Okay. Welcome, everyone. My pleasure to host this Fireside Chat with Travere Therapeutics. I'm Joe Schwartz from the Biotech Equity Research team at Leerink Partners, and I'm very pleased to be joined by Eric Dube, CEO, and Peter Heerma, Chief Commercial Officer. Thanks so much for being with us and giving us an update today. Of course. Thanks for having us. Maybe we can start by just having you give us a quick level set in order to bring us up to speed on all of your latest progress and the goals that you expect or you hope to fulfill this year in 2025. Sure. 2024 was an outstanding year and a really critical year in laying the foundation for Travere, but I'd say even more importantly for a transformation that we're seeing within the rare kidney space. We received full approval of FILSPARI for IgA nephropathy, which really allows for a much broader patient population that could benefit from FILSPARI. Near simultaneously, we saw a very important update from the global guidelines, the KDIGO Guidelines, that also advocated for a much more aggressive approach to treating this disease that historically has been seen as really slow-progressing, lower risk. We know that's not the case. It was really nice to see the guidelines really pushing for that, which is really our number one goal as we go into 2025, is continuing the great momentum that Peter and his team have had with the launch of FILSPARI, establishing it as the new foundational therapy to replace the role that ACEs and ARBs have played for the overwhelming majority of patients and also the overwhelming majority of patients are failures to those therapies that never get close to remission. Our second goal, which is incredibly exciting to us, is to potentially bring FILSPARI to the FSGS community. This has been an area that we've been working on for over 10 years. It's an area that has no approved medicines, and it's one that, with our successful data in proteinuria in the context of the PARASOL findings in the fall, gives us the opportunity to be able to submit an SNDA more on track to do that within a month. Our third priority, which is longer term but still incredibly important, is pegtibatinase in classical homocystinuria or HCU. This is a community that really has not had much innovation at all, and it's one where pegtibatinase as an enzyme replacement therapy really could serve as a really game changer for this community. This year is important in all three of those and really sets us up for very strong growth in the near and the long term. Great. Okay, so thanks. FILSPARI's had a really nice launch so far. Where do you see how would you envision where we are in terms of the phase of the launch? Can you put that into perspective based on your understanding of where we are on the adoption curve? Sure. Yeah, absolutely. I think overall, really strong progress, especially in Q4 of last year after we got the full approval to Eric's point. The broad label really created a momentum. We saw basically a 40% growth both in patient start form as well as in revenue. If I look at comparing FILSPARI now to the most recent three other rare and orphan launches, we outperformed basically on every KPI and over 30% in revenue. Very strong on the continuation of the launch. I think to the point that you made earlier with FSGS, I think there will also be a halo effect on IgA nephropathy if there is a broader utilization for the product. I think the way I think about where we are in the launch is very bright. Great. If we were to zero in on the new treatment guidelines, can you remind us what these say and how FILSPARI's positioned in light of those? Yeah, I'm happy to take that one. I think there's two elements that really helped FILSPARI in driving growth. One is the target proteinuria levels was reduced basically from 1 gram per day to 0.5 or preferably 0.3 grams per day. Basically full remission, that's the new target. To Eric's earlier point, historically, IgA nephropathy was seen as a relatively benign disease, a more slowly progressive disease. Based on the work that we did investing in registries, now physicians are much more aware that this is actually a much more progressive disease. The guidelines incorporate that as well and basically say now full remission is the target. I think that's number one. The second one is the positioning of FILSPARI. The guidelines basically say that FILSPARI is the only product that has shown head-to-head superiority versus the established standard of care or the historical standard of care ACE and ARBs. That really helped us, one, to position FILSPARI in the broader patient population, but two, also to get across that superiority claim versus ACE and ARBs. Maybe the third thing that I'll add about the KDIGO Guidelines is really to address what I think within the investor community is the debate around where do these emerging innovative classes fit. The KDIGO Guidelines, seeing the potential evolution of the treatment landscape, really laid out a nice framework that should be robust regardless of what comes to the patient community. That is that this is a disease that requires simultaneous combination therapy at diagnosis. That's very, very, and talk about aggressive treatment. It's really aggressive and shifting from the conservative of start