Okay, good afternoon and welcome to day one of the Barclays Global Healthcare Conference. My name is Carter Gould, covering US biopharma here at Barclays. I am pleased to welcome Travere Therapeutics to the stage. Already a very eventful year for Travere. Yesterday they completed their filing for their FILSPARI sNDA. Joining from the company, Eric Dube, President and CEO, and Peter Heerma leading the commercial front. Before we launch into Q&A, Eric is going to make some opening comments.
Excellent. Well, thank you very much for hosting us. We are excited not just about the year ahead, but also about the future within the rare diseases in which we play. We've got an incredible opportunity in both IgA nephropathy, where we expect FILSPARI to be a foundational therapy for these patients, helping them to delay or prevent kidney failure, as well as with our enzyme replacement therapy, pegtibatinase, that recently entered into phase 3 for the treatment of classical homocystinuria, or HCU, where we also believe that will be the only disease-modifying therapy in the foreseeable future, and really the only innovation on the horizon for patients that are desperate for something that is going to be able to address the fundamental cause of their disease.
We are really excited about the leadership role that we can play within these diseases, as well as the potential for us to bring sparsentan to the FSGS community that are really desperate for something in that devastating rare kidney disorder. We are well capitalized to be able to invest in these three priorities, and the launch, as well as our regulatory engagements for this year, have started off on a very strong footing, and we expect to see strong performance throughout the rest of 2024.
Great. I think that's a great place to jump off into the FILSPARI commercial launch. And I don't know if Eric or Peter want to take the lead here, but now that we've a little bit more than a year since you've launched, what are sort of the key learnings from year one? What surprised you? What are the takeaways?
Yeah, overall, I think we use my mic as well. Yeah. Overall, I think we are up to a very strong start. I mean, first year, launching a product, and both Eric and I have been involved in many launches, is really building the fundamentals, making sure there's demand by educating the physicians, making sure there's coverage, in particular broad access for patients, and making sure there's a first good experience for patients and physicians. And I think across the three fundamentals, I think we made really good progress. Continuous growth of demand, I think it's the first rare nephropathy product that showed quarter-over-quarter growing demand, and we're off to a strong start of the year as well. If I think from a payer perspective, really strong coverage in the first year.
We have now 90% of the patients that have a pathway to reimbursement, but also the criteria of those formularies are very strong. And we hear almost on a daily basis from patients and physicians about the incredible effects that they are seeing with FILSPARI, which is very consistent with what we saw in the PROTECT study. So I think very good progress. We had a good inflection in Q4 when we also presented our two-year confirmatory data, simultaneous late breaker session, as well as publication in The Lancet that really created a momentum. And since then, we also see that the majority of the thought leaders are prescribing FILSPARI, and that strong momentum continues in Q1. So overall, really pleased with the progress we have been making so far.
Let me add two other things that, from my perspective, we learned that are, I think, incredibly telling about the opportunity ahead. There's been a lot of discussion about how conservative nephrologists are as a specialty. And I think what we've seen, as Peter alluded to in the strength of our fourth quarter, was really in the presentation and simultaneous publication at ASN of our two-year data. That's really where we begin to see a step change in the number of new prescribers and in patient start forms. And I think it set us up very well for a strong start for 2024. So while there has been conservatism, there's also been a recognition based on a lot of the data that we've been able to support through databases and IgA nephropathy that really how nephrologists have been thinking about this disorder as a slowly progressing disorder has been wrong.
In fact, most patients are going to face kidney failure with IgA nephropathy within 10 years. And so there is a real growing sense of urgency that I think is helping to create the change in thinking and in prescribing moving forward. The second thing that we learned last year that I think might be surprising to some as well is that from a patient perspective, the REMS that we have in place, they see as a very strong support for their care. And I think that that's a critical part of why we see some of the highest rates of compliance adherence in the first year of launch that I've seen in any oral therapy.
We're very pleased with the feedback that we've received so far, and I think that that gives us great confidence and some really good insights about how we continue to invest in this launch moving forward.
Okay. So I definitely want to dig into the education piece a little bit more, but I want you to expand first on that last bit about how patients view this, the REMS as supportive of their treatment. Can you maybe just expand on that?
Yeah, Peter, why don't you share a bit more what your team's learned?
Yeah, you talked about the REMS?
The REMS.
The REMS, yeah. Yeah, I think, I mean, for physicians, this is an easy process, and they can easily conceptualize it as well. For the physician, it's really like one or two minutes to certify for the REMS program. What we learned in the beginning of the launch, and especially in the first 120 days, and you have to realize that FILSPARI was approved through accelerated approval, there is a limitation with how you communicate and what you communicate in the first 120 days. So we didn't have the patient-friendly materials. I mean, basically, you had the package insert that you could communicate to patients. So initially, there was a pocket of patients that wanted to have some further conversation with their physician when they saw a box warning and a REMS obligation.
