's been a significant movement in advance towards using surrogate biomarkers, uh, that can support at least accelerated approval, uh, and even full approval in some indications. Uh, so now we're looking at a rare disease of a 300 patient, uh, phase three trial, uh, that can run over a couple of years duration. Uh, at much less significant cost. So it really does open the opportunity for efficient drug development, uh, to help address the huge unmet need in these underserved populations. [00:11:28] Kevin Folta: Very good. So in the first part of the podcast here, we've defined what the problem is, that there's a significant amount of chronic kidney disease, some of which are based upon these rare disorders that can occur. And there are some good reasons to try to focus on the rare ones. So on the other side of the break, we'll talk about solutions. So we're speaking with Dr. Andrew King. He's the Chief Science officer of Chinook Therapeutics. This is Collabs talking Biotech podcast, and we'll be back in just a moment. And now we're back on talking Biotech podcast with Dr. Andrew King. He's a Chief scientific officer of Chinook Therapeutics and we're talking about chronic kidney disease and some rare chronic kidney diseases in which his company is developing some new therapeutics. And what I would like to focus on in this last part is a little bit more about etiology. What are these, uh, diseases underlying pathologies, and then how are the. Uh, how are the therapies, the new novel therapies targeting them specifically? So when we look at the pipeline on your website at Chinook, the most advanced therapies are for I g a nephropathy and, and i a n. And what is this and how were the therapies discovered? Yes. So I, [00:12:44] Andrew King: IGA nephropathy is actually the, the most common, uh, primary glomerular nephritis, uh, in the world. It's an autoimmune disease, uh, which results from the production of an abnormal form of iga, uh, that's recognized by the immune system as foreign leading to the formation of these iga containing immune complexes, which for a reason that's not well understood, selectively deposit in the kidney, uh, where they drive kidney inflammation and kidney fibrosis. Over 50% of IG a n patients. Are at risk for progression to end-stage kidney disease, uh, requiring dialysis or transplantation. Uh, so an important unmet need, uh, in a patient population that are generally relatively young, uh, in their first, in their second or third decade, uh, of life when they're diagnosed. So they have a lot of life to live, uh, with kidneys progressively losing function. We think this is a really important opportunity, uh, to deliver innovative solutions, uh, to these patients. Uh, and therefore have two late stage programs, uh, that focus complimentary aspects of the disease. Pathogenesis, atrasentan, uh, is our most advanced program where top line, phase three data that could support registration are anticipated to read out later this year. Naro Senti is an endothelial and a receptor antagonist. That works in the kidney to block the pathogenic pathways that are activated following immune complex deposition. Our earlier program by on 1301 is a monoclonal antibody, uh, that blocks April, which is a TNF superfamily cytokine member, uh, that's involved in the excess production of that abnormal variant of iga I mentioned. Uh, so by blocking April, you can decrease the production of the abnormal IGA and potentially have a disease modifying mechanism of action by intervening very proximal in the disease pathogenesis. Given the high unmet need in ig a n and the complex pathogenesis, we believe having two programs that target distinct aspects of that pathogenesis and are very complimentary will help more completely address that high unmet need. Yeah. [00:15:09] Kevin Folta: It almost seems that these two things separately would potentially relieve the issue, but it seems like they may be especially effective in combination because you're not only not creating the variant, you're also stopping deposition of the, uh, variant in the glomerulus when it, when it happens to deposit. Yeah, [00:15:29] Andrew King: absolutely. We're actually very excited as the only sponsor that has two separate IG a n drugs and development. Uh, with these distinct and complimentary mechanisms, as you described, uh, to combine them together and we think they could really be helpful in changing the trajectory of these young i a m patients lives by addressing both aspects, the formation of immune complexes, uh, and that abnormal response, uh, in the kidney. We're working on our strategy to assess that clinically and, and really focused on. When would the timing of that combination study be, uh, to help support, uh, potential combination use? [00:16:10] Kevin Folta: Yeah, the other nephron associated disorder that we think of is, uh, proteinuria. And