Started again here, and thanks to anyone for joining us for the Guggenheim Biotech Conference this year and for day 2. Today, I'm Vamil Divan, one of the biopharma analysts here. Next up in this track, we have Travere, and I'm pleased to be joined by Christopher Cline, the CFO of the company. We're going to do a fireside chat format, so I have some questions that I'm going to try and get through, but if any of you in the room want to ask a question too, please just raise your hand and we can work that into the conversation. So, Chris, thanks for taking the time to join us this year. Obviously, a lot going on in the company with FILSPARI getting on the market, obviously pegtibatinase. I think a lot of interest and excitement there as that moves into phase 3 now.
I want to start with FILSPARI, and maybe just before we even get to that, just a quick overview of the story for people maybe a little bit newer to Travere in terms of the progress you've made to date, and then we'll get into the details on the program.
Sure, great. Thanks, Vamil, and thanks, Guggenheim, for having us. And before I jump in, I will be making forward-looking statements, so please make sure you review our risk factors and all the information on our SEC filings that can be found on our website. But at Travere, we're exclusively focused on rare disease, and really our focus is squarely focused on two areas or two medicines that have the potential to become new treatment standards in markets that are in excess of $10 billion. And really the first of those is FILSPARI, which got accelerated approval last year for IgA nephropathy, a rare kidney condition, and we're still working on a second indication, potentially an FSGS, to add to the label.
And that launch has gone, which I'm sure we'll talk more about here shortly, but has gone well in setting the foundation in the first year, and we're very excited about what's to come in 2024. Then we also have pegtibatinase, which is an enzyme replacement therapy for a disease called classical homocystinuria. We're very excited about this program because it has the potential to be the only disease-modifying therapy for these patients in a market that we expect is going to continue to grow in terms of the patients that are going to be diagnosed and treated over years. Certainly a lot going on and exciting 2024 ahead.
Great. So maybe let's start with FILSPARI, and maybe if you can just kind of give us an update on the progress you've made today, almost a year now to the day of the initial accelerated approval. So the feedback you're getting from both the patient side and the physician side, and in terms of kind of the patients that are getting on therapy, there's the REMS program associated with it, navigating that component of it. So just kind of how things are going. Obviously, we'll wait to see. You've already pre-announced some of your results, but just kind of the details behind that would be helpful.
Sure. So it's actually it's a well-timed question because I just returned from our national sales meeting that we do every year, and I've been to a number of them over the years. But this year was particularly exciting to see the high energy, and I think the team feels very good about where we ended the year, and you could really feel that. But even more importantly, it was great to hear directly from patients and their families how they're having a positive impact from FILSPARI in their lives. And I think that that's a great way of thinking about the launch overall. What we've heard from both physicians and patients is that they see a rapid and sustained reduction in proteinuria.
They know that that will portend to a kidney benefit over time and that it's got a favorable safety profile that they feel confident in using long term. You asked a little bit about what kind of patients are coming on in the early stages. That's going to be the patients that are going to be more progressive and especially aligned with the label that says generally 1.5 grams. We're certainly seeing that. I think as physicians gain their experience, as you typically see, we're seeing more patients that are while they're still aligned with the label, you're seeing more flexibility around that and patients are moving early or physicians are moving earlier to treatment.
When I take a step back and look at 2023 as a whole with the launch, I think we did a very good job of setting the foundation, and really that was focused in three key areas. One is demand and making sure that we had high demand from physicians, and we saw that certainly with FILSPARI as the only non-immunosuppressive treatment available for IgA. But we also wanted to make sure that we had broad access for patients. And so a key focal point there was engagement with payers, and we got to approximately 70% of U.S. lives covered by the end of the year, which is a great achievement for our team. And we also saw an inflection in net revenue throughout the year as the whole fulfillment process and demand continued to align. And so we made great progress on all those things.
You asked about the REMS. We certainly, while we made that progress, we had to work through the early restrictions that come with accelerated approval. So you're sort of restricted in the first 120 days in how you can market. So we managed through that. Then our team adapted to some of the things that we learned about the REMS program. And when we overcame some of those challenges, we really did see the really the fourth quarter results that ended the year very strong. And maybe specifically on the REMS, what we saw was there was a subset of patients who in the early stages of the launch, they didn't quite understand the full meaning of the REMS.