with one, then add another. It's combination therapy, and it's addressing the two core defects in this disease. You have to address the kidney damage because by nature, every single patient that is diagnosed at biopsy has chronic kidney disease as part of their IgA nephropathy. That requires a therapy, a foundational therapy that is non-immunosuppressive, and it addresses mechanisms of damage in the kidney. That's where FILSPARI fits in. The other aspect of the treatment paradigm is the immune overactivation, which is the etiology of the disease, but it's complementary to what goes on in the kidney. Historically, steroids have addressed the overactivation and the immune suppression, but in the future, complement B-C ell will fit in. It is not an either/or. Nothing is curative and nothing is a winner takes all in terms of the treatment landscape. It's about combination therapy. That really sets FILSPARI up nicely to be the new foundational therapy. Really the only competitor that we see are generic ACEs and ARBs that we know fail most of these patients. Okay. Yeah, very helpful perspective. You have a lot of experience now commercially and in dealing with payers. Is it your sense that they'll be aligned with this need? Do they appreciate the total cost of ownership of these patients who go on to consume a lot of healthcare resources if their proteinuria is not under control? Yeah, if I look at the payer front, I think we have made incredible progress with the rate of patients that have access to care. Over 96% of the patients in the U.S. have a pathway to reimbursement for FILSPARI. That's incredibly strong. I think where you're alluding to is like an evolving landscape and you have new products, also modalities that are impacting the overactivation of the immune system. We don't know yet what the price is. We can only control what we can control ourselves. That is that we have a very strong inclusion in the formularies, but also we priced for broad access. I mean, FILSPARI is priced for broad access, and that's also being reflected in the current formularies. New modalities that come to market have to make the case that they should be added on top of that. To Eric's earlier point, I think what I really liked, Professor Jürgen Floege from Germany, who is the chair of KDIGO Guidelines, he basically made the case when KDIGO was introduced, you have kidney damage. Patients that show up in the nephrology office have kidney damage. You have to target the kidney damage in addition to the overactivation of the immune system. The nephroprotective effect of FILSPARI is well known, and I think that is being reflected at payers and formularies as well. Yeah, I think just to add an additional layer thinking about what payers really are looking for. Of course, they want to have the data from the phase three as well as approval, but the quality of evidence is really important. The data from our phase three PROTECT Study is the only head-to-head data. Everything else is placebo-controlled on top of standard of care. That level of evidence in the eyes of a payer is really important because it tells you why are they making a decision to invest in something like FILSPARI versus something like ACE or ARBs. They're not going to have that level of evidence with all of the other therapies that are coming that are looking at, from a positioning standpoint, replacing the role that steroids have historically played, but with a lower level of evidence because you're not looking at head-to-head. I think that's really the question that payers are going to have is we know where FILSPARI fits in. Yeah, where do the rest of them fit in relative to the generic therapies that are there? I would take it even one step further. It's the head-to-head, but it's also now we have the full approval and you have demonstrated that impressive 50% reduction in proteinuria actually results in long-term kidney preservation as well. New entrants to the market, they won't have that data, and most likely they will have a more limited label as well for more rapidly progressing patients with proteinuria levels of 1.5 and higher. To Eric's point, I think we have the highest rigor of evidence, both head-to-head as well as long-term data. Yeah, the value proposition seems pretty clear. It is striking to see that you've been able to achieve such strong uptake in light of a liver REMS, which you're working to hopefully ease a bit. Can you give us the latest update on that front? Sure. We do have an accepted SNDA for that REMS modification, and we have a PDUFA date of August 28th. We are very pleased with the engagement with the agency, both before submission as well as with the SNDA in. Our current assumption is that we are on track for that modification. I think what is important is that the REMS as it is now has not been a barrier for patients that we have been able to treat. The question is how many more patients have their nephrologist decided, this is a patient that may not be compliant, and I am not going to offer FILSPARI. For something like FILSPARI that is so unique relative to other treatment options, we want to make sure that it is available for all of those patients. We have been incredibly pleased with the performance to date, and we believe that the best is yet to