this is a glomerular disease. Uh, and tell me a, in the beginning of the podcast today, I talked a little bit about the glomerulus and what it is, but if you could give us a little more sophisticated idea about what is the glomerulus and what is its role in the nephron and filtration, and why leaking protein is a bad symptom. Yeah, the, the [00:16:36] Andrew King: Glomerulus is the functional unit of the kidney, which is involved in filtration of the blood, uh, which works to excrete the waste products, uh, through the urine. The glomerulus is essentially a very specialized, high-pressure vascular bed, uh, to support that filtration function. Normally, the glomerulus functions to exclude the filtration of valuable things that the body wants to retain. Uh, including, uh, the cellular components, uh, like blood and white blood cells, but also high molecular weight proteins, uh, including albumin and immunoglobulin normally are too large to be filtered through the kidneys. However, in glomerular diseases, there's a disruption to this glomerular filtration barrier that now becomes permeable to proteins such that protein now leaks into the urine and can be detected. On routine diagnostic uh, tests, so often the presence of proteinuria in the urine would trigger additional investigation, uh, to a potential underlying kidney disease. Not only is proteinuria, uh, an important indicator, uh, to look for a diagnosis, it appears to also be involved in the progression of kidney disease, uh, by promoting kidney inflammation, uh, and kidney fibrosis, uh, and is used as a surrogate endpoint in certain settings. Uh, to assess treatment benefits of new, new agents. [00:18:06] Kevin Folta: Yeah, so this one seems like a harder nut to crack. So how are proposed drugs addressing this particular problem? There's a [00:18:15] Andrew King: whole range of reasons, uh, to have proteinuria and generally there's two strategies. Uh, one is just conventional conservative therapy that's, uh, suitable irrespective of what the initiating cause is. So they could be things like decreasing the pressure in the kidney, uh, decreasing the drive for protein to be filtered. So anti-hypertensive drugs, particularly renin, angiotensin system inhibitors like ACE inhibitors and ARBs are essentially a backbone of treatment of all proteinuric, glomerular diseases. Other hemodynamic agents like SGLT two inhibitors that were originally approved in type two diabetes also have a similar effect to decrease the pressure in the kidney. And they can be helpful to decrease proteinuria, uh, and delay progression. But where the nephrology field has shifted now is really looking at what's the underlying cause for the proteinuria in the first place and try to directly, uh, target that pathogenic mechanism. Uh, one great example, uh, has been the recent recognition. Of a gene variant, uh, in people of West African descent, uh, in the APO L one gene that confers significantly increased risk of chronic kidney disease, uh, by damaging cells in the glomerulus responsible, uh, for preserving the GLM filtration barrier. So agents are in develop now that can be added on top of these supportive therapies I mentioned to directly target that gene variant to more completely address. The underlying cause [00:19:53] Kevin Folta: of the diseases. Okay, so that's in that gene variant, is it because it's producing something that's just changing the permeability of the glomerulus, the glomerular vasculature itself? Or is it something that's changing the uptake from the glomerulus? Yeah. [00:20:10] Andrew King: In this particular situation, in a O L one associated nephropathy, this risk variant is expressed. In specialized cells of the glomerulus podocyte cells, uh, which actually form the filtration barrier. And this is a gain of function variant, uh, and essentially results in increased ion channel activity on the cell surface of those podocyte cells, causing damage to those cells, uh, and disruption to the filtration barrier itself. [00:20:42] Kevin Folta: Okay. That makes a lot more sense that the basic idea in repairing glomerular problems is you either turn down the pressure in the pipes or find ways to limit the leakage from the pipes. In other ways, I kind of patched them in other ways. So do I have that right? [00:20:58] Andrew King: Absolutely. That's exactly right. [00:21:02] Kevin Folta: Okay. Yeah, I'm, I'm, I'm a plant biologist by training, so I'm a, we work with kidney beans now and then that's about the closest I get actually. I had a lot of, uh, a lot of anatomy and physiology in high school and college, so I kind of know this stuff a bit. Um, so, uh, other issues with, um, the kidney have to do with oxy acid, and you talked about this with, uh, briefly earlier, but when you have cases of, um, hyperoxaluria. This is really starting in the liver when it's