Episode 5: Industry Perspective with Jula Inrig: Endothelin Antagonism, IgAN, FSGS, Clinical Trial Career Paths, and the New Era of Nephrology Trials
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[00:00:00] Laurel Damashek: Welcome to GN in Ten, a bite sized podcast brought to you by the International Society of Glomerular Disease. Our hosts are nephrologists and glomerular disease experts Dr. Kenar Jhaveri of Northwell Health and Hofstra University on Long Island, New York, and Dr. Koyal Jain from the University of North Carolina Chapel Hill.

[00:00:25] Kenar Jhaveri: . Welcome to GN in Ten. This is Kenar and Koyal joining. And this time we have a special guest, Jula Inrig. She is a topic expert in sparsentan and FSGS. We'll be talking a little bit about different things that she might be interested in.

Welcome, Jula.

[00:00:44] Koyal Jain: Thank you so much for joining us. Why don't you tell our listeners a little bit more about yourself?

[00:00:49] Jula Inrig: Thanks for having me here today. I'm Julia Inrig. I'm a nephrologist, and I've spent my career across a number of different venues, I would say. I started out in academia for a number of years, did my own clinical and translational research. And then went to a service center called IQVIA, it was Quintiles at the time, that does clinical research and designs trials and works with a number of industry type sponsors, helping them get their drugs eventually approved.

And then I spent the last few years as the chief medical officer at Travere Therapeutics, where we focus solely on rare diseases.

[00:01:25] Kenar Jhaveri: Looks like you have a fascinating career. Your initial research was intradialytic blood pressure issues. How did that change into glomerular diseases? Was it just serendipitous or you always had a little love for the glomerulus?

[00:01:35] Koyal Jain: We all do.

[00:01:36] Jula Inrig: Always a little love for the glomerulus. How can you not as a nephrologist? I trained originally at Duke down the street from UNC. I will say they stole a lot of the GN patients. So my original career didn't have as much of the fascination of glomerular disease. Until I went to UT Southwestern, and we had a lot more pathophysiology, a lot more diseases to treat.

And that's, I would say, when my interests got more sparked. And you ask about intradialytic hypertension. That was my own research, starting with epidemiology and then translational research into a clinical trial. And what I identified during that research was the role of endothelin in intradialytic hypertension, and designed a trial with carvedilol at the time 'cause really that was about the only thing that we could use that had some role in improving endothelin cell function and endothelin. So that's how I forayed into the endothelin biology space. And then fast forward, spent a number of years working on a public-private partnership with the FDA, academia and industry called the Kidney Health Initiative. And really one of the things we were very interested in is helping develop the path for new therapies in nephrology. As you guys know, we haven't had a whole lot of trials. And it was really through that work and developing paths in rare kidney diseases that brought me full spectrum to designing a bunch of trials in IgA nephropathy, FSGS, membranous, other diseases.

And then now to a company that solely focuses on rare kidney diseases and other metabolic conditions.

[00:03:07] Koyal Jain: So I think this whole world of endothelin antagonism is really interesting. But before we even go further in this discussion, why don't you tell our listeners, about endothelin antagonism? What are the benefits? What are the receptors? Let's start there before we go more in detail.

[00:03:24] Jula Inrig: Yeah, so endothelin is a peptide that can have bad actions really in pathophysiologic states. What we knew back over 20 years ago is that, particularly in patients who have pulmonary artery hypertension and heart failure and complications, that if you block the adverse effects of endothelin 1 on its receptor.

It's got multiple receptors, but ETA and ETB, that there's beneficial effects on the ways that patients function. They can walk longer, breathe better. So that's where the first therapies got approved over 20 years ago. Bosentan is one of the first, and we've had multiple other agents approved for patients with pulmonary artery hypertension.

Now, what was identified during some of these trials and particularly sparsentan, which is the therapy that we have approved for patients with IgA nephropathy, is that in disease states of kidney injury, there's an elevation in endothelin-1 that you see across the spectrum of kidney disorders. In the urine, you can identify elevated levels of endothelin-1. And if you antagonize the ETA receptor in particular, which has a number of adverse effects that are beyond just vasoconstriction, they cause damage on cell proliferation, inflammation, fibrosis. So if you can block that, you can reduce proteinuria and remodel the kidney in a number of different ways .

