Targeting Rare and Chronic Kidney Diseases

Chronic kidney diseases represent a growing worldwide problem with a lack of effective treatments. An improved understanding of the biology of kidney disease is fueling growing drug development activity. Chinook Therapeutics is focused on rare, severe chronic kidney diseases with well-defined clinical pathways. Its lead clinical program, atrasentan, is in a late-stage study in IgA nephropathy, a leading cause of chronic kidney disease. We spoke to Tom Frohlich, chief operating officer of Chinook, about rare kidney diseases, the company’s lead therapeutic candidate, and its plans for commercialization.

Daniel Levine: Tom, thanks for joining us.

Tom Frohlich: It’s great to be here, Danny. Thanks for hosting me.

Daniel Levine: We’re going to talk about Chinook, rare and severe chronic kidney diseases, and Chinook’s efforts to develop precision medicines to treat them. We’re going to spend most of our time discussing your lead experimental therapy and the condition it is being developed to treat. Before we do that, I wanted to take a step back. Can you give us some sense of chronic kidney disease broadly and how big a problem this represents?

Tom Frohlich: Yeah, happy to and obviously this is a passionate area for me. Kidney disease is probably one of the most underserved areas of pharmaceutical medicine currently. It’s a huge problem globally. Up to 10 percent of the global population, at some point in time, will have some form of kidney disease. Despite that fact, there are very few good treatment options out there. If you think about the current state of somebody who is diagnosed with any type of progressive kidney disease, most often what happens is they’re treated with very old medications, usually old blood pressure medications is all that they’re offered. If they happen to have diabetes, they’ll get some form of glycemic control. It’s mainly watchful waiting as the disease progresses. In some cases, physicians will try an old steroid to try to generally stop inflammation and some of the damage that’s occurring. In most cases, it really does end up being a one-way track towards end-stage disease. When patients do get end-stage disease, the only thing that’s out there is dialysis. So, they go to a center where they get their blood filtered externally, and that’s a treatment that has a lot of morbidity associated with it, people generally feel extremely lousy, their blood levels are quite often dysregulated, and it’s extremely expensive as well. Last year in the U.S. alone, about $120 billion was spent treating patients with end-stage disease. That’s the second biggest line item on the Medicare budget, which, as you know, is the second biggest line item on the government’s books. So, it’s a huge problem for patients and their families who end up on dialysis and it’s also a huge burden economically for a society. On top of that, it’s seldom talked about but dialysis itself actually has extremely poor outcomes. Not only is it expensive, but one of our KOLs, key opinion leaders, loves to talk about the fact that once a patient ends up on dialysis, prognosis is actually worse than if you have metastatic cancer. Survival rates are around 50 percent at the five-year mark, and it gets even worse if you have diabetes and kidney disease as well. So, it’s a big problem. Some patients do end up with the transplant, but kidneys are hard to come by. That’s also a very difficult medical procedure where you’re on lifelong immuno-suppressants afterwards. So, not a perfect outcome. A huge problem that affects a lot of people and there’s very few good treatment options that are out there.

Daniel Levine: Well, there may be limited therapeutic options today. It seems that there’s a lot of activity going on around these diseases. Why are we seeing so much drug development activity in this area today?

Tom Frohlich: Great question, Danny. I think it’s a really exciting time for kidney disease. As I mentioned, one reason is that it is a huge problem. So, a lot of resources are being put towards trying to solve kidney disease. Also, the science is quickly catching up. The kidney is a very complicated organ, with over 30 different cell types. Historically it’s been very difficult for clinicians to understand what is going on and what is actually driving disease. Over the last, let’s say 10 years a lot of groups are starting to apply omics technology to look at some of the genetic, metabolomic, and proteomic dysfunctions that are going on and starting to identify what are the molecular drivers of disease. It’s giving companies, like ours, the opportunity to tease out what’s causing disease and then more specifically target it from a drug development point of view. The other thing that helps is we’re beginning to be able to start splitting up the patients by what is driving the disease. In the past, patients were often lumped together as chronic kidney disease. When you’re trying to study that in a clinical trial, it’s very difficult to prove benefit. Regulators like the FDA have always required these long outcome trials were you’re showing that you’re preventing progression to dialysis or transplant to understand if the drug is creating a benefit or not. Now, if you’re targeting smaller populations where you can say, it’s this genetic dysfunction or this biochemical pathway that’s driving disease, you can more selectively start studying those patients and then get approval based off of surrogate biomarkers because you know what the clinical course of disease is. So, it’s really the biology that’s evolving quickly and allowing us to have targeted therapies and precision medicine, which also helps us study the drugs in a more expedient fashion.