Now we are past that, and we started that late summer, early fall, to have additional materials, more patient-friendly materials, patient videos, but also giving the right guidance to physicians, how to have the conversation with their patients, how to have the nurse educator, how they have the conversation with patients from Travere Total Care. And we see that we really made an impact. And one of the key indicators that we are following is how many of those patients are certifying within the first 14 days. And we saw a really strong improvement in those numbers, and that translates into patients that are being shipped commercial product. And that's what you saw in the inflection in Q4 as well. So I think the messages and the learnings that we took are materializing now also on.
Peter, why don't you expand a little bit more on what we've heard from patients and how that ties to their adherence and their clinical experience? I think that's a really important part of the REMS that has been really underappreciated.
Yeah, I think just to put it in context, in the last 30-40 years, no therapies have been improved for IgA nephropathy. And so now that there are products approved, it's the first time that patients also start to see like, "Hey, you know what? I'm taking something that actually works." Because you have to take in consideration, these patients are seeing their nephrologist at least every three months, sometimes every month. And every time they hear, "Your levels are still not to the target, but I'd like to go." So the patient always feels like, "I'm losing." Now with FILSPARI and the incredible proteinuria reduction that we are seeing, and we have 50% in the PROTECT Study, we hear that same feedback from physicians and patients as well.
For the patients, they feel for the first time, "We are winning against our disease." Actually, some other medications, they stop taking. I think that is so motivating for the patients. That puts the REMS into perspective as well. To Eric's point, that's why we see very strong compliance rates so far as well.
Okay. So as we think then over the balance of the year, the submission went in. Definitely getting questions around expectations for an adcom, yes, no. And then as you think about then upon full approval, what that might mean commercially.
Yeah, maybe I can start with the regulatory expectations, and Peter can speak about the dynamics for commercial performance. First of all, we expect that this will be a priority review with a six month PDUFA date. And certainly, we will provide that information once we hear from FDA in about two months in the acceptance letter. That's the first occasion upon which they might say that they would want to see an advisory committee. And certainly, that is a possibility. And if they do request an advisory committee, we will be prepared. We believe that there is a very strong case based on the evidence and the unmet need that the FDA will approve this. We don't feel that the probability of an advisory committee is all that high because the evidence is very clear.
While we missed narrowly on one measure of eGFR, the FDA has already publicly stated at ASN last year in November that they've learned a lot about the measurement of eGFR in IgA nephropathy, and they're moving away from the measure of eGFR slope. In the pre-NDA meeting, they've asked us to provide all the sensitivity analyses on other ways of eGFR. In that ASN meeting, they indicated that what they really are looking for is an accumulation of benefit on kidney function or eGFR over time. That's precisely what you see in the two-year data from PROTECT when we go against a head-to-head active comparator. What we see at one year is a 1.7 milliliter per minute difference. At two years, that continues to improve and accumulate, where it's a 3.7 milliliter per minute per year.
Both of those time points, very clinically meaningful, but importantly, statistically significant nominally when you account for the total slope analysis. And again, clearly reflects an accumulation of benefit that they've stated that they're looking for.
Okay. Yeah, building upon that, I would say based on the fundamentals that I was describing before and how we established that in 2023, we are off to a strong start of this year as well. And the reason why I'm so excited about the year ahead is basically for three reasons. First of all, we expect the new global guidelines to be updated in the near term. That's probably somewhere in the springtime. I think for two reasons, that's important. I think FILSPARI will be included as a foundational treatment option for patients that fail ACE inhibitors and ARBs, which is the vast majority of patients. But also for a second reason is that based on the investments we have been making and that we have been initiating in registry data sets, much more understanding of the disease has been established right now.
This is, to Eric's earlier point, a much more rapidly progressive disease that is diagnosed mainly with young adults, patients in their 20s, 30s. They're on a path of kidney failure in 10, 12 years. And so with that data that was not established before, the KDIGO guidelines, the global guideline committee also wants to update the guideline and go to a lower proteinuria target. Why that is relevant is that it opens the addressable patient population for FILSPARI. At launch, we said we anticipate that the addressable patient population in the U.S. is about 30-50,000. With that broadening of the guidelines and potentially also the broadening of our label, we think that opens up to 70,000 patients. So that's why I'm excited. First reason, the update of the KDIGO guidelines.
The second is what Eric was talking about, the full label and the confirmatory label that we expect in the second half of the year. We anticipate there will not be a proteinuria threshold that we have right now. And I think that is relevant for physicians because they see a validation of their choice. But it's also important for payers because I was talking about a broader patient population, but the payer always has restrictions in their criteria. But if you have a broader label accompanied by also a guideline that goes for a broader patient population, that criteria would also become lower and opens up more reimbursement opportunity for patients with lower proteinuria levels as well. So that's the second reason. The third reason is that we are anticipating an evolving landscape as well.
