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

Great. Now looking at ex U.S., what are your expectations in Europe, for example, if approved in IgAN? And maybe just if you could talk us a little bit through your agreement with the partner over there.

Sure. So we did decide to partner with CSL Vifor. We believe that they are a leader within the renal space and have the depth of experience, both commercially and from a regulatory and an HTA/payer perspective. So we're really pleased with that partnership. And when we look at the addressable population, largely it's a similar size in IgA nephropathy to the addressable population in the U.S. So we think that it is a very important opportunity for us to be able to provide a treatment option that fundamentally should become the new foundational therapy, replacing the roles that ACEs and ARBs have played off label for such a long time. The dynamics within Europe are quite different. Both Peter and I worked in Europe and know that it's not just about getting approval, but it's about getting access through the national and regional HTA bodies. And so this is a major part of what we've been working on to have a strong evidence base for those dossiers. And that's really where the CSL Vifor team will be able to provide their expertise in navigating those processes. As part of the agreement, they have the commercial rights in that region. We did receive an upfront payment with this partnership of $55 million. We have additional milestone payments that are tied to regulatory and commercial milestones up to $135 million with then a tiered royalty up to 40% on revenues from that region. That start above the royalty obligation that we have to Ligand. So we believe that it's a great deal. It's a great team. We have every confidence that they'll be able to navigate success as we expect to have also in the U.S.

Great. Let's move on to the DUPLEX update. Maybe if you could just walk us through the data we saw there and the benefit you saw on proteinuria and then the extent to which that translated to eGFR?

Sure. Well, I think if we take a step back to say, what did we see at the interim analysis, which was a primary end point for proteinuria. We saw a very consistent reduction in proteinuria with sparsentan that we saw in our Phase II DUET study. What we saw was a 50% reduction in proteinuria at 36 weeks. The primary endpoint at that time was a partial remission. So a very robust measurement of proteinuria control. And importantly, what we now see at the conclusion of the 2 years is that patients were not only able to get their proteinuria down quite substantially, 50% quickly after initiating sparsentan, but they were able to maintain that through the 2 years. And that is a very profound result in the context of a very severe proteinuric and progressive disease. So we were very encouraged by that. But more importantly, the investigators and a lot of key thought leaders in the FSGS space were very reassured by the rapid and consistent benefit and the predictable benefit on proteinuria. There are other measures of proteinuria that are even more rigorous and predictive of longer-term endpoints. The first and primary one is complete remission. So we saw 18% of patients on sparsentan achieve complete remission of proteinuria versus 7% on active control irbesartan. Now when we look at irbesartan, I think the thing that surprised us in this trial was just how well this did. I mean in many -- in all other trials in this space, they are comparing them to placebo on top of standard of care. This is perhaps a much more rigorous trial design where patients were washed out of their medicines for 2 weeks and then randomized to sparsentan or active control irbesartan. And what we saw is that at that 36-week time point, irbesartan achieved a 30% reduction in proteinuria, which was sustained through the 2 years. That was quite surprising because when we look at the natural history of these patients, because there are no other trials to rely on looking at ACE or ARB in FSGS, we do see that these patients progress despite being treated with off-label ACE or ARB or other therapies. And so we were surprised to see that patients were able to sustain that. So effectively, what we saw is that -- the effect size on proteinuria while we saw a very strong result for sparsentan, it was less than what we had hoped for and power the trial. And in FSGS, we believe that proteinuria at 36 weeks does predict or should predict what happens 2 years on eGFR, which is more the longer-term measure of kidney function. And that, that 2-year period, what we saw was a clinically meaningful difference, a benefit of sparsentan of 0.9, which would be clinically meaningful and likely to translate into about a 3-year delay to end-stage kidney disease. However, it was not significant. And we believe that, that's likely for 2 reasons. One is that irbesartan performed better. In fact, the rate of eGFR decline actually was lower than what you see in the natural history of these patients. And also the variability was far greater. And we do know that FSGS is quite a heterogeneous population with a relapsing and remitting progress. So all of that really led to what we believe is a nonsignificant effect on eGFR, which was the primary endpoint at 2 years. But when we look at all of the other measures of efficacy, whether it's proteinuria, eGFR or hard endpoints like progression to renal death or kidney failure, they all favor and trend in favor of sparsentan. And then importantly, we also looked at the safety database. And we were very pleased to see that there was a consistency between the 2 treatment arms. So it gives us quite a bit to then say what is the totality of evidence that we need to then go to regulators who have stated that if we don't achieve a significant endpoint or difference on the eGFR endpoint that they could evaluate the totality of the data in recognition of just how difficult this disease is to study. A long answer, but I think it's hopefully a good overview of what we've seen. There's a lot more work that we need to do. I mean when we think about the heterogeneity of FSGS, subgroup analyses are going to be particularly important here. We want to make sure that we can help in understanding who might be benefiting. So a bit more work for us to do, but we want to quickly go to FDA and understand how they think about it and whether there is a regulatory pathway. We should be in a position, hopefully, to do that by the end of this summer.

Okay. Great. Just one quick follow-up on that. And that's -- when you think about the unmet need there in FSGS and the strong trends in favor of sparsentan that you saw, what are the potential paths forward in terms of evaluating the totality of the data versus would you be willing to generate additional clinical data?