Daniel Levine: The kidney is a complex organ. I think most people would be surprised to know how many different cell types make it up. Chinook is developed a platform for validating targets in kidney disease. It’s also working with Evotec datasets of kidney disease patients. What’s the process you go through to validate a target? What exactly does your platform enable you to do?

Tom Frohlich: That’s a great question, Danny. We’re standing on the shoulders of giants in the field. There is new technology that is evolving, things like single cell RNA sequencing. One of our academic founders, Ben Humphreys at Washington University in St. Louis, is one of the pioneers in the use of this technology in the kidney. That really allows you to understand what cell type is driving disease. Then within that cell type, is there a genetic dysfunction or is there some pathway that is dysregulated? So, you really can understand exactly what’s happening. We’re employing that type of technology here at Chinook Therapeutics. As you point out, we’ve partnered with Evotec, a European research organization, and they’ve got access to large cohorts of patients out of the UK, thousands of patients. They’ve collected tissue and blood samples and plasma and urine samples on all of those patients, as well as some biopsies. They can look at this data and apply these omics platforms to really understand what are the dysfunctions that are occurring and match them to the clinical data sets to start identifying what is going on in these patients and what pathways we should be targeting from a drug discovery point of view. So, that helps us identify new targets, it helps us validate current targets that are suspected of being responsible for disease progression, and it also helps us stratify patients for clinical trials to make sure we’re including the patients that are most likely to benefit from the drugs that we’re developing.

Daniel Levine: Your lead experimental therapy Atrasentan is in development to treat IgA nephropathy. What is IgA nephropathy?

Tom Frohlich: IgA nephropathy, nephropathy is the kidney, is actually a very interesting disease and exactly the type of disease that we want to go after at Chinook, where it’s a smaller subset of chronic kidney disease patients. There’s probably about 150,000 patients in the U.S. who have this disorder. It’s caused by a dysfunction in an immunoglobulin, so part of the immune system. IgA is an antibody that is present in the mucosa. So, in your lungs and in your digestive tract and it stops bacteria when they come in through either your lungs or your digestive system, it’s there as the first line of defense. So, everybody has IgA. In patients with IgA nephropathy, there is a slight mutation that actually causes an aberrant sugar to be on that antibody and what ends up happening is the body recognizes that as being foreign. It ends up causing these immune complexes that end up depositing on the kidney and then causing cellular changes and inflammation and damage. Then, the kidneys actually end up getting fibrotic and inflamed, and then there’s a progressive disease. We’re able to target that because there’s a very specific pathway that’s recognized and that we can go after in a very precise way. It’s an interesting disease because people are usually diagnosed in their late twenties or thirties and then about half the patients progressed to end-stage disease in a 10 to 20 year period. So, quite a severe and progressive disease.

Daniel Levine: What usually leads to a diagnosis, what brings a patient to a doctor?

Tom Frohlich: As I mentioned, because of the antibody in the mucosa, it’s usually some sort of a chest infection that occurs and that probably aggravates the IgA. Then people usually show up because they have blood in the urine. When there’s blood in the urine, that is usually a sign that there’s something going wrong in the kidney. At that point, a GP would usually refer them to either a urologist or a nephrologist, and they can quite quickly make a diagnosis by excluding other factors that usually could cause blood in the urine. Then they ended up doing a kidney biopsy if there is high protein in the urine and they’ve excluded all those other factors.

Daniel Levine: What’s it like to live with this condition? What’s the impact of quality of life on patients?

Tom Frohlich: It is a slowly progressing disease. It isn’t highly symptomatic, but it is quite worrisome for patients because it is a progressive disease. Patients do know that they’re slowly losing their kidney function, and that over time they will require dialysis or transplant. So, it is something that weighs heavily on patients’ minds.

Daniel Levine: What treatment options exist for people. What’s the prognosis for someone with the disease?

Tom Frohlich: Like almost every chronic kidney disease, there’s very few treatment options. Patients are generally put on blood pressure medications that have been around a long time and that seems to help slow patients’progression. It does decrease protein in the urine and it can help in about half of the patients. In the other half of patients, there’s really no good treatment options. Physicians reluctantly will use steroids to try to stop that inflammation and disease progression, but they really have not been shown to work very well. So, there’s no approved therapies for IgA nephropathy. It’s really just these older medications that are kind of repurposed.

Daniel Levine: What is Atrasentan, your experimental therapy in development for this?

