Travere Therapeutics, Inc. (TVTX) Earnings Call Transcript & Summary

I wanted to ask on that. I mean, obviously, PROTECT there was the disappointment, the setback regarding eGFR total slope. But that you have, I think, fairly good evidence that FDA is comfortable with the entire data package. What does that mean to a physician who looks at that data point versus kind of the body language, if you will, of regulators?

Well, I think part of this is going to come down to what is in our label. That's going to be the basis upon which Peter's team and our medical affairs team will be able to educate nephrologists on the data. And I think part of this is going to be imperative for us to continue to discuss the rigor of the trial design. Keep in mind, this is the only head-to-head trial that has been or is being conducted in this space, and it was one of the first and this is rare disease. You oftentimes have to find and identify endpoints that are imperfect early on because you just don't have a strong literature upon which to design these and that's exactly what we saw here. But when you take a step back and look at the profound improvements in proteinuria that Peter mentioned as well as how that translates not just into a benefit on eGFR versus the standard of care RAS inhibitors. You also look at the numeric benefit in hard endpoints that we saw in 2 years. This is what's meaningful to patients, and this is what's meaningful to nephrologists. And this is what I think ultimately is going to allow us to replace the inadequate role that ACEs and ARBs have played in the treatment of patients with IgAN for years.

Wonderful. Well, moving to actually the treatment paradigm itself in IgAN, it's evolving. Where do you think FILSPARI ultimately fits in? I mean, in a world of potential combinations, do you think the drug could ultimately be foundational?

So absolutely, yes. And in fact, that's what we're starting to hear quite a bit from the nephrology community. Now if we take a step back and look at how these patients have been treated for decades, it's really in 2 components. The first is foundational therapy that really address the damage in the kidney. This is the role that ACEs and ARBs. And now for many patients, SGLT2s play. They're renal protective and they work in the kidney. There's another target that has been used for decades, and that is to address the immune overactivation. And in IgA nephropathy, that's really where the damage comes from and that's the role that steroids have played for years. Now as we look forward, what's really exciting for IgA nephropathy is that we're going to have better therapies to be able to address both of those. What's going on in the kidney, we now know that FILSPARI provides a superior benefit versus standard of care. And with the potential for complement B-cell and better steroids, you're going to be able to replace the role that traditional steroids have played. We do not see nor do most nephrologists see that those are competing. Those are complementary approaches that for most patients, in order for them to get to complete remission, you've got to have both. And in fact, that's what we believe the evolution of the treatment paradigm. In the best interest of patients, you want to get them to complete remission, you really have to have both. And in fact, when you look at all of the therapies that are in development now, to address the immune overactivation and replace steroids, they're all being studied on top of foundational therapy. And so we think that we have a unique role to play in improving foundational therapy and also as a non immunosuppressive but working complementary with anything else that comes to market to address and prevent further damage.

It makes complete sense, I think, on paper. But as you mentioned earlier, nephrologists are a conservative bunch. Obviously, the treatment paradigm hasn't changed much over the last several decades. Again, from a practical standpoint, what does it take to get them to change their prescribing habits? Is it guidelines? Is it FDA? Is it just getting out there into the conferences and whatnot. I mean what does it take to overcome that barrier?

Yes. I'll say a few words, and I'll have Peter share his view. It takes data, it takes guidelines, it takes full approval and I think it takes clinical experience. And it also needs to be easy. And I think that's exactly what we see with FILSPARI and the strong data with the profile that we've seen thus far. And in fact, when you look at some of the data in the only trial done in a treatment-naive setting in IgA nephropathy, this is our SPARTAN trial, FILSPARI reduces proteinuria by 80%. It gets 2/3 of those patients -- if you start with FILSPARI, 2/3 of them get into complete remission, and you see no change or stabilization of eGFR over time. That really is, I think, what physicians are looking for. And it's one pill, it's oral, it's once a day, and it's non-immunosuppressive. So I think it starts with that and really replacing what they've been already comfortable doing, which is using RAS inhibition to address the damage in the kidney. So we think that that's really playing into how physicians already think about treating patients with IgA nephropathy. Peter?