And that's been shown in animal models. So fast forward to, I think you guys are probably familiar with some trials that used sole endothelin-A receptor antagonists in diabetic kidney disease. The challenge that you find it's because endothelin does so many different things within the kidney. It also helps regulate salt and water homeostasis.

If you block it, there is a potential for fluid overload and there was concern of just antagonizing the endothelin-A receptor alone that you need to counterbalance that. And what we identified is if you have maximum antagonism of angiotensin 2, which is what sparsentan does , and then add the endothelin antagonist component on top of that, you can help ameliorate some of the fluid related complications from sole antagonism of just endothelin-A. So that blockade of angiotensin 2 and endothelin 1 has a better safety profile. That's how it got moved into testing in FSGS and then testing in IgA nephropathy as well.

[00:05:48] Kenar Jhaveri: I remember as a resident hearing about endothelin antagonists and heart failure and treatment for heart failure and it went downstream and nothing happened ever to that. And then we see a rise of these drugs in diabetic kidney disease and now IGA and others. So what do you think was the problem?

And what did we learn from the heart failure trials?

[00:06:10] Jula Inrig: To my point earlier, endothelin has a role in salt and water homeostasis. And so there is a concern that there can be fluid overload in some of these patients. Certainly a younger patient population that's lower risk for heart failure can have a greater benefit from endothelin-A antagonism in particular.

And, there was some concerns in the SONAR trial, older age population, higher risk for heart failure. If you have unantagonized endothelin-A, then there is some concern about fluid overload. We have not seen that when you move into patients who are younger, who are healthier and lower risk for heart failure. You may have a slight imbalance in edema, but the rates are so low and you don't see heart failure.

The dual antagonism of angiotensin-2 and endothelin-A is a very safe profile.

[00:06:59] Kenar Jhaveri: So there's what I remember of physiology, there's two types of endothelin. I think you mentioned that receptor type A and type B. So the more inhibition you have of A, the more beneficial it's for the kidney. Is that correct? So if the percentage of inhibition of A to B is where we get the most beneficial effect and least side effects.

[00:07:20] Jula Inrig: Yes. So the endothelin-A, historically it's been thought if you block ETA, you help reverse vasoconstriction and the counterbalance is with the ETB receptor, but basically most of the agents now, at least that are in development for kidney disease, block endothelin-A and have almost negligible effects on the ETB receptor.

And what with that profile is you help with not just vasoconstriction, but all the cell proliferation that occurs in disease states of kidney injury. Also inflammation, apoptosis, fibrosis, multiple animal models where you just block endothelin-A. And in addition with angiotensin-2 blockade, we've got animal models of IgAN, of dual blockade, significantly better on cellular function in the glomerulus and the podocyte and the glycocalyx. That dual blockade appears to be the sweet spot and then that translates into a reduction in proteinuria and then preservation of kidney function in humans.

[00:08:21] Koyal Jain: A controversial question: IgA and FSGS, two different diseases. You've done trials with both, sparsentan with IgA nephropathy, with FSGS. And while it reduced proteinuria with the FSGS, it really didn't help with the GFR decline in that study. With IgA it was a little bit more beneficial, especially with the proteinuria reduction. Why the differences?

[00:08:44] Jula Inrig: Well it's a great question, and I would say for the two trials that tested sparsentan in IGA and FSGS, there's a reason why you see a different effect on one of the endpoints, which is EGFR slope. I'd point to one, the trial design, And two, I would point to the disease state. So first, I'll talk about IgA nephropathy.

In IgA nephropathy, you have a relatively progressive rate of EGFR decline that's relatively linear. And so if you can reduce proteinuria, then you can preserve EGFR and avoid kidney failure. We've modeled that, we understand that relationship. And true, when sparsentan was tested in patients with IgA nephropathy, you had a 50 percent reduction in proteinuria.