producing too much oxalate and, uh, what is actually happening. And, uh, why is this a problem ultimately to the kidneys? [00:21:45] Andrew King: Yeah, it's, it's really interesting crosstalk between the liver in the kidney and the setting of hyperoxaluria the liver, uh, can in certain circumstances, overproduce oxalate. Uh, which is essentially a non metabolizable waste product that's essentially exclusively excreted by the kidney in the urine when oxolate production is increased by the liver and that excretion levels elevated, uh, in the kidney. You can get calcium oxalate precipitation of crystals that can form into calcium, oxalate kidney stones. So you really get. Deposition of this insoluble calcium oxalate stone in the kidney, which causes dramatic pain, uh, in the form of kidney stones and in some situations can also cause significant kidney damage leading to progressive kidney function, loss, uh, and dialysis. [00:22:45] Kevin Folta: And how much does diet play a role in that? I know that there's some fruits that are really high in oxalic acid, things like star fruits. Yeah, that's [00:22:53] Andrew King: an important consideration there. There's really two forms of hyperoxia. One is from endogenous overproduction, uh, in the liver as we just described, but there are settings in which dietary hyper absorption, uh, can occur and contribute significantly to kidney stone formation that can be associated with the foods you described, high oxalate diet, but is also, uh, commonly observed. In other gastrointestinal diseases, uh, including following gastric bypass surgery, that sets up a phenomenon of dietary oxalate, hyper absorption, significant elevations in blood oxalate concentrations that ultimately deposit in the kidney. So both dietary sources, intestinal absorption as well as endogenous hepatic production overall are important contributors [00:23:47] Kevin Folta: to kidney stones. Well, the solution, at least of the hepatic arm of this is, uh, pretty well described enzyme that's lactate dehydrogenase. And what is the role of lactate dehydrogenase and oxylate metabolism, and how does inhibiting that slow accumulation and oxylate? [00:24:05] Andrew King: Yeah. L D H A is the final and only committed step in oxalate biosynthesis in the liver. So blocking L D H A, uh, with a small molecule. Uh, which we're doing, uh, with Check 3 36, our third clinical program, uh, that's currently in phase one, healthy volunteer study, uh, blocks L D H A, so blocks the final step in oxalate production, uh, in the liver. So that has broad potential to impact forms of hyperoxaluria that result in overproduction of oxalate from the liver, from a variety of different, uh, initiating sources. So blocking that oxalate production in the liver will reduce the [00:24:50] Andrew King: burden, uh, on the kidneys for filtration and reduce the production of calcium oxylate kidney [00:24:55] Kevin Folta: stones. Okay, so you don't produce oxalate because you inhibit the enzyme that makes it, but then do you hyper accumulate the substrate and is there a problem with that there? There's [00:25:07] Andrew King: actually numerous detoxification pathways which the substrates can shuttle through. Uh, without concern causing, uh, any clinical concern. There's actually a rare, uh, human mutation, uh, resulting in complete loss of function of L D H A, and they're essentially feet atypically normal, uh, with the exception of an exercise, exercise-induced muscle phenotype. But their liver and the accumulation of substrates is not problematic, uh, elsewhere. Uh, and that observation in humans showing that liver L D H a loss of functions completely well tolerated, motivated our strategy with check 3 36 to discover, develop, and optimize a liver targeted small molecule inhibitor of L D H A, such that you get high concentrations of the drug in the liver to block hepatic oleate production, which has been shown to be well tolerated. While minimizing systemic exposure and avoiding any inhibition in the skeletal muscle. [00:26:13] Kevin Folta: Now see, this is the part that always intrigues me with drug discovery. So you have this enzyme that you'd like to inhibit that hangs out in the liver, and how do you find a small molecule that selectively impairs the function of that enzyme? Yeah, so [00:26:29] Andrew King: one of the advantages of targeting the liver is the liver is loaded with different transporters. The liver plays a really important role of extracting substances, nutrients, chemicals, observe, absorb, absorbed by the gut, uh, before they enter the systemic circulation. So to prote protect the systemic circulation. So we have been able to harness those transporters that have normal physiological functions in the liver to design drugs with structural elements that those transporters recognize. So once the drug's absorbed from the intestine, these