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

Okay. Good morning, and welcome to day 2 of the Barclays Global Healthcare Conference. My name is Carter Gould, Senior Biopharma Analyst here at Barclays, and it's my pleasure to welcome Travere Therapeutics up next. Representing the company is CEO, Eric Dube. The company is really entering what we've called a defining period over the next, call it, 6 to 9 months. We recently initiated on Travere and they've had some positive data. Their key drug sparsentan in an initial indication and are engaging with regulators and other studies on the horizon. So with that, Eric, welcome, and thank you for joining us today.

Absolutely. Thank you, Carter, and thank you to Barclays for hosting us today.

We were just talking before it's fitting with World Kidney Day set for tomorrow.

I think with that in mind, Eric, a lot of people are familiar with CKD. But as we think about the initial indications you're taking sparsentan into, if you could just set the stage and put a little color around FSGS and IgAN. And maybe you kind of flesh out those indications a little bit better before we get in some of the nitty-gritty details.

Sure, Nick. So FSGS or focal segmental glomerular sclerosis is 1 of the areas of highest unmet need when we think about renal disease. It is a rare disease, and it is considered 1 of the most rapidly progressing, where, on average, over the 10-year patients with FSGS, 50% of them roughly will be an end-stage renal disease over that 10-year period. And for those patients who are diagnosed with a nephrotic range of coronaria. Typically, these patients will progress to end-stage renal disease within 1,000 days. So there's a very high unmet need. The disease is characterized by a high degree of proteinuria. And as I just alluded to, a rapid progression and decline in kidney function. These are conditions that disproportionately affect younger patients, typically patients that are considered otherwise healthy and disproportionately affect patients of African descent and Latinx patients. For IgA nephropathy, there's a lot of similarities with FSGS. It's a rare disease, although a bit more prevalent than FSGS. It's characterized by -- for proteinuria that continues to worsen over time and disproportionately affects younger, healthy patients that make many of these patients actually don't realize that they have IgAN until it's far too late and disproportionately affects patients with Asian descent. So there's a lot of work that we're doing to make sure we can characterize the patient journey because there are some differences between these diseases. But fundamentally, there is a consistency in terms of proteinuria being a hallmark characteristic of this disease, and there is an underlying pathway that we believe sparsentan can help given that progressive proteinuria that we see with both FSGS and IgAN.

Great. I think that helps at the stage. So as we think about sparsentan and being probably a good segue into your recent Phase III data. How should we think about that differentiation relative to all the agents that have come before?

Sure. Well, unfortunately, there's been nothing approved, no pharmacotherapies that are approved for FSGS and IgA nephropathy. Many of these patients are being treated off-label with ACEs or ARBs because they are known to lower proteinuria. And we also know that many patients are being treated with chronic steroid use or other immunosuppressants that can have devastating consequences with long-term use. And so there's really a high degree of unmet need. And of the rare glomerular diseases, many clinicians will indicate that FSGS and IgA nephropathy are the most difficult to treat and are the areas of highest unmet need. Not just because of the lack of therapy and the lack of innovation over the last few decades but because of the progressive nature of the diseases. And even for something like FSGS, where patients that do progress to end-stage renal disease and are fortunate to have a kidney transplant. Unfortunately, about 40% to 50% of these patients have recurrent FSGS. So even with those types of interventions are not always met with success. And so we're really excited about sparsentan being able to tackle the common pathway of proteinuria with these diseases, where through a unique dual mechanism of blocking endothelin and angiotensin. We believe we're able to address some of the issues with podocyte injury that is responsible for the progress of proteinuria as well as some of the inflammation that we see characteristic of both of these diseases.

Great. So we were alluding to some of the positive data you recently had out of DUPLEX, specifically reported out on this composite endpoint -- FPRE endpoint. Can you maybe just help put into context for the people on the line around the clinical and significance of this as well as what gives you confidence this will be acceptable to regulators?