Yes. The only thing I would want to add is like it's typical market development. I mentioned earlier in the last 30, 40 years, there has been no innovation in this patient population. So physicians have been treating in a certain way and also have a certain level of satisfaction with levels that they shouldn't be satisfied with. And what we did early on, and we started this like 3, 4 years ago, was like really building a registry to get a better understanding of the natural history of disease and how are those patients progressing actually in real life. I mean if you read the text books like 5 or 10 years ago, IgA nephropathy was being discussed as like a generally slower progressive disease. Well, if you look at the data, the longitudinal data of patients following them, the majority of those patients will be on dialysis within 10 years. You have to realize this is a younger patient population. Many of those patients are being diagnosed in their early 20s, that means that you have patients ending up with kidney failure on dialysis in the 30s, 40s, sometimes 50s. So now I think that you start to see like a whole wave of innovation. The market is being developed, guidelines will follow to your point, and that's why we anticipate also the treatment targets will go down. But the noise, I think, from us together with others, and I think we are really the leaders and the front runners in this field will allow for more addresses treatment, more early on and likely combination therapy with some of the new modalities that may come out as well. But I think in the grand scheme of things to Eric's earlier point, it's a 2-step approach. First thing you do, nephroprotective foundational medicine to address the damage in kidney. And that's why patients show up in the nephrology office in the first place. That's good to realize, like proteinuria is the main reason patients are being referred to the nephrologist. The first thing a nephrologist is doing is RAS inhibition, even before the biopsy is done. That's where we play, that's what we replace because FILSPARI has that RAS inhibition component, but as endothelin part and that together allows for the magnitude of benefit that we saw.

Great. And maybe just a quick follow-up here. What does it take to get FILSPARI earlier in treatment? Is -- this is an opportunity where combinations can be your friend by maybe pairing with an SGLT2?

Yes. I think that's going to be critical. I mean what really physicians are looking for early on and what we've heard from them and a lot of the research that Peter's team has done; one, you want to have non-immunosuppressive. These are patients, particularly when you think about what they experienced during COVID. They want to be on a non-immunosuppressive therapy. Second, once-a-day oral with 1 pill is really important. So I think that, that's going to be something that is going to be considered. Again, given that many of these patients are being seen in a community setting, these physicians are phenomenally busy. So to make it easy for them is important. But again, it's going to be the clinical data. We have 2 studies that are looking at FILSPARI in combination with SGLT2 and as I mentioned, our SPARTAN study, which is the only study currently in looking at patients in a front-line setting, which shows profound improvements for these patients.

Great. Well, I certainly don't want to overlook this, but we recently got a first look at the data to be presented at ERA. What are your main takeaways here in some of the data that you can talk about that was in the abstracts?

Yes. I mean, I think overall, what is really exciting is that this is a renaissance within the renal space, particularly within rare kidney diseases that have just been underserved. And we do expect to continue to lead in the data that we're generating. One of the things that really struck out to me was just how strong our positioning and our clinical profile is with FILSPARI, particularly the first look that we have of another endothelin receptor blocker atrasentan showing their interim data. And I think we have a very strong case for the benefit of dual blockade with FILSPARI. If I were a patient looking side by side, you've got FILSPARI with 50% reduction at 9 months in 1 pill versus having to take 2 pills and you have a 38% reduction. I know what I'd pick. And I think I know what the community nephrologists are going to be thinking about when they think about the ease, but also the confidence that you have in the clinical experience you can expect with FILSPARI. But Peter, maybe you can share a bit more about what you think.