Now, the trial was designed to compare against a max dose of irbesartan, and we got almost everyone up to that max label dose. We didn't have a washout as well in the PROTECT trial where we tested sparsentan versus irbesartan. And you had a nice reduction in proteinuria compared to irbesartan, which had about 15 percent versus 50 percent reduction in proteinuria, respectively.

That translated into a more stable EGFR, and that benefit accrued over time, and you can imagine that because both drugs have a slight hemodynamic effect, and then what you should see is a flattening of EGFR, and that's what we saw at year one, there was a 1.7 milliliter greater preservation of kidney function with sparsentan versus irbesartan.

That increased to 3.7 milliliters greater EGFR at two years with sparsentan versus irbesartan. Now linear progression, no washout in the PROTECT trial.

Now let's go to FSGS. FSGS, we recruited kids down to age eight. Patients with normal kidney function and hyper filtration. I would say hyper filtration is part of FSGS, similar to diabetic kidney disease where you give a medication, you reduce the blood pressure, you are gonna see an acute decline in EGFR.

We had patients with GFRs up to 200 and greater in this trial, and kids. We had a washout and then compared sparsentan versus irbesartan after a washout. Now it was great. We saw a 50 percent reduction in proteinuria in patients with FSGS, with sparsentan. However, we saw a greater than 30 percent reduction in proteinuria in the active comparator irbesartan arm.

So that differential treatment effect wasn't as great as what we saw in IgA nephropathy. The other thing that I'll point out is because of that washout, we get a fairly large acute decline in EGFR of about four milliliters in the first six weeks. They continued to have a slight decline that didn't reverse until about 12 weeks.

Now, what did we see on EGFR, our endpoint? We did see a favorable preservation of kidney function that was not statistically significant after that acute effect. About a one ml benefit per year in chronic slope. And at two years they had overall about 1.8 milliliters higher EGFR on sparsentan versus irbesartan.

However, again, not statistically significant. Part of that is because of the differential proteinuria effect, we were underpowered based on the treatment effect that we saw in proteinuria. And then high variability. When you have a large acute decline, that's really hard to overcome in two years. And even if you believe that a one ml per minute per year is comparable to what we saw in PROTECT, the standard deviations in the variability around that estimate, much too large to be able to show a statistically significant effect in FSGS.

But the one nice thing is we saw multiple things that were favorable beyond proteinuria and non significant preservation of EGFR, but the composite kidney failure endpoint as well was similar across both trials in avoiding that composite of 50 percent decline in EGFR, kidney failure, dialysis, or death.

[00:12:48] Koyal Jain: So just thinking about what the bottom line is, right? Lots of data for our listeners, but in my mind, it sounds like sparsentan is something that you could use for IgA and I have used for IgA nephropathy, But the data is not quite there for FSGS yet. Where are we headed with FSGS?

Are you pursuing more trials?

[00:13:10] Kenar Jhaveri: Want to just interject before you answer that question, because I think that there is some room for sparsentan in FSGS. I think the problem is the heterogeneity of the disease itself. Were you dealing with podocytopathies, true podocytopathies that are immunologic, or are you dealing with FSGS, that is kidney disease that's burnt out?

So I think if we separate those two, maybe there is a role for endothelin antagonists in almost any kidney disease that is burnt out. Perhaps it's almost like an ACE and ARB, an additional effect of that. But for maybe for podocytopathies. I don't know. Is there really truly, is there, maybe there is no effect there and maybe that's where we're seeing the mixed signal.

I don't know. I'm just postulating.

[00:13:56] Jula Inrig: Yeah, it's a great question. We tested early disease states because we didn't exclude the upper range of EGFR and saw consistent proteinuria effect. And when you look at the animal models of treating very early before disease starts, either in IgA nephropathy or FSGS, you see a benefit on the podocyte number, the podocyte function, on the glycocalyx, and then the downstream effects of the interstitial fibrosis.

We do have a trial in very early IgA nephropathy before they've seen an ACE or an ARB. We've presented some of that at Kidney Week last year and then additionally it'll be coming at additional meetings. And if you treat within six months of a kidney biopsy, early, no cutoff on upper EGFR, you see about an 80 percent reduction in proteinuria and stabilization of EGFR in IgAN.