Certainly. Well, DUPLEX is the largest interventional study conducted to date in FSGS, the largest and the longest. And so it really is, I think in many ways, a landmark trial within FSGS. And from the interim results that we saw and announced last month, it's the greatest impact that we've seen on proteinuria yet for this disease. What we announced was a 60% relative likelihood that patients on sparsentan are able to achieve FPRE or the FSGS partial remission endpoint relative to active control irbesartan, which irbesartan in arbs are commonly used for these patients. And these results build on the results that we saw from our successful Phase II DUET study. And in fact, 1 of the most encouraging things that we've seen is the consistency of the response of sparsentan between Phase II and Phase III, where approximately 40% in the interim analysis from DUPLEX, 42% of patients on sparsentan were able to achieve FPRE at 36 weeks. And that's very similar to what we saw in DUET, in fact, to DUET the open-label extension longer term showed a continued improvement in the proportion of patients that achieved this. Now FPRE is important because it is clinically meaningful and correlated with longer-term renal function and kidney outcomes. And a lot of the results -- a lot of the work that we helped to do and is available in the literature, looking at a really rigorous control of proteinuria, FPRE being 1 of them, complete remission being another, did show the greatest probability of longer-term renal survival over 3 years. So not only is it the most profound results that we've seen and the consistency between Phase I and Phase II. We believe that it is building confidence in what we expect to see longer term in the treatment of sparsentan and the renal health of these patients.

One of the points that people, I guess, have focused in on is maybe 1 of the points that maybe was a little bit less consistent, but I want to give you an opportunity to respond to this, and that was sort of how the placebo arm performed? And you've talked about this on the most recent earnings call. But I guess, again, just in terms of the evolution of that placebo response from DUET to DUPLEX. Can you maybe just help put that into context and what gives you confidence that this still is an acceptable data set for -- as you think about engaging with regulators?

Certainly. So I think, first and foremost, there's very little research that's been conducted in FSGS. And much like so many rare diseases and clinical programs. There's very little literature to go on longer term. Particularly for something like irbesartan that was used as the active control, where there's not long-term data available. And so we really relied on the data that we had at 8 weeks from our Phase II. And what we saw in Phase III interim results was well within our powering assumptions. And we believe that the robust treatment effect at a 60% relative improvement over irbesartan, does confer, one, it's within our powering assumptions. Two, we believe that it is sufficient for us to pursue accelerated approval pathway with FDA. Given that, that proteinuria is considered an appropriate surrogate marker for these rare glomerular diseases. But also the treatment effect that we saw at 36 weeks, we believe, based on the way that we've designed it and power the trial should reflect a longer-term treatment effect on eGFR at 2 years, which is the confirmatory endpoint for the DUPLEX trial.

Great. Thank you for the correction there. Yes, it's easy to forget that, again, this was against an active control. So now as you seek to engage with regulators, there's this interesting dynamic where there's suddenly a number of drugs being up for approval across a range of renal conditions. And I guess it's interesting as you think about how FDA is going to be considering those agents, different indications, different endpoints, different strength of the data sets. I guess, generally speaking, though, is that a positive or negative as you think about engaging with the FDA, just that there's a lot of noise in the space.

Well, I think, first, let me say that this has been an area of -- in fact, nephrology and glomerular diseases has been the area of the lowest clinical trial activity over the last 40 or 50 years. So I think that all of this renaissance of clinical trial is great for patients. We believe that there is a growing recognition of the unmet need within the nephrology community and within regulators. And that we believe that there really is encouragement and focus on bringing new approved therapies to patients. I think in terms of all of the other clinical programs that are in this deal. We believe, and I don't want to speak specifically for FDA or any regulators, but we think that they're going to be looking at each individual program and therapy on its own independently. And we've been very focused on engaging with FDA throughout the clinical development of sparsentan. And there's been a consistency in terms of what they expect to see from a program like this, where we have a confirmatory endpoint and an interim analysis. And we believe that we have what we need to pursue that accelerated approval, given that we have a positive interim analysis of proteinuria and that we have the confirmatory eGFR endpoint. And in fact, at a recent CKD3 conference last week, Dr. Aliza Thompson from FDA and the cardiorenal division really reinforce the FDA's commitment to innovation in this space, including that accelerated approval is a pathway recognized within these diseases. But there are some specific expectations of how clinical trials with interim analyses are conducted, including making sure that we're very limited on what data are disclosed so that we don't unintentionally bias the trial. And I think their expectation that they continue to share with us and at this recent conference was we have to make sure that we do all we can to retain these patients all the way through the full trial. So that we can demonstrate that longer-term benefit that we believe proteinuria impacted in a shorter time frame will confer. And that really is our priority now is to file these data through accelerated approval and to make sure that we have a very high degree of study conduct through the full 2 years. So we believe that we're really excited. There's a lot of work in the space. But most importantly, we're confident in the profile and the conduct of the DUPLEX and PROTECT trials.