When we had additional education that we could provide for both physicians and patients and then do additional onboarding work with patients as they were getting prescriptions written, you saw that change meaningfully. The leading indicator of that for us was the number of patients who were certifying for REMS within 14 days of having a prescription written. That correlates directly with the number of patients that are initiating therapy each month. A lot of great progress to end the year, which gives us a lot of confidence going into this year.
Okay, great. That's very helpful. So one quick point I wanted to touch on because we've talked about this, but some of the other companies in the IgAN space this week is sort of your view of the market and sort of the market potential overall. I think we see a lot more interest in IgAN, a lot more interest from doctors, potentially biopsy patients, and also maybe treating to lower targets and not being as sort of maybe passive in how they manage. I'm wondering about how that sort of you've seen that evolve over the year on the market and as you look forward, just the opportunity more broadly in IgAN for FILSPARI.
Sure. Sure. So I mean, it's certainly been an exciting evolution. I mean, I can remember when we first started working on PROTECT, there was very little in development for IgA, and now there's a significant amount. And with that, greater awareness and greater action among physicians and patients. I think that one of the other big things that we expect to come through that's really going to help catalyze that further are the KDIGO guidelines. And so with the KDIGO guidelines, what we're expecting are two things that are relevant for FILSPARI, one being FILSPARI included for the first time into the KDIGO guidelines. And so that gives a standardized place for physicians to look to the treatment paradigm and how to use FILSPARI.
But then also if what we're hearing is that there's a potential that they're going to lower the treatment guidelines for when to start. And so right now it's around 1 gram. If they lower that to something like 0.5, that's going to open up earlier diagnosis. It's going to open up earlier treatment. And I think that that's great for all medicines in IgA, but specifically for FILSPARI because we are working towards that foundational care. And so when you think about the evolution of where things are going, what we believe, and this is shared with many of the KOLs that we spend time with, is that you need that foundational care that's going to be taking care of the damage that's specifically happening in the kidney.
FILSPARI, historically, that role has been played by ACEs and ARBs, and FILSPARI is looking to replace that. Then you'll have for patients that need it, the other approaches that need to come from either somewhere upstream or around that area that can add on additional benefit. So when we look back at even prior to launch, one of the most desired combinations was FILSPARI plus SGLT2 for that reason, to be able to have that sort of one-two combo. I think you're going to continue to see that just whether their modality is coming through.
Okay. You mentioned PROTECT, obviously have the accelerated approval, have the data from last year. Any update in terms of the conversation with the FDA for submitting PROTECT and then your expectation in terms of the full approval?
Sure. So after we had our PROTECT data late last year, we had a pre-NDA meeting with the FDA in which we aligned with them on support on submitting the sNDA. And really that was a very helpful conversation, very collaborative, where they gave us additional guidance on how to think about some analyses even for labeling. And so our team has been working tirelessly since that point to get to a submission, and we're on track for submitting our sNDA this quarter, assuming we get priority review. That would translate to a potential approval in the third quarter, and we're looking forward to getting to that point.
Okay. Then one question that comes up frequently is around the REMS and sort of the updated safety you have both from PROTECT, also from DUPLEX, and then I guess some real-world safety you've generated. So when does that sort of discussion happen if it does around the REMS, and can the wording there be softened, removed, maybe just any updates to your thoughts there?
Sure. Well, ultimately that will be up to FDA. But the way that we look at it is the next natural juncture to have that conversation is really within this sNDA review process. And so as you highlighted, Vamil, we'll have a year's worth of commercial experience. We'll have the two-year data from PROTECT. We'll have additional data from all of our other studies in the program. And what we see is a very compelling argument that there is no real risk to drug-induced liver injury or anything else that they're really looking out for in that accelerated approval time frame. And so we'll have that conversation with FDA as part of the review. Where it lands, it's hard to say.
I think that you could end up with a modification coming out of that, or the FDA could also choose to take a more process-based approach and go out longer. But we'll provide insight into that as soon as we have some clarity, probably at the end of the sNDA review process.
Okay, great. So maybe if we can just talk a little bit about that competitive landscape. Obviously, a lot of companies now in the IgAN space, so along with FILSPARI, the other approved product is TARPEYO. They have the updated eGFR data last year, then they have the full approval. Just your views on how the two products are sort of playing together, competing in the market right now, and then have a follow-up question on some of the things that are in development.