This is out of Jon Barratt's group. And so I think there is a benefit early rather than waiting until later stage disease particularly for IgA nephropathy.

More to say about FSGS because we did allow earlier stage disease, not, we tried to exclude secondary. So these were more, you could think of them akin to a prevalent FSGS patient who you've tried multiple things including ACE and ARB, steroids, immunosuppression. You've gotten them in the range of three grams now, but that's just still there and sitting. And that's who we tested in that DUPLEX trial.

Now, Koyal, you asked specifically about where we're going next. So how the field got to where we are with now two therapies approved in IgA nephropathy, ours and budesonide, is we worked with the FDA on what these trials would look like. What the patients would agree to participate in and what the end points should be. We published work under the Kidney Health Initiative in IgA Nephropathy of defining the relationship between proteinuria, GFR, and kidney failure. We had a similar project that's still ongoing under the Kidney Health Initiative, defining the endpoints of what they should be in FSGS, knowing patients won't participate in a trial beyond two years.

There's a second initiative called PARASOL , which is a partnership with academia. They're going to be bringing industry into the mix to get the data sets, to be able to define the relationship between either proteinuria and EGFR or preferably proteinuria and preservation of kidney function , avoidance of dialysis over five to ten years. That work hopefully will be completed by the end of this year so we can then look at what additional trials can be done because there's such a high unmet need in FSGS and we need therapies for this patient population. But also they need to be developed within a practical time frame and a trial that's feasible for a patient and feasible to recruit.

[00:16:43] Kenar Jhaveri: I guess if I throw in GLP-1s in the mix , we're looking at really a golden era in nephrology, right? This is really amazing to see such promising therapies for kidney disease.

[00:16:55] Jula Inrig: So the GLP-1s, I look forward to hearing the FLOW trial results and having them presented, I think it's going to be at ERA, but that's diabetic kidney disease, and CKD in maybe a little bit more advanced stage because they need to have proteinuria and somewhat impaired EGFR. Whether they'll be beneficial in some of the rare glomerular diseases? Hard to say, but I do believe that we are moving into an era of combination treatment where you want to maximize the benefit for patients. And whether it's a GLP-1 in DKD or a dual endothelin and angiotensin receptor antagonist in IgA nephropathy, we are likely going to need combination to get patients so that their rate of EGFR decline is less than one.

We know from the RaDaR data in particular that IgA nephropathy patients, most of them are going to face kidney failure in their lifetime. So they're going to need a combination of treatment options to preserve kidney function. And in my mind, this is one of the biggest areas where we need to push harder because we haven't had new innovative therapies.

And now we're in an era of implementation science. I think every day in a patient's life is nephron loss and we shouldn't sit by and wait. We need to be treating with the agents that we have now to keep people off dialysis. I remember 10 years ago, 12 years, the word cure came into our nomenclature.

We now have enough tools to preserve enough kidney function to reduce the number of patients going on dialysis within our lifetime. It's very exciting, but it's going to take multiple things in our toolbox to be able to get there.

[00:18:30] Koyal Jain: To be honest I'm really looking forward to the time where all of this information is out there. All of these medicines are out there that I can actually identify patients and then match them up. Sort of precision medicine. You're the right person for SGLT2 and budesonide, you're the right person for sparsentan and so trying to figure out who's the right patient, do you think we'll get there?

[00:18:51] Jula Inrig: We've got a number of great people doing work in this area, trying to figure out what the markers should be, but oncology is the one where you get so excited at what they've been able to do, but they have tissue and they are able to look at gene mutations. We're at least doing genetic analyses on more and more GN patients in particular, but our precision medicine biomarker right now is proteinuria.

Does the patient reduce their proteinuria when you treat them with a specific agent? If not, then that's probably not the right agent for them. It's really hard to use EGFR decline because it's so long to see that effect. The other thing we look at is hematuria and how patients are responding overall, but I think it'll be a number of years before we get to knowing exactly which patients respond to what therapy.

And look at cardiologists, they use it all. 25 years ago, I was in the ICU and algorithm based medicine and there's your aspirin, your statin, all the other 2b, 3a antagonists and Plavix and they don't stop the treatment because they know that what you can do that benefits arterial health in general, so the thought for cardiology is going to benefit the patient over the long term.