I think you had all the points. I mean it's an exciting time, first and foremost, for patients, because patients didn't have any medicine that was approved for IgA nephropathy. Now you have to potentially have more in the future. So -- in different modalities. So I think that is great news. I think the profile of FILSPARI, I'm very confident in. I mean 50% reduction in proteinuria, where we have seen none of the other compounds in Phase III has shown that. It's all in the 35, 38 range, including SGLT2, you mentioned SGLT2 earlier on, promising data, but they had a proteinuria lowering effect of 25% to 30%. So it's in combination, and I think with more aggressive treat line targets, I think it requires more combination therapy as well. And I think it comes back to Eric's earlier point, it's a 2-pronged approach. You want to address the damage in the kidney, you want to go upstream in the immuno overactivation. That's the process moving forward, and you have different medicines in those 2 classes. But I think the profile that we have is very competitive and next week at the European Renal Association Conference, we will see more of the data as well and discuss that.

Got it. Does that extend to like the back April antagonists that are coming online, again, when you think about combination approaches and maybe FILSPARI is thus far, pretty superior profile.

Yes, I would say the back April, very promising data so far, but it plays more into the immuno activation. So I think it's more competing with steroids. To Eric's earlier point, like how long do you want to suppress the immune system because that's what those drugs do. So I think it has probably a place if they will be approved. And again, this is Phase II data that we're talking about. We haven't seen a Phase III data yet. But it's in combination with. I mean, the studies are done on top of current standard of care and the current standard of care is foundational therapy, RAS inhibition and ARBs, that's where FILSPARI plays. So it's not like a winner takes all. It's a 2-step approach anyway, and those products are being used on top of FILSPARI is taking the space of ACE inhibitors and ARBs.

Great. Well, in the time we have left, I do want to kind of cover what comes next. Obviously, you're looking to expand sparsentan into FSGS. What does this opportunity look like? And what were the lessons learned from DUPLEX?

Well, I think the opportunity really is to help give hope to the most difficult and severe of the rare glomerular diseases. These are patients that oftentimes are diagnosed as kids, I met a father at a patient, a rare kidney disease conference this weekend whose son was diagnosed at 18 months. And when you see how rapidly progressing this disease is and that there's very little in clinical development. This is a high unmet need. What we learn from the DUPLEX study is that FILSPARI has a very consistent and profound benefit on proteinuria. It's the most -- FSGS is the most proteinuric of the rare kidney diseases and most patients that -- and particularly those that we studied are nephrotic in their proteinuria range. You were still able to get patients into their 50% reduction in proteinuria. 1 in 5 of these patients in DUPLEX were able to get into complete remission, 3x greater than the current standard of care ACE or ARB. And while we did not achieve statistical significance on eGFR, I think the medical community and the FSGS treatment experts very quickly, in fact, within a matter of days after the New England Journal of Medicine published the DUPLEX trial, came together and said, "This is not about whether FILSPARI or sparsentan works in this disease, it's how we measure it." The treatment effect on eGFR versus active compared to irbesartan was actually quite similar between IgAN and FSGS but the variability in FSGS and DUPLEX was more than double. And that's because FSGS is a highly, highly variable and heterogeneous disease. And so the experts as well as regulators now are looking at what is the right measure, what is the right endpoint longer term to be able to prevent these patients from going into kidney failure. Because it is a matter of years to less than a decade where many of these patients are going to be facing kidney failure.

Great. We have about a minute left, but I did want to give you some time to talk about HCU and I apologize, it's not much, but what is the opportunity here look like?

Well, I mean, these are patients that have a rare metabolic disease that is genetic in origin, and they, over time, have a toxic accumulation of homocystine based on their diet. Patients basically have to have an incredibly restrictive diet for protein because that's where you get much of the methionine and homocysteine. And so these patients typically will face eye problems, skeletal problems, developmental problems and perhaps most scary ischemic events in their teens and 20s. And so we really are looking to transform that with a pegylated human enzyme replacement. It's the only therapy in development and one that we believe will be disease modifying for these patients. There are about 10,000 patients that are addressable in the U.S. and Europe. And we believe that pegtibatinase can offer a real change in how these patients manage their disease.

Well, exciting times. We'll look forward to those data when they come. Gentlemen, thank you so much for joining us.

Thank you.

Thank you.