Sure. So I would look at it more as playing together than competing. And because of that, or maybe why is because you kind of have to look at them as apples and oranges in a number of different ways. One, mechanistically, they have two different effects on the initial eGFR impact, right, when you start therapy. Two, when you look at the studies, we're the only study in the space that's compared against an active control of irbesartan and maximum dose irbesartan, whereas all the other studies are being measured against optimized standard of care, which we know isn't what you can get to.
It's not optimized.
Yeah, it doesn't get up all the way to if you have full irbesartan. And then the third piece that's very different is just when you look back at sort of historically, you have RAS inhibition that has been used as standard of care plus a steroid. So we're working towards the RAS inhibition side of things to become foundational care. And I think TARPEYO is more towards going into that steroid area to sort of replace that. As it comes to eGFR, I think the important thing for us is that we saw a clinically meaningful difference on all of our measurements. But the most telling one is probably the fact that we see an accrual of benefit over time.
And when you look at absolute eGFR in our two-year PROTECT Study, after one year, you see a 1.7 mL/min per year favorable benefit versus irbesartan, and that grows to 3.7 mL/min per year at year two. And so that's an important piece. And when we talk with nephrologists, things that really resonate are the fact that FILSPARI has deep and sustained proteinuria reduction. It has that ability to accrue benefit over time, and it's safe and can be used in combination with other medicines. So I think that those are the things that sort of set us apart. And we know that some patients are actually on FILSPARI and TARPEYO together. So look at it more as working in tandem rather than otherwise.
Okay. And then on the development side, obviously several companies now pursuing sort of B-cell modulation, the APRIL or APRIL and BAFF sort of approaches. How do you see those sort of getting some still in phase 3, getting some earlier data from some of these assets? How do you see those sort of coming into the market and impacting FILSPARI, if at all?
Sure. So I think it goes back to what you highlighted earlier, where we expect to see that market continue to grow overall. And I think that it also goes back to what I was mentioning, where we still believe, and the KOLs share this opinion with us, where you have to have that foundational care. And if you look at all of these studies, they're all being done on top of foundational care, RAS inhibition, and actually some of them now have FILSPARI in them. And so you're going to have that key role that FILSPARI needs to play in the kidney and for long-term use. For any of the other mechanisms that are coming, they're going to play an important role in preventing damage from upstream and in intermittent courses, especially for any kind of progressive flare-ups or just progressive IgA in general.
But I think you're going to see more and more combination use that's going to be individualized for treatments for patients going forward. Ultimately, that's a good thing for everybody in the IgAN space.
Okay. So one last one on FILSPARI before we shift gears, just around ex-US under review, I believe, in the EU, any sort of updates, or what should we expect any update from a decision there?
Sure. So we expect to have an opinion this quarter. So everything is on track there. And just for some background, what we had originally done was we had the CMA that was under review. We had anticipated an opinion late last year, but we submitted the two-year data when those became available, and that had back and forth that came with it. And then there was a procedural clock stop around the holidays. So we are moving forward with that. We expect an opinion this quarter. And then if that comes through, then we would expect the full approval or conditional approval in next quarter. So all is on track.
Okay. So let's shift gears. You mentioned, obviously, the two key assets. You also pegtibatinase, I think maybe less understood, maybe HCU and kind of what the unmet need is. Maybe you can just talk about that condition and what you see as sort of the unmet need, and then we'll talk about pegtibatinase specifically.
Sure. So classical homocystinuria, or HCU, is an autosomal recessive metabolic disorder that is caused by a breakdown in the CBS enzyme. Currently, patients are attempting to use either vitamin B6 or dietary restrictions. And what we're finding is that that's really not benefiting most patients. When you think about the actual outcome and the progression of disease for patients, what's driving it is a buildup of toxic homocysteine. And when you get above 100 micromoles, then you start to become more susceptible for these clinical outcomes. That can include things like ocular lens dislocation or cognitive impairment and thrombotic events to the point where up to 50% of patients by the age of 30 are facing a heart attack or stroke.
And so we're talking about very serious, life-threatening outcomes and really nothing that has any kind of disease-modifying potential for the vast majority of these patients. So significant unmet need, and we're very pleased with the progress we've been able to make with pegtibatinase and getting it to the phase 3 program that started up at the end of the year.
Okay. So maybe we can talk about the data sort of to date for pegtibatinase. We'll talk about then we'll talk on sort of the phase 3 and sort of how that's structured, but what you've seen so far. I know you had multiple doses that you were looking at, but kind of what drove the decision to move to phase 3 and the dosing that you chose?