That point in terms of keeping the data blinded, 1 question that we've got from investors is around -- to the extent that maybe limits the potential for any ADCOM on the back end. I mean, I don't know, how would you respond to that?

Well, I think that certainly is a decision that FDA will need to make with regard to an advisory committee or not. And we will be prepared whether we are requested to have an advisory committee or not. I think our focus is to make sure that we have a strong NDA that we continue to have the highest degree of integrity and study conduct within the trial and that we prepare for any questions that FDA or an advisory committee have. And so we really can't speak to whether there will be 1 or not, but we plan to be prepared.

Okay. And now as investors look through -- look forward, excuse me, to the forthcoming PROTECT data. Can you just talk through about what gives you most confidence around -- as we think about read-through from FSGS to IgAN and some of the nuances across the different indications?

Sure. Well, I think first of all, the consistency of effect that we saw in DUET and now with DUPLEX in the interim results, in terms of proteinuria reduction, gives us great confidence in the effect we expect to see for the PROTECT trial in IgA nephropathy. Because in many ways, the trial designs are similar in that we have an interim measure at 36 weeks compared to irbesartan on proteinuria. Now there is a difference in terms of how proteinuria is measured in DUPLEX versus PROTECT. As I mentioned, in DUPLEX, it's the partial remission endpoint, whereas in PROTECT, because a lot of the literature in the IgA nephropathy space and specifically, clinical trials shows that a change from baseline in UPC of 30% or greater really confers longer-term renal survival. That's what we've used for that interim result is the change from baseline in UPC. But fundamentally, the mechanism and that common pathway hypothesis of sparsentan being able to address and reduce proteinuria that then would confer longer-term impact on eGFR is consistent. And so we do believe that, that's confidence building. But I think the other aspect that's really important for these patients but also for regulators is what we shared on the interim analysis for safety from our DUPLEX trial. We saw that there was a comparability between sparsentan and the control arm, irbesartan, in the interim results. Now that is an interim analysis. The studies continue. So thing -- who knows what we may see longer term. But we believe that that's very important, especially given that we have looked at patients longer term in our Phase II trial out to 6 years of study. So we think that, that also is confidence building. But I have to caveat that there are different trials, they're different diseases. So we need to wait until quarter 3 to see the interim results from PROTECT.

Okay. And I guess as we then just stick with FSGS since we have data there. But as we think about how the treatment paradigm may evolve with a sparsentan on the market down the road. Are there specific segments or parts of the market that might be quicker to adopt than others? How do you think about market segmentation within FSGS?

Sure. Well, I think, first, there are no approved therapies. And most of these patients, once diagnosed, are placed onto a regimen of an ACE or an ARB and/or a steroid. And in fact, when you look at the DUET study, about 85% of patients that enrolled into that study were already on an ACE or an ARB and were not well controlled with their proteinuria. And that really reflects, I think, the high degree of unmet need within this disease. So we believe that, assuming approval of sparsentan, the profile that we see emerging really resonates with nephrologists that you have a significant reduction in proteinuria that is well tolerated and the safety profile is well understood by nephrologists. We believe that, that will help to establish sparsentan as a new standard of care, the foundational therapy of FSGS. And the other classes of medicines that are in development may be additive to sparsentan, that's really the feedback we receive from nephrologists is that because nothing in development is curative at this point, that they really are looking at multiple mechanisms to be able to address it. And we think that the unique dual mechanism of sparsentan really helps to establish that as the standard of -- the potential standard of care if approved.

Particularly with the safety we've seen so far, which, again, look promising. One of the questions we often get are, and I guess investors think about the opportunity here is, how to think about duration. And I recognize it's very early in the study, but I don't know if there are lessons or learnings from the existing ACEs and ARBs that maybe provide a floor as to think about duration when we think about sparsentan. Any color you can provide there?