Tom Frohlich: Atrasentan is a really exciting program. It’s an endothelin receptor antagonist. We came across this because, as we mentioned, we were looking into what causes IgA nephropathy and looking at some of the drivers of disease. We know that IgA depositing on the kidneys causes changes in the cellular architecture. It also causes fibrosis, scarring in the kidney, and then also general inflammation. We know that endothelin receptor antagonists can actually improve that inflammation and fibrosis in the kidney but also reduce the level of protein that’s being excreted, which itself is known to damage the kidneys. So, it’s an exciting mechanism that can really help us slow down disease progression. We’re particularly excited by it because Atrasentan, as a molecule, was previously studied in a large phase three study for diabetic nephropathy, and in over 5,000 patients it was shown to be very well tolerated and did decrease proteinuria, one of the main signposts of damage in the kidney. It reduced that by 30 to 35 percent in this large trial and actually did slow progression of kidney disease. We believe it’s a well-studied molecule that has a high probability of providing benefit for patients with IgA nephropathy.

Daniel Levine: Was that the endpoint for the study?

Tom Frohlich: Exactly. We’ve just initiated a phase three study in IgA nephropathy. So, the final study that we believe will provide the data we need to register the drug with the FDA. It’s roughly a 320-patient study, where the primary endpoint is looking at reduction in proteinuria at a six month time point. We believe with that data we will be able to get accelerated approval with the FDA.

Daniel Levine: In terms of the timing of this, when might you expect, if all goes well, to be able to seek an approval?

Tom Frohlich: We’re enrolling this study now. We just got the IND, so the approval from the FDA to start this study, early this year. So, we are enrolling patients now. It does take some time, because this is a somewhat rare disease, to fully recruit the trial. Right now we’re anticipating having that registrational data at some point in 2023. Then we’ll follow all the usual filing procedures to be on the market after that.

Daniel Levine: You’re also looking at Atrasentan as a potential treatment for glomerular disease. What are glomerular diseases?

Tom Frohlich: The glomerulus is the part of the kidney that filters the blood into urine. What happens in a lot of these diseases is there’s some sort of a dysregulation in that filtration process that actually ends up breaking down that filtration barrier. That does happen in IgA nephropathy and that’s why you get this protein in the urine, proteinuria, because that filtration barrier actually becomes leaky and lets through bigger particles than it should. Then that protein causes damage. One of the aspects of the mechanism of the endophilin receptor antagonist, which is Atrasentan, is it can slightly decrease the pressure that is occurring in that filtration barrier. So, you actually get less protein flowing through. All of these diseases, and there’s several familiar diseases, that we believe can benefit from the mechanism of Atrasentan. IgA nephropathy is the main one that we’re looking at, but we’re also studying several others. There’s FSGS, which is Focal Segmental Glomerular Sclerosis, is also a severe rare disease affecting about 40,000 patients in the U.S. that we believe can benefit from Atrasentan. Then also another rare disease called Alport syndrome, which is another glomerular disease that we believe can benefit from Atrasentan.

Daniel Levine: I should note, you have a second candidate in development for IgA nephropathy. What is it and how does it differ from Atrasentan?

Tom Frohlich: We are studying BION-1301. As I mentioned, Atrasentan actually acts in the kidney directly on some of the cell proliferation, the pressure in the kidney, it has some hemodynamic effects, and then also fibrosis and inflammation. BION-1301, we believe can have a disease modifying potential. As I mentioned, IgA nephropathy is caused by an antibody with a mislabeled sugar because it’s recognized as foreign and it ends up being attacked by the body’s own immune system. Now BION-1301, targets the molecule that actually creates that IgA. We believe that by taking away that root cause of the disease we can actually prevent the progression of IgA nephropathy. It’s a very exciting program. We’re in phase 1 right now where we studied healthy volunteers and reported some data last year, showing that you do get big drops in this aberrantly glycosylated IgA. We believe in taking away the root cause. Then we reported some preliminary data earlier this year in a small subset of IgA nephropathy patients showing the same lowering of this disease causing IgA, but also significant drops in proteinuria, which we believe shows that it will have benefit in the disease. We believe these two mechanisms are complimentary, and potentially, at one point, could be used in combination or in different types of patients with IgA nephropathy to provide benefit. So, we’re really excited by both compounds.

Daniel Levine: Do you expect to be building your own sales force or are you going to take these to market with partners?

Tom Frohlich: That’s a really good question. At Chinook we definitely have ambitions of becoming the leading company addressing kidney disease. There are not very many companies who are specializing and focusing on this area. We think there’s a lot of opportunity. We believe with our pipeline with Atrasentan, 1301, and then some of our research programs that are still preclinical, that we have the ability to have the industry leading pipeline for kidney disease. We also believe we can translate that into being a fully vertical company. So, we do plan to commercialize, at least in North America and likely in Europe as well, with our own sales force. We think that the nephrology community is fairly small. So, we believe that we could build out our capabilities to commercialize the drugs on our own.

Daniel Levine: Tom Frohlich, chief operating officer of Chinook Therapeutics. Tom, thanks so much for your time today.

Tom Frohlich: Thanks so much. It was a pleasure, Danny.

This transcript has been edited for readability and clarity.