I think in the future, with also lower proteinuria targets, you would expect also that you will see more combination therapy. You have multiple modalities right now. We anticipated that, and we already have data in combination with SGLT2. Some of the data we have presented at ASN, we will have a continuation of data revealing this year. Then we have also first-line therapy and patient naïve first-line patient setting. We presented some data last year at ASN. You saw an incredible 80% reduction in proteinuria with basically an eGFR that remained stable. I think we are well set up for different patient categories and different patient profiles in an evolving landscape. I think the trajectory for growth for FILSPARI remains very strong.
So we didn't plan that segue, but you couldn't have done it any better, Peter, in terms of discussion around some of these new mechanisms of actions, disease-modifying therapies. It's ironic that while you're showing so much momentum, the street has become sort of myopically focused on BLA in April and changes, as we were talking about earlier, to a little bit more of a winner-takes-all perception. Can you talk about the role for sparsentan in a world where you might have these new MOAs?
Yeah, I'm happy to kick it off. And Eric, I'm sure you will join on that one. I think it's really where do you play? There's damage in the kidney that you need to address. Proteinuria is a marker of damage. And when IgA, the IgA complex, is depositing in the mesangium, you see an upregulation of angiotensin and endothelin. Those are bad actors that amplify damage in the kidney. And so you want to address those. Historically, physicians have been addressing that with angiotensin inhibition, but endothelin also upregulates angiotensin. So even though you inhibit it, you have a continuous feedback loop. So you need to have that dual inhibition. And that's why you see the effect with FILSPARI, the strong proteinuria effect with FILSPARI. The newer modes of action, modalities that may come to the market, and it's still early days.
I mean, it's phase 2 data that you are referring to is more upstream and is more with the production of the IgA complex. So I think ultimately, there will be a place for both because I think they are inhibiting in different pathways in the disease continuum. But you have to realize all the new modalities are studied on top of RAS inhibition. And so RAS inhibition, that's where FILSPARI's place. That's what we are replacing. And then for some patients that don't see the levels of proteinuria that they want, there are additional modalities.
Well, I think if I can take it from a high-level perspective, let's look at how patients are being treated today. Based on when patients are being diagnosed, patients with IgAN are being diagnosed based on a biopsy. That biopsy shows very clear damage in the kidney. It means that patients are being caught currently. And I think for the foreseeable future, nothing's going to change in the diagnostic route. Patients are already showing both activation of their immune system, so that upstream approach, as well as damage in the kidney. And the way that nephrologists are treating is the use of RAS inhibition to be nephroprotective and to tamp down that overactivation in the kidney. And they're using steroids, the only real tool that they have to tamp down the immune system and that upstream.
What's really exciting for the future of IgAN and for this community is that there should be tools that will be able to address both of those with therapies that are developed specifically for this disease. So as we think about the evolution and the superior profile of FILSPARI as that foundational therapy addressing the kidney, as Peter mentioned, you have to address both RAS as well as endothelin. We clearly see the superior profile from our trials. There likely is going to be, with the B cell, potentially complement, the ability to more effectively target that upstream overactivation in the immune system.
So this two-pronged approach that physicians are using now of treat the injury in the kidney and prevent further injury in the immune system is exactly the same paradigm that we expect to see in the future, which is address the injury with FILSPARI in the kidney and then address and prevent further damage by potentially APRIL/BLyS or other mechanisms. So this whole idea of one therapy is going to address it all is, I think, certainly not aligned with the nephrology community. And it's not aligned with the science. So I think it's really important for us to see that combination is going to be critical in preventing these patients from entering kidney disease. It's going to require that combination. And I think that that's going to absolutely expand the opportunity in us helping more and more patients in the future.
From a strategy perspective or clinical development strategy perspective, does this mean we're going to see more combination strategies or combination trials from you, or is this going to be something more that they're going to have to come to you anyway and you're going to be well-positioned to diagnostic or pick and choose?
Yeah. I mean, look, this is rare disease. The best innovation that we've seen and the improvements in clinical care have been through collaboration, whether it's with industry, with academia, with regulators, with the patient community. It is a very unique opportunity within IgAN that we have so many different mechanisms. As we're doing with SGLT2s in the two trials that we are supporting, I believe that there likely is going to be more of that in the future. But I think that typically occurs after phase three is completed. What we're encouraged to see right now is that endothelin receptor blockers, including FILSPARI and SGLT2s, are being considered as standard of care in many of the phase threes that are currently ongoing. I think that really reflects the aligned view that we have for the future of this two-pronged approach.