Sure, Carter. So I think first, these are chronic diseases. And again, nothing is curative that we have seen. And so we believe that nephrologists will be treating these patients in the future, much like they're treated now. Once diagnosed, they're essentially on an ACE or an ARB for the duration of their therapy until they reach End-Stage Renal Disease. And the goal here really is to delay as long as possible that journey to End-Stage Renal Disease and for that intervening time to make it -- these patients' quality of life as good as possible, including avoiding things like immunosuppressive therapies, which we know in the times of COVID has been a real concern for these patients. And we believe sparsentan can help in meeting many of these needs. And so we believe that in terms of duration of therapy, that once a patient is on sparsentan that they would be on sparsentan until if they do actually progress to End-Stage Renal Disease and hopefully, we don't see many patients that are progressing in that regard. And I think this is very reflective of the open-label extension that we've seen in Phase II, where the longest patients in that open-label extension who's been out to 6 years with a median of about 4 years of therapy. And so we believe that this is going to be reflective of how nephrologists will look to treat these patients.

Okay. And then, I guess, clearly, FSGS and IgAN are priorities 1 and 2 and probably repeated further on down the list. But as we think then around the effect you're showing on proteinuria, are there other kind of like logical life cycle management opportunities or line extension opportunities that could be on your horizon in the future?

Sure. So I think our -- first, the rationale for us selecting FSGS and IgA nephropathy as the 2 lead indications is because a lot of our research consistently showed that these are the areas of highest unmet need within the glomerular diseases. We think that there could be potential utility in other indications that do demonstrate the degree of proteinuria. But our focus right now is really in ensuring success with FSGS in IgA nephropathy. There's a lot of work that we need to do to complete these trials to ensure that we have success with regulators and to prepare for commercialization. Once we do that, I think we'll be able to look at whether there is opportunity for clinical development in other areas. But again, our focus right now is within these 2. And when you think about the addressable population at launch, these are significant numbers of patients that we'll be focusing on within these 2.

Absolutely. In the fall, while we were all focused in the run-up to the sparsentan data, you did do an acquisition and you brought in an orphan asset from Orphan Technologies. Can you talk about the strategic importance of this deal? How it fits in with your portfolio and your end business?

Certainly. I mean our model within Travere is really to tap into external innovation. And that is -- that was a space homocystinuria that we were looking at because there's a high degree of unmet need in the space, and we believe really fit well with our capabilities and our therapeutic expertise. Our capabilities are around late-stage clinical development and commercialization. And also therapeutically looking at the rare metabolic space that really leverages a lot of the expertise that we have, particularly within our bile acid portfolio. For example, we have within our clinical or commercial space, relationships based on our CHOLBAM program with the majority of pediatric geneticists in the U.S. That is a critical specialty for patients with homocystinuria. So just should give you a flavor of strategically why this was a great fit for us. And again, because this is the lead program for homocystinuria and a high degree of unmet need, we felt that it was strategically very important for us to acquire.

And we're going to get data on -- or I guess the expectation is we're going to get data from the Phase I/II study later this year. So to whatever extent you can, just can you help level set expectations on what we should expect to see with the sort of the period that you're expecting to treat patients, either in terms of reduction of plasma homocysteine or on some of the other measures, cognitive function, et cetera?

Sure. So the real objectives of the Phase I/II is to identify an optimized dose that really ensures safety for these patients. And so that's really what we're looking at this year is how do we make sure that we identify the right dose. Alongside that program, we have a natural history study. And we're doing a lot of work with homocystinuria patient community to really reflect what's important to them. And certainly, we want to make sure that we delay or prevent some of the devastating clinical outcomes of this disease, such as eye and lens dislocation, bone malformation, cognitive and psychiatric symptoms and thrombotic events. Many of these patients have thrombotic events in their teens and 20s. And so we want to make sure we understand how homocysteine levels are predictive of those outcomes. And the current literature right now suggests that the treatment goal was to get homocysteine levels below 100 or 50. So we want to reflect that. But when we listen to patients, really what they want is not only to prevent these outcomes but to relax their diet. I mean the diet is so restrictive and really awful tasting that that's what's important for them, that quality of life and ensuring that. So we're going to be looking at those as potential measures as we explore what's important to patients. And then, of course, continue to work with regulators on what is going to be meaningful for them in terms of homocysteine level reductions.

Perfect. Well, Eric, we've come to the end of our time. Really looking forward to seeing the outcome of your discussions with regulators here in the very near term and then PROTECT data in 3Q. Again, a very exciting opportunity as you're entering this defining period for the company. And thank you for your time today.

Absolutely. Thank you, Carter. Appreciate the time. And yes, we've got a lot of really exciting catalysts that we believe will deliver incremental value as we move forward through the rest of the year. Thanks so much for the time today.

Thank you.