come. Yeah. Is there any way to contextualize? Actually, let me just back up a bit and first ask, what was the proposal that you brought to the FDA exactly? Sure. Based on the existing data from clinical trials as well as the exposure within the commercial market, we continue to see no cases of drug-induced liver injury. What we've said is that the current framework for the REMS, which is liver testing once a month for the first year and then quarterly thereafter, yes, of course, that's going to help in figuring out who may have elevated AST/ALT, but the burden for patients is far too great, particularly relative to the fact that we've not seen any cases of liver damage and that it is much more frequent testing than what we did in our phase two and phase three where we had very good kind of safety oversight. We have asked for a shift from monthly in the first year to quarterly, which is much more aligned with how the average IgA nephropathy patient is seeing their nephrologist and getting their testing done. Okay, great. Maybe we should shift to FSGS. The more things change, the more they stay the same, right? I mean, this is how the story started so long ago. I remember when we began covering you, and you're getting great traction now, it seems, in the community where there's a lot of demand. Can you just update us on the latest initiatives there as it relates to PARASOL and the FDA? Sure. I think in the context of FSGS, this is one of the most proteinuric rare kidney diseases. It is a heterogeneous disease, which makes it difficult to study because it's not a singular disease. It is a podocytopathy, is the way in the kind of way that nephrologists and experts in the field think about it. When you think about this disease in the context of sparsentan, sparsentan has a direct effect on podocytes and is one of the most antiproteinuric medicines that has been studied. Of course, it's a very good fit for FSGS. What I would say is our phase two and phase three in some ways was ahead of its time because we've been working, as you alluded to, for 10 years. We've learned along the way. We've learned from our phase three, which is the only phase three ever done in this study. I think the conclusion that is now being drawn from our study as well as PARASOL is eGFR, while meaningful in any kidney disease, is not feasible in a clinical trial setting and as a regulatory endpoint because of the heterogeneity in this disease. Very different from IgA nephropathy. We could have assumed that years ago, but we didn't know. Now we know. PARASOL has now said, you've got to understand that proteinuria is independently predictive of longer-term outcomes, which is largely what we see in our phase three program. When we now take a step back from PARASOL and engage with the FSGS thought leader community, it is consistently positive, saying, of course, we need to have FILSPARI in our armamentarium. We know the effect that it has on podocytes. We know the effect that it has on proteinuria. Even though the study was not powered to show a difference in hard endpoints in kidney failure and dialysis, you see a 50% reduction in the number of patients that were getting those endpoints. It is a really exciting time. For us to get a file into the FDA is our next step, and we are very excited about where we are. Yeah, that squares with a lot of our checks. How are you thinking about whether or not the FDA might want to convene an adcom in order to review this, just considering there's been so much back and forth with the agency? It seems like it's been a very organic process, which is good because it's data-driven and it's robust from that perspective. I'm just wondering procedurally if the FDA is going to want to do that. Yeah. We'll certainly know whether FDA wants an advisory committee or not by the time the file is accepted. So roughly 60 days after the file goes in. You're right, this has been a very organic driven from the community, both nephrology as well as patient community, which is in large part how a lot of innovation happens within rare disease. There is precedent for these things to happen. I think what we're seeing coming out of PARASOL and this movement is a consensus that proteinuria should be an endpoint for full approval. In fact, we heard that from Eliza Thompson, the Director of Cardiorenal, as part of the PARASOL readout that the FDA really does foresee approving for full approval, something like a proteinuria based on a proteinuria endpoint. Now, with regard to whether there is going to be an advisory committee or not, you can make an argument either way. You can say that in the context of PARASOL, there is consensus around the endpoint if that's the question that FDA has. On the other hand, they can say, this is precedent setting. This is the first potential full approval on a proteinuria endpoint, and we may want to be able to have the public forum that an advisory committee has. At this point, it's anybody's guess, and we'll be prepared regardless. Yep. Okay. Great. How do we think about, how do you think about the commercial opportunity in FSGS? These are a lot of the same doctors, but the patients are a little bit different. Help us think through that. Yeah, I'm happy to take that one. I think the commercial opportunity in FSGS is