high capacity transporters are very effective at pulling the drug out of the circulation and into the liver before they're able to reach the systemic circulation. An example of drugs that work through a strategy like this are the statin drugs used to lower LDL cholesterol. Their target is in the liver. They also need to avoid. Significant exposures in skeletal muscle because, uh, skeletal muscle injury is a side effect of statins. They, they take advantage of these transport spotters as well to get high liver plasma ratios so they can do their pharmacologic work, uh, in the target tissue while minimizing exposures to other sites that could lead to side effects. [00:27:57] Kevin Folta: Well, very good. So when you're talking about these, uh, different strategies, you may have mentioned this during the course of this, how far along are these in clinical trials? [00:28:06] Andrew King: Yeah. Our Check 3 36 program is currently in a phase one healthy volunteer study. Uh, that's to establish safety, tolerability, pharmacokinetics, uh, and proof of mechanism. So it's still in early phases of clinical [00:28:20] Kevin Folta: development. Yeah. Pretty cool. So, and the other ones are in, uh, the ones for, um, iga, IGA nephropathy. That's in, uh, phase three, I think you said [00:28:32] Andrew King: that. That's correct. Atrasentan uh, is in phase three and we'll have top line data, uh, later this year. And Bio 1301, our second program in ig a n is just going into phase three, uh, in the middle of [00:28:45] Kevin Folta: this year. No, that's, that's pretty exciting. So you have a couple things that are moving along through the pipeline here rather soon. If, if things go extremely well, when do you think that patients experiencing these, uh, diseases, when do you think they may have access to these kinds of therapies? [00:29:02] Andrew King: Yeah. Right now, without lead program, attra Center, if the data towards the end of this year is positive, that will give us an opportunity to submit a new drug application, uh, to the fda. Uh, in the early period of next year, uh, following FDA review, which is typically eight to 12 months, depending on whether you get priority review or not, that would be the timing of when there could be a potential, uh, approval, uh, in I g a nephropathy. So towards an end of next year, uh, if things go well, we'll hopefully be preparing, uh, to launch our first drug and provide access to patients. [00:29:43] Kevin Folta: Yeah. That's really one of the bittersweet parts about doing this podcast every week is you hear of these therapies first you hear of the problem, and imagine people going for, uh, you know, dialysis or waiting on a list for four years and. Uh, you hear of a potential solution, but then you hear of the bureaucratic time lag, and I know you can't really get too upset about that as a chief science officer, you gotta play by the rules, but I just, from my perspective, it sure would be nicer if there was a way to connect people with the therapies faster, and at least we can talk about them here and give a little bit of hope that these things are. On the agenda and maybe coming soon. So if listeners wanted to learn more about this and maybe monitor the progress, uh, where would they look? [00:30:30] Andrew King: There's certainly, uh, a lot of scientific information about our specific programs, uh, at Chinook on our website, uh, at chinook, tx uh, dot com. There's also other resources through the American Society of Nephrology. The National Kidney Foundation and other advocacy groups that provide a lot of important information about kidney diseases, as well as a broader overview of, uh, drugs that are in development, uh, from other sponsors to treat kidney [00:31:04] Kevin Folta: diseases as well. And if people wanted to learn more from social media, do you have a presence, say on Twitter or LinkedIn? Yeah, we do [00:31:12] Andrew King: have a Twitter at Chinook, tx, and we also have a presence on LinkedIn, uh, Chinook Therapeutics. [00:31:20] Kevin Folta: Very good. Well, thank you very much for joining me today. It's always fun to talk about new areas that we haven't discovered yet and talk about some of the rare problems and some of the coming solutions. So thank you very much for joining me today. [00:31:34] Andrew King: Thanks very much Kevin, and really appreciate your interest in chronic kidney disease. [00:31:39] Kevin Folta: And as always, thank you for listening to the Talking Biotech podcast. Tell a Friend, because this is a problem in so many places, chronic kidney disease affects many people, and having a little bit of hope for a solution could go a long way and making somebody have a little more rosy outlook towards the future. So share, share, share. Thank you very much for listening to The Talking Biotech podcast by Collabora, and we'll talk to you again next week.