But it's a great question. I would love to know that we don't have to use tons of medicine. Polypharmacy is hard for patients.

[00:20:08] Koyal Jain: But especially for geriatric patients, right? Our patients are getting older and polypharmacy for those, that patient population is really hard. I understand that.

[00:20:16] Jula Inrig: Yeah, and that's why I like sparsentan, because you get to stop a pill and start something else. That certainly can help the mindset of it's one less pill.

[00:20:24] Kenar Jhaveri: I want to just go back to some of your older work and kind of highlight what has happened in the last few years. One of my favorite articles by you was in AJKD that showed that nephrology has the least clinical trials of all subspecialties. You think that the formation of KHI and this partnership with industry, Patients, academia will eventually make the change and maybe when you redo that study in 20 years, we probably won't be as far behind oncology and cardiology?

[00:20:55] Jula Inrig: Thanks for bringing up that paper 'cause we did redo that analysis 10 years later. It was probably a little too early. We looked at the eras preclinical trials a couple years before KHI was formed and then 2014 to 2018 and looked at a meta-analysis of clinicaltrials.gov and it was Reem Mustafa. We did that work with some of her fellows as well.

And we presented at ASN in 2019. We did see an increase in clinical trials. And the important aspect is the quality of the trials as well, that they were blinded. More large scale clinical trials that were being done . And then we also saw more glomerular disease trials.

So we started to see that early uptick, which I think was a lot of the output from the Kidney Health Initiative. We need to do a later data cut, to your point, in 20 years and see how much better we've done. We definitely need to do that. The other thing I'm really interested in is if we've got all these great therapies and we're using them, we should see the prevalence of end stage renal disease, particularly due to some of these diseases go down over time.

And I'd love to see us end that. Look at that data in 10 years when we know it's going down somewhat. I think it's because of the number of new therapies we have that are beneficial to general health as well, and diabetic kidney disease. But then if we can make that same impact in some of these rare kidney diseases, that would be a huge benefit to human health, I would say.

[00:22:16] Koyal Jain: Jula, you have successfully gone from academia into the clinical trials world and made a career out of it .

What recommendations do you have and, or how should a trainee think about it should they go down this pathway?

[00:22:29] Jula Inrig: I think it is really important that as we have new trials, that are in development and as we understand the biology more and more, we're only going to innovate and have more trials that we need to have experts in nephrology be available for. I would say in each step of my career path, I made a conscious decision to learn and to grow.

I did a master's of clinical research when I was at Duke, and that helped me understand the ins and outs of doing clinical research and then designed my own trials. The hard choice is to leave behind your own research in academia. That was a soul searching many months of can I give up my own research?

And really the overall thought was I'm spending so much time writing grants. How much benefit am I giving to society with my single center trials that are really hard to get funding from the NIH or I was AHA funded as well to then help develop and innovate new therapies for patients on a broader scale.

And for that step, from academia to really helping support many different sponsors, because I was at what's called a clinical research organization, I felt like I could have a bigger impact on society using the skill set that I had to be able to help innovate and get new therapies to patients.

I will say the other hard one is to go to one sponsor. How do you pick all the babies that you love? All the amazing things that are in development and then move to just one company, not working with every company. But I really felt like the era and all the work that we've done over the many years to get new therapies, we really do have to have patients take them.

And that was the choice that I made was to make sure that we have these therapies that get to patients so that we can change the future trajectory of kidney health.

[00:24:13] Koyal Jain: Dr. Inrig, this has been really fun and fascinating. And to be honest, this is a wonderful time to be in the field of nephrology. I often tell my trainees this is where you should be. There's so much happening and there's so much potential and opportunities for the future. But thank you so much for joining us and helping us understand the endothelin antagonism world better.

[00:24:35] Jula Inrig: Thanks for having me. This was fun.

[00:24:37] Laurel Damashek: This has been GN in 10 from the International Society of Glomerular Disease. You can listen and subscribe wherever podcasts are found and tweet at us at ISGDtweets. Thank you for joining us.