even bigger than in IgA nephropathy to the point that you're making, like this is basically the same prescriber base. Over 80% of the prescribers are the same as for IgA nephropathy. You build upon a very strong brand awareness. Many of the physicians have already experience with FILSPARI. Through the conversation that we just had from a payer perspective, we have a very strong placement in formularies already. You build upon a strong base. There are slightly fewer patients in the U.S. We think there is an addressable patient population at launch of about 30,000 patients, but it's linear pricing. We expect from a pricing perspective, you have an opportunity there, and there is no competition basically. I mean, it's a wide space. We really have an opportunity to occupy this field. Other than IgA nephropathy, where you really had to establish the urgency to treat earlier to the point that I made earlier, historically, IgA was seen as a more benign disease. Every nephrologist really understands the high urgency to treat those patients and treat those patients more aggressively. High unmet needs, well-established urgency to treat patients earlier and a very strong established brand awareness and experience level at nephrologists, coupled with strong payer access, I think will allow for a very rapid uptake in FSGS. Interesting. I understand that there's an overall higher urgency to treat, but I also hear so much from the physicians that see these patients that it's so heterogeneous and almost a diagnosis of by biopsy, and some of the biopsies are scary. Are there any particular patient subgroups that within this setting are the most urgent to treat? Yeah, it's a great question. This is an area where I suspect that with additional clinical data and with additional companies looking to go into FSGS, we're going to learn more. We're going to learn more as we are seeing different subsets of FSGS are going to require different potential therapeutic approaches. If we think about what we know today, there are four categories of FSGS. There's primary FSGS, which is typically driven by a circulating factor thought to be within the immune system. There is genetic FSGS, and there's a panoply of different genotypes that may lead to FSGS, APOL1 being one of them as an example. There is secondary FSGS, which is secondary to another condition such as diabetes, hypertension, infection. The cause-effect of those is often uncertain because you've got to follow these patients for a long term. There is unknown causes as the fourth. We are starting to see much more targeted areas of focus. For example, APOL1, which is about 10% of FSGS. There is anti-nephrin as a potential immune-directed therapy. That is about 10%-11% of FSGS. There likely will be some segments for those therapeutic areas. As we think about sparsentan or FILSPARI, what we have been very pleased with is regardless of what the etiology of this disease, you see a consistent benefit of about 50% reduction in proteinuria. Even the most difficult to treat, the most refractory and steroid-resistant patients, the genetic patients, we see a consistent benefit. That was really eye-opening to the nephrology community when we presented those data at ASN in the fall. From our standpoint, when we think about the opportunity of FILSPARI, it does not matter where you start with FSGS. If you have proteinuria, FILSPARI would be the foundational therapy, that non-immunosuppressive kidney-targeted therapy. That then potentially may serve as the kind of basis upon which you can add more targeted therapies in the future if they are successful. Yeah, that's super helpful. Yeah. I mean, the consistency of effect, I think that impresses me most of this product. I mean, Eric was talking about the 50% reduction in proteinuria in FSGS. We saw the same in IgA nephropathy. What we hear on a daily basis from nephrologists is basically, with a few exceptions, basically every nephrologist talks about the rapid and sustained proteinuria effect. Basically, the next time a nephrologist is seeing the patient, they have 50%, 60%, 70% proteinuria reduction. That is really the consistency of the effect across what we're seeing and hearing from physicians. Great. Why is the dose twice as high in FSGS? Is that consistent across all the different subgroups? I know that, yeah, we'll pause there. Yeah. I think when we look at our phase two study, we did study 200 mg, 400 mg, and 800 mg. We did see that for adult patients, 400 mg and 800 mg, you do see a benefit in reducing. There is a marginal difference between the two. What's important is when you look at the pharmacokinetics and pharmacodynamics of the medicine and you take into account also that sparsentan is highly protein-bound. When you think about how proteinuric these patients are, they're basically peeing out a lot of the protein. You want to make sure that you have enough sparsentan in your system to be able to have the coverage. When you think about that in FSGS relative to IgA nephropathy, increasing the dose allowed for sufficient exposure to have the benefit in the broadest number of patients. There are other earlier studies with other therapies that looked at the same dynamic where they had to go up in dose in order to have the effect. Right. Is that the same