Sure. So we've been very pleased with the phase 1/2 results that from the beginning, so we've got 6 cohorts' worth of data, and you could really see a transition in effect once you got to the twice-weekly dosing. We started with once-weekly and had ascending dosing through that, and then switched over twice. And you see a very nice dose-dependent response on total homocysteine reduction to the point where in our highest dose cohort, the one that we're moving into phase 3, 2.5 mg/kg, you see an average reduction of 67% from baseline. And the important thing within all of that is we're getting patients below that 100 micromole cutoff of when they're at risk for some of these clinical outcomes.
In the highest dose cohort, we even saw we got patients into normalization, below 50 micromoles and into normalization, which that isn't something that we have seen or as far as we can tell, any other programs have seen. That's important not only because it lowers the risk for some of these awful clinical outcomes that I talked about, but it also helps in the sense that it enables physicians to start thinking about diet liberalization for these patients. When you're thinking about a really restrictive diet that is expensive to do on a monthly basis, hard to find, it creates a very difficult social setting. Patients really look to that as a big quality of life benefit. Getting patients to that point and having the potential to introduce protein is a very meaningful achievement in that.
So that's an important piece of what we'll be looking at in the phase 3 as well.
Okay. And then maybe just sort of sizing this opportunity, kind of the work you've done so far just in terms of the number of patients and the sort of potential penetration, peak sales, either as a market as a whole or for pegtibatinase specifically?
Sure. And this is, I think, an area that probably is not yet fully appreciated because in part, HCU is not diagnosed well. And so right now we believe that there's about 7-10,000 patients globally that are addressable. And right now, the way that many patients are diagnosed is through newborn screening. But newborn screening is biochemical assay on methionine levels, not total homocysteine. Not all patients have methionine levels elevated at birth, and state by state has differing levels that they look at. And so with the advent of better diagnostics, and if you're looking at total homocysteine, not to mention greater awareness of the disease and a disease-modifying therapy, we expect that that market will grow by up to 50% or more over the coming years.
So when you think about that ability to not only have a meaningful opportunity now to help patients, but for that to almost 50% or more grow, that's a very exciting place to be. That's part of the reason why our enthusiasm continues to grow for this program because we do believe it'll be the only disease-modifying therapy available.
Okay. One question we get asked sometimes is just around the competitive dynamics. It doesn't seem like there's much else in development, but anything you'd point to in terms of competition in HCU?
I think you hit it. There's not much that's really been at least that's come into the clinic yet. I know that there are some early programs that are out there and looking at different mechanisms and specifically acting in the gut, but there isn't anything that we've seen so far enter the clinic or anything that we think would have any kind of disease-modifying potential anywhere in the time frame in which we would become in the market.
Okay. Maybe the last few minutes here, just kind of more big picture, if you can kind of give us an update on the cash position for the company and any comments around cash runway?
Sure. We ended the year with $567 million in cash, and what we've guided to there is that that can support operations into 2028. We feel like we're in a very strong financial position.
Okay. And then we touched on some of these throughout the conversation, but maybe just sort of laying out the key events over the next year, two years, what should investors be focused on?
Sure. So I'll start with FILSPARI in there. I think all of this sort of paints a picture of continued growth for FILSPARI from a commercial perspective. We expect to see the KDIGO guidelines come out and have a public review period sometime in the near future here. And with that, we expect to see FILSPARI added to the treatment paradigm and also see where they land on the proteinuria cutoff. And if that goes lower, then I think that, like we talked about, helps all patients and physicians in the IgA space. We also expect to have our sNDA go in this quarter. And so as we talked about, we expect that to translate to a potential approval if we get priority review in the third quarter. And then we anticipate having the European opinion in this quarter and a potential approval in the second quarter.
All of those for FILSPARI are milestones that we're looking forward to in addition to the normal sort of quarterly updates on how we're doing from a commercial perspective. Then for pegtibatinase, it's really about enrollment in phase 3. That one, we don't have as many sort of touchpoints necessarily, but we've been very pleased to see the initial interest in participating in the study, and we're looking forward to building momentum in that.
Okay. I think just in the interest of time, we can wrap it up there. Thanks again for joining us. Enjoyed the conversation.
Thanks for having me.
Thanks.