Certainly, we would be open to combination studies because I think that's going to be in the best interest of patients.
Okay. There's plenty more where you go into FILSPARI, but I don't want to give short shrift to Peter Heerma because I think it goes underappreciated a lot. We did a deep dive, I think, late last year on this. You're moving into a pivotal study right now. I think the first thing, it may be just helpful to frame for folks either on a relative basis to other kind of rare diseases they may be more familiar with, but just sort of the opportunity here and maybe some context in terms of the lack of historical treatments.
Do you want to talk about the opportunity first?
Yeah. So for pegtibatinase, I mean, it's really like enzyme replacement therapy, first disease-modifying therapy in development with very little competition in the field. There's basically nothing behind us. It's a large opportunity. We see 7,000-10,000 patients worldwide. And like I said, there is basically no treatment for the patients other than B6, vitamin B6, and betaine that have been around for quite some time. And so I think it's really an opportunity for us to establish pegtibatinase in that treatment.
Okay. As we think about the HARMONY Study that's kicking off, can you walk through kind of the key nuances to kind of demonstrate that clinical benefit to the community?
Yeah. Why don't I take that one? So I'm very excited and proud of the work that our team has done in working with regulators on what is an innovative trial design. One of the biggest risks that therapies like this have in a metabolic disease where diet is part of the insult in the disease is how do you control patient behavior and how do you control the diet, particularly during the double-blind period? Now, we hear very loudly from the patient community that the number one goal that they have is to be able to eat a normal diet. And they want to be able to have protein in their diet because they are on such a severely restricted diet that in and of itself is not just socially challenging, but can present some complications for their health.
What we see in this trial design is first a 10-week screening period. That's pretty extensive for a screening period. We want to be able to do two things. The first is to be able to ensure that we have steady homocysteine levels so that they are elevated enough to enter the study, but also to be able to ensure that the patient's diet is stable during that period of time. Because if they can be stable in that period of time, then it's more likely that they're going to be stable during the six month double-blind period and not eat into their treatment effect or introduce unnecessary variability. That's a critical part of the trial design. We enter into the double-blind period, which is pegtibatinase versus placebo.
We're going to be looking at the efficacy of reduction in total homocysteine between weeks of six and 12, much like we've done in our phase 2. Essentially, if we can replicate what we've done there, we should see a profound reduction. In our phase 2 study, we saw 67% reduction in total homocysteine compared to no change on placebo out to week 12. All patients were able to get below the therapeutic kind of threshold of total homocysteine of less than 100 that reduces their risk of complications in this disease. We have some patients that were able to normalize their levels and reintroduce protein into their diet. So we're going to measure total homocysteine between that. Then we're going to look at the durability of that out to week 24 and continued safety exposure out to week 24.
What gets really interesting is what happens after the double-blind period, where patients enter into an open-label extension period, and they're able to then, in a protocolized manner, increase their protein intake so that we can measure how much protein they're able to take and still maintain control of their homocysteine levels. That is what's the most interesting to patients. But it's also interesting to regulators who see this not only as a patient-reported outcome, but potentially evidence of a clinical benefit. And so the agreement we have with FDA is to study total homocysteine as the primary endpoint, as a biomarker for full approval, but with support potentially for introducing more protein into their diet, which should not only be better for the quality of life, but ultimately the overall health of these patients.
As we think about those protein measures, is it being necessary for ultimate submission, or is that something that would just play out over the course of multiple years thereafter to supplement the profile?
Right. So it's not required for the submission. We do feel strongly that we want to have that evidence because it is the number one need that patients tell us and was the number one need that came out of the FDA's Patient-Centered Drug Development panel in the fall. So we do want to make sure that we have evidence to be able to speak to that. But really, what the agreement with FDA is to be able to have reductions in total homocysteine given the evidence that we have and in the literature linking that to the complications of this disorder.
Okay. Just given the small size of the population and the fact that we haven't had trials in this space much before you guys sort of started, just your level of confidence that you'll hit the timelines in terms of enrollment and that we could have data in—I can't remember if you guys got it at 2025 or 2026, but.
2026.
2026. Yeah.
We're confident. The patients are out there. They're raising their hands now that they know that the phase 3 study has started, whether they want to be part of the study or they want to know when pegtibatinase will be available for them. We also have done extensive work to understand where these patients are being treated for clinical trial sites. Like we have 100 patients in our natural history study, we're confident we'll be able to identify these patients. We want to make sure that we do this the proper way so that we're able to have not just meaningful data for regulators, but we make sure that diet is managed, but then that we're able to potentially liberalize diet in the end.
Okay. We're going to have to leave it there. But Travere, thank you very much for joining us on stage, and best of luck with the FILSPARI launch.
Great. Thank you.
Thank you.