for children as well as adults? For children, the dose is half. For FSGS, you would start at 200 mg and then up titrate to 400 mg as the target dose. Okay. Great. Why don't we shift gears to pegtibatinase and HCU? Maybe you can just start by telling us where you were in development before you hit the speed bump and what needs to be done in order to resolve that manufacturing issue. Sure. Last year, we were very pleased to have started our phase three program. This was based on very strong engagement with the FDA. We have breakthrough therapy designation, so we had very good engagement. This is a very innovative trial design because not only do we want to replicate what we saw in our phase one two, which is a standard reduction in homocysteine levels, which is central to the theory of why you see the clinical outcomes, but also central to the core kind of enzymatic defect. We also wanted to be able to address what is the number one need of patients. We were working with FDA on an endpoint that also allows for liberalization of the diet. Essentially, the standard of care for these patients is restricting protein oftentimes to less than 10 grams of protein a day, plus a terribly tasting medical protein powder. This is what patients want and really need for their overall kind of health and well-being. We were able to protocolize that. We had initiated this phase three. There was a real excitement within the community to enroll. There was an additive incentive that they might be able to increase protein in their diet. All of that was going very well. We ran into an issue with manufacturing where we go from clinical scale manufacturing to commercial scale. Very common to kind of run into challenges. This is a challenge that we ran into that our CDMO partners had seen before with these types of therapies. We decided that while everything was within spec, some of the companies have run into challenges later, particularly in their file, that we wanted to say, let's pause. Let's resolve this. We know that it's resolvable based on the experience of our CDMOs. The best thing to do is to pause enrollment of further patients, continue those patients that are already enrolled through to the completion of the protocol. We're on track to be able to do that. We've seen really good progress with our CDMO partners, but we've also seen really good progress in identifying further patients so that when we do open enrollment, we're on track to do so next year, that we'll be able to accelerate the rate of enrollment. Great. Okay. What does the market look like in HCU? I imagine it's really underserved, obviously, with nothing but very traditional means of trying to manage these patients. What does Travere hope to do in order to develop the opportunity? Right now, if we think about the addressable population, these are patients that are actively under the care of a physician that have a diagnosis of classical homocystinuria and have elevated homocysteine levels. That's about 3,500 patients. When we take a step back and look at those patients that are diagnosed, there's about 12,000 patients. We believe, like so many other rare diseases, that this is one where the diagnosis rate is low. Also, the number of patients that are under the care actively of a physician is also low. I'll explain that in two reasons. The first is this is part of the newborn screening panel. Because the methodology looks at methionine levels rather than homocysteine levels, which does vary at birth, you get about a 50% hit rate. Fifty percent of babies that are born with classical homocystinuria go undetected until they have clinical symptoms like lens dislocation, psychiatric issues, bone malformation, or God forbid, what, 50% of these patients have by the time they're 30, an ischemic event. That may precipitate a diagnosis. There is really an opportunity to do that. We've been working over the last couple of years to modernize newborn screening for HCU and to do other methodologies to be able to catch these patients earlier. That's a longer-term play that we believe will be able to help serve these patients and catch them earlier. The other aspect of this disease is these patients, what else is there that a treating physician is going to say, typically a metabolic specialist, then watch your diet? Who wants to hear that? You actually hear patients, by the time they become young adults, they actually fall out of care. That is where you typically see patients' homocysteine levels rise because they are now adults. They have been under this restrictive diet. Teenagers and young adults like to form their own identity, and they start to have liberalized their own diet. There is a real opportunity for education, for giving them something more than just scolding them on diet and catching them earlier. Those are the things that we believe will be able to help in reaching more patients. We believe it is certainly far greater than the addressable population that exists today. One thing to add, Eric was talking about 3,500 patients and 12,000 patients. That's in the U.S. alone. In Europe, we anticipate a similar amount of patients as well. Fantastic. We covered a lot of ground, but we're out of time. We'll leave it there. Thank you so much for the update. All right. Thanks, Joe. Enjoy.