Sure. Well, I would say, first, this is the only Phase III trial ever to be done and completed in FSGS. It's an incredibly difficult study to -- type of trial to enroll and to study. And we've seen, unfortunately, a number of other companies ending their programs in FSGS, I think, because of the difficulties in this. So we do see this as an incredibly important database to be able to understand of the disease. The early feedback that we're getting from experts in the field is that we do need to move forward in understanding the totality of evidence because you are seeing a very consistent benefit with sparsentan on proteinuria. The question is, is eGFR the right measure of confirmatory evidence long term. We don't know that. We need to continue to explore that, but that really is now the question that's beginning to emerge. That's very different than what we see in IgA nephropathy, where there is a consistent predictive value of proteinuria to longer-term eGFR and renal outcomes. So I think we've got to continue to ask our questions about the disease as well as the benefit risk of sparsentan. And again, we want to move very quickly. We want to provide the certainty of what this means for this patient community. And again, we'll hope to do that by the end of summer, early fall. In the meantime, we'll look to complete the IgAN study and obviously continue the strong execution of the FILSPARI launch.

Great. Yes. So that brings us to the next point, which is you'll have the update from the PROTECT trial in 4Q, where you'll be looking at eGFR in IgAN patients. Could you help us set some expectations there for what that data could or should look like? And what would be successful?

Sure. Well, I think the trial is designed to be able to first show a superiority in the reduction of proteinuria at 36 weeks. And what we saw was a 50% reduction, strikingly consistent to what we saw in FSGS Phase II, Phase III, but the treatment effect versus active control irbesartan was even greater. So I mentioned in DUPLEX that at 36 weeks irbesartan reduced proteinuria by 30%. In the IgAN PROTECT study, it reduced it by only 15%. So the effect size on proteinuria is far greater in IgAN. . Now the other important aspect of that 36-week proteinuria is that there's a meta-analysis of about 13 clinical trials in IgA nephropathy really to look at what is the predictive value of a reduction in -- or a treatment effect on proteinuria to a 2-year eGFR endpoint. So a much more robust literature upon which to rely compared to FSGS. So when we look at that, we actually have -- we powered and designed the trial to show a single -- a low single-digit difference in eGFR slope at the end of 2 years. And that would, we believe, based on the 41% treatment effect at 36 weeks that we observed is greater than what we powered the study on, which was a 30% treatment effect. So we believe that we're in very good position to be able to then demonstrate that 2-year eGFR. There are some important differences between our FSGS trial and our PROTECT trial that we believe there's very limited read-through in what we saw at DUPLEX, which was a nonsignificant difference on eGFR. We believe that those do not apply based on trial design and population differences. So we remain very confident in being able to demonstrate that. And if we show a low single-digit significant difference. One, it allows us to go to FDA for full approval, but it also would then be a very important database on safety and efficacy to be able to hopefully expand the indication and be able to reach more patients with a therapy that is superior to how patients are currently treated with off-label ACE and ARBs.

Great. Now if the data are positive for PROTECT, how does that help accelerate the launch in IgAN?

Peter?

Well, certainly, we'll build further confidence in the marketplace and we'll further expand our prescriber base as well. I think it's really almost like a rolling launch. I was talking about earlier the publication that we recently had. We had UpToDate, where you have the inclusion of FILSPARI, the full data set of PROTECT will help there. You have the KDIGO guidelines are likely to be updated by the end of the year. I think all those data points further confirms the confidence of the profile and also further expand the prescriber base. It certainly will help. I have to say what I'm seeing so far is that based on the robust and strong magnitude of proteinuria-lowering effect of FILSPARI, I haven't heard physicians that say like, well, I'm waiting for that data. But that may also have to do with the targeting and segmentation that we did. We are very focused on the patient -- the physician population that are more eager to adopt innovation, but it will certainly help in the broadening the prescriber base.

I think maybe, Greg, if I can add one more thing to what Peter has outlined is we will have a robust data set that allows us to really leverage this 2-year lead time that we have in our launch compared to anything else that might be coming to the IgA nephropathy market. So it's really important that we continue to stay ahead of what may be other medicines and other classes that come to this community, and we think that it's going to be very important for us to take advantage of this 2 years, to establish FILSPARI as the new foundational therapy given the robust and consistent profile that we've seen to date.

Yes. That's helpful. Well, a couple of minutes left, I wanted to make sure and touch on the pegtibatinase program. We're expecting an update there later this year. What's clinically meaningful there when we're trying to interpret this data? And what are the next steps in development for the program?

Sure. We're really excited about our pegtibatinase program. This is a PEGylated enzyme replacement therapy for classical homocystinuria. This is a genetic metabolic disorder where patients really are not able to consume protein other than medical protein. So very challenging and can lead to thrombotic events in adolescents and early adulthood up to 50% by the time patients are in their 20s. So a high unmet need. We believe that pegtibatinase could potentially be the first and the only disease-modifying therapy in HCU. And really for success coming out of our Phase II program and our Cohort 6 at the highest dose we're studying, really would be incremental efficacy and a consistent tolerability and safety profile compared to what we showed at Cohort 5. In Cohort 5, we were able to demonstrate that within 2 weeks, patients were able to get -- all patients on pegtibatinase were able to get below the threshold of 100 micromolar of total homocystinuria. That's important because that's the threshold recognized in the literature that would help in substantially reducing the risk of some of these symptoms and complications. So what we would be looking for in our Cohort 6 is even further reduction in homocysteine levels so that we are able to then test the ability for what patients want most is to actually liberalize their diet. To be able to even just 1 day a week eat a normal diet with their family, with their friends. While we do absolutely need to stay focused on reducing some of the clinical outcomes in homocystinuria, we do really want to make sure that we're delivering on the #1 need that we hear from patients consistently. And so that incremental efficacy really -- it would allow us the ability to explore that potential.

Great. Well, with that, our time is about up, but I'd like to thank you, Eric and Peter for joining us today, and thank you, everyone out there for listening